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WO2020020119A1 - Inhibiteur de rip1 et son utilisation en médecine - Google Patents

Inhibiteur de rip1 et son utilisation en médecine Download PDF

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Publication number
WO2020020119A1
WO2020020119A1 PCT/CN2019/097202 CN2019097202W WO2020020119A1 WO 2020020119 A1 WO2020020119 A1 WO 2020020119A1 CN 2019097202 W CN2019097202 W CN 2019097202W WO 2020020119 A1 WO2020020119 A1 WO 2020020119A1
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Prior art keywords
compound
disease
derivative
rip1
cells
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English (en)
Chinese (zh)
Inventor
夏宏光
杨淑颖
何福生
段树民
陈智
岑旭峰
楼国华
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Zhejiang University ZJU
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Zhejiang University ZJU
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Priority to CN201980043726.4A priority Critical patent/CN112351979B/zh
Publication of WO2020020119A1 publication Critical patent/WO2020020119A1/fr
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    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, the invention provides a RIP1 inhibitor and its use in medicine.
  • Receptor-interacting protein kinase 1 has functions of regulating inflammation and cell death.
  • RIP1 kinase inhibitors are effective in inhibiting cell death, including programmed cell necrosis and RIP1-dependent apoptosis.
  • RIP1 kinase inhibitors can also inhibit a variety of inflammatory reactions. The current mechanism is not clear. It may be through regulating the receptor-interacting protein kinase 3 (RIP3). It may also be through inhibiting cell death to prevent the amplification of inflammatory signals .
  • the inhibitory activity of RIP3 kinase inhibitors on inflammation may be higher than that of RIP1 kinase inhibitors, but RIP3 kinase inhibitors can cause apoptosis and prevent drugs from entering the clinic.
  • RIP3 kinase inhibitors can cause apoptosis and prevent drugs from entering the clinic.
  • RIP3 kinase inhibitor-induced apoptosis may be because it only inhibits RIP3 kinase activity and not RIP1 activity, leading to the pattern of cell death becoming RIP1-dependent apoptosis.
  • RIP1 inhibitors there are few and few RIP1 inhibitors in the clinical stage.
  • Denali's RIP1 inhibitor (Nec1) has entered clinical phase 2 and its indication is neurodegenerative disease; and GSK's RIP1 inhibitor (GSK963) , Has been in clinical Phase 2, the indications are autoimmune diseases, including rheumatoid arthritis, ulcerative enteritis, psoriasis and so on. Therefore, the development of highly effective RIP1 inhibitors is of great significance to the art, especially in terms of inhibiting inflammation and cell death.
  • the object of the present invention is to provide a RIP1 inhibitor with novel structure and its use in medicine.
  • the first aspect of the present invention provides a compound represented by formula (A) or a derivative thereof;
  • R 1 is C 1-6 alkyl
  • R 2 is hydrogen
  • R 3 is hydrogen, C 1-6 alkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; one or more of the 5- to 10-membered heteroaryl (for example, 1, 2 , Three, or four) ring atoms are each independently a heteroatom selected from nitrogen, sulfur, or oxygen;
  • the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • the C 1-6 alkyl group is a C 1-3 alkyl group.
  • the C 6-10 aryl is phenyl or naphthyl.
  • the 5- to 10-membered heteroaryl is 5- to 6-membered heteroaryl or 6- to 10-membered heteroaryl; for example, furan, thiophene, pyrrole, thiazole, imidazole, pyridine, Pyrazine, pyrimidine, pyridazine, indole, quinoline.
  • the compound is selected from the group consisting of:
  • the compound is a compound of formula (I):
  • the derivative is a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers.
  • the second aspect of the present invention provides the use of the compound or derivative thereof according to the first aspect, which is used as a RIP1 inhibitor or for preparing a medicament for preventing or treating RIP1-related diseases.
  • the compound or a derivative thereof can also be used as an inhibitor of programmed cell necrosis or a medicament for preventing or treating a disease related to programmed cell necrosis.
  • the compound or a derivative thereof can also be used to reduce the interaction between RIP1 and RIP3.
  • the compound or its derivative can also be used to degrade TDP25 protein or to prepare a medicament for preventing or treating diseases related to TDP25 protein.
  • the compound or a derivative thereof can also be used to degrade the NLRP3 protein or to prepare a medicament for preventing or treating a disease related to the NLRP3 protein.
  • the compound or a derivative thereof can also be used for preparing a medicament for preventing or treating liver injury.
  • the third aspect of the present invention provides the use of the compound of the first aspect or a derivative thereof for preparing a medicament for preventing or treating a disease related to programmed cell necrosis.
  • the fourth aspect of the present invention provides the use of the compound described in the first aspect or a derivative thereof for preparing a medicament for preventing or treating a TDP25 protein-related disease.
  • a fifth aspect of the present invention provides the use of the compound of the first aspect or a derivative thereof for preparing a medicament for preventing or treating a disease related to the NLRP3 protein.
  • a sixth aspect of the present invention there is provided the use of the compound or the derivative thereof according to the first aspect, which is used for preparing a medicament for preventing or treating liver injury.
  • a seventh aspect of the present invention provides the use of the compound or its derivative according to the first aspect, the compound or its derivative having one or more of the following uses:
  • the cells are selected from the group consisting of leukemia T cells, lymphoma cells, microglia, and colon cancer cells.
  • the cells are selected from the group consisting of Jurkat-FADD-/-cells, U937 cells, BV2 cells, and HT-29 cells.
  • the liver injury is acute liver injury.
  • the liver injury is toxin-induced acute liver injury.
  • the toxin is LPS.
  • the RIP1-related disease is selected from the group consisting of: neurodegenerative disease, ischemic injury, autoimmune disease, atherosclerosis, psoriasis, Gaucher disease, pain, inflammation, retina Shedding, tumor.
  • the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the like.
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • MS multiple sclerosis
  • the autoimmune disease is systemic lupus erythematosus, rheumatoid arthritis, and the like.
  • the pain is neuropathic pain.
  • the inflammation is pancreatitis, ulcerative enteritis, hepatitis, and the like.
  • the tumor is melanoma, glioma, colon cancer, glioma, lymphoma, T-cell leukemia, and the like.
  • the multiple sclerosis is induced by cuprizone.
  • the programmed cell necrosis-related disease is selected from the group consisting of neurodegenerative disease, ischemic injury, autoimmune disease, atherosclerosis, psoriasis, Gaucher disease, pain, Inflammation, retinal detachment, tumor.
  • the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the like.
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • MS multiple sclerosis
  • the autoimmune disease is systemic lupus erythematosus, rheumatoid arthritis, and the like.
  • the pain is neuropathic pain.
  • the inflammation is pancreatitis, ulcerative enteritis, hepatitis, and the like.
  • the tumor is melanoma, glioma, colon cancer, glioma, lymphoma, T-cell leukemia, and the like.
  • the multiple sclerosis is induced by cuprizone.
  • the cells are selected from the group consisting of leukemia T cells, lymphoma cells, microglia, and colon cancer cells.
  • the cells are selected from the group consisting of Jurkat-FADD-/-cells, U937 cells, BV2 cells, and HT-29 cells.
  • the TDP25 protein-related disease is a neurodegenerative disease.
  • the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the NLRP3 protein-related disease is selected from the group consisting of neurodegenerative disease, autoimmune disease, inflammatory bowel disease, atherosclerosis, type 2 diabetes, gout, obesity, and tumor.
  • the neurodegenerative disease is Alzheimer's disease (AD).
  • the autoimmune disease is systemic lupus erythematosus.
  • the tumor is melanoma, glioma, colon cancer, glioma, lymphoma, T-cell leukemia, and the like.
  • An eighth aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a derivative thereof and a pharmaceutically acceptable carrier.
  • a ninth aspect of the present invention provides a method for preventing or treating a disease, the method comprising the step of administering to a subject in need the compound described in the first aspect or a derivative thereof or the pharmaceutical composition described in the eighth aspect;
  • the disease is one or more selected from the group consisting of RIP1-related disease, programmed cell necrosis-related disease, TDP25 protein-related disease, NLRP3 protein-related disease, and liver injury.
  • a tenth aspect of the present invention provides a method for inhibiting RIP1 activity in a cell, comprising the step of: contacting the cell with the compound or a derivative thereof according to the first aspect or the pharmaceutical composition according to the eighth aspect.
  • the cells are selected from the group consisting of leukemia T cells, lymphoma cells, microglia, and colon cancer cells.
  • the cells are selected from the group consisting of Jurkat-FADD-/-cells, U937 cells, BV2 cells, and HT-29 cells.
  • the cell is a cell treated with an inducer; the inducer is one or more selected from the group consisting of: TNF ⁇ , z-VAD-fmk, LPS, SMAC, compound B3, 5z -7.
  • the compound or its derivative is applied at a concentration of 1-50 ⁇ M; preferably, 5-20 ⁇ M.
  • the invention further provides the use of a compound of formula (I) or a derivative thereof,
  • the compound or a derivative thereof is used as a RIP1 inhibitor or for preparing a medicament for preventing or treating a RIP1-related disease.
  • the compound or a derivative thereof can also be used as an inhibitor of programmed cell necrosis or a medicament for preparing or treating a disease related to programmed cell necrosis.
  • the compound or a derivative thereof can also be used to reduce the interaction between RIP1 and RIP3.
  • the compound or its derivative can also be used to degrade TDP25 protein or to prepare a medicament for preventing or treating diseases related to TDP25 protein.
  • the compound or a derivative thereof can also be used to degrade the NLRP3 protein or to prepare a medicament for preventing or treating a disease related to the NLRP3 protein.
  • the compound or a derivative thereof can also be used for preparing a medicament for preventing or treating liver injury.
  • the invention further provides the use of a compound of formula (I) or a derivative thereof,
  • the compound or a derivative thereof is used for preparing a medicament for preventing or treating a disease related to programmed cell necrosis.
  • the invention further provides the use of a compound of formula (I) or a derivative thereof,
  • the compound or a derivative thereof is used for preparing a medicament for preventing or treating a TDP25 protein-related disease.
  • the invention further provides the use of a compound of formula (I) or a derivative thereof,
  • the compound or a derivative thereof is used for preparing a medicament for preventing or treating a disease related to the NLRP3 protein.
  • the invention further provides the use of a compound of formula (I) or a derivative thereof,
  • the compound or a derivative thereof is used for preparing a medicament for preventing or treating liver injury.
  • the invention further provides the use of a compound of formula (I) or a derivative thereof,
  • the compound or its derivative has one or more of the following uses:
  • the cells are selected from the group consisting of leukemia T cells, lymphoma cells, microglia, and colon cancer cells.
  • the cells are selected from the group consisting of Jurkat-FADD-/-cells, U937 cells, BV2 cells, and HT-29 cells.
  • the liver injury is acute liver injury.
  • the liver injury is toxin-induced acute liver injury.
  • the toxin is LPS.
  • the RIP1-related disease is selected from the group consisting of: neurodegenerative disease, ischemic injury, autoimmune disease, atherosclerosis, psoriasis, Gaucher disease, pain, inflammation, retina Shedding, tumor.
  • the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the like.
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • MS multiple sclerosis
  • the autoimmune disease is systemic lupus erythematosus, rheumatoid arthritis, and the like.
  • the pain is neuropathic pain.
  • the inflammation is pancreatitis, ulcerative enteritis, hepatitis, and the like.
  • the tumor is melanoma, glioma, colon cancer, glioma, lymphoma, T-cell leukemia, and the like.
  • the multiple sclerosis is induced by cuprizone.
  • the programmed cell necrosis-related disease is selected from the group consisting of neurodegenerative disease, ischemic injury, autoimmune disease, atherosclerosis, psoriasis, Gaucher disease, pain, Inflammation, retinal detachment, tumor.
  • the neurodegenerative disease is ALS, AD, PD, MS, and the like.
  • the autoimmune disease is systemic lupus erythematosus, rheumatoid arthritis, and the like.
  • the pain is neuropathic pain.
  • the inflammation is pancreatitis, ulcerative enteritis, hepatitis, and the like.
  • the tumor is melanoma, glioma, colon cancer, glioma, lymphoma, T-cell leukemia, and the like.
  • the TDP25 protein-related disease is a neurodegenerative disease.
  • the neurodegenerative disease is ALS.
  • the NLRP3 protein-related disease is selected from the group consisting of neurodegenerative disease, autoimmune disease, inflammatory bowel disease, atherosclerosis, type 2 diabetes, gout, obesity, and tumor.
  • the neurodegenerative disease is Alzheimer's disease (AD).
  • the autoimmune disease is systemic lupus erythematosus.
  • the tumor is melanoma, glioma, colon cancer, glioma, lymphoma, T-cell leukemia, and the like.
  • the invention further provides a pharmaceutical composition, which comprises a compound of formula (I) or a derivative thereof and a pharmaceutically acceptable carrier.
  • the present invention further provides a method for preventing or treating a disease, the method comprising the step of administering to a subject in need thereof a compound of formula (I) or a derivative thereof or comprising a compound of formula (I) or a derivative thereof and a pharmaceutical A pharmaceutical composition of an acceptable carrier;
  • the disease is one or more selected from the group consisting of: RIP1-related disease, programmed cell necrosis-related disease, TDP25 protein-related disease, NLRP3 protein-related disease, liver damage;
  • the invention further provides a method for inhibiting RIP1 activity in a cell, comprising the steps of: combining a cell with a compound of formula (I) or a derivative thereof or comprising a compound of formula (I) or a derivative thereof and a pharmaceutically acceptable Exposure of the pharmaceutical composition of the received carrier;
  • the cells are selected from the group consisting of leukemia T cells, lymphoma cells, microglia, and colon cancer cells.
  • the cells are selected from the group consisting of Jurkat-FADD-/-cells, U937 cells, BV2 cells, and HT-29 cells.
  • the cell is a cell treated with an inducer; the inducer is one or more selected from the group consisting of: TNF ⁇ , z-VAD-fmk, LPS, SMAC, compound B3, 5z -7.
  • the compound of formula (I) or a derivative thereof is applied at a concentration of 1-50 ⁇ M; preferably, 5-20 ⁇ M.
  • Figure 1 shows that ZJU-37 inhibits programmed necrosis of Jurkat-FADD-/-cells.
  • FIG. 2 shows that ZJU-37 inhibits programmed necrosis of U937 cells.
  • Figure 3 shows that ZJU-37 inhibits programmed necrosis of BV2 cells.
  • Figure 4 shows that ZJU-37 can effectively inhibit the content of P-RIP1 in cells, thereby inhibiting its kinase activity.
  • Figure 5 shows that ZJU-37 can effectively inhibit the content of P-RIP1 in cells, thereby inhibiting its kinase activity.
  • Figure 6 shows that ZJU-37 can effectively reduce the interaction of RIP1 and RIP3.
  • Figure 7 shows that ZJU-37 can effectively degrade TDP25 protein.
  • Figure 8 shows that ZJU-37 can effectively attenuate the interaction of RIP1 / RIP3 proteins in mouse brain tissue.
  • Figure 9 shows that ZJU-37 can effectively inhibit acute liver injury in mice.
  • Figure 10 shows that ZJU-37 is effective in degrading the NLRP3 protein induced by inflammation.
  • Figure 11 shows that ZJU-37 can effectively improve the occurrence of RIPK1-dependent coke death.
  • Figure 12 shows that ZJU-37 is effective in relieving multiple sclerosis.
  • Figure 13 shows that ZJU-37 can quickly cross the blood-brain barrier.
  • Figure 14 shows a pair of RIP1 ZJU-37 Inhibition IC 50.
  • Figure 15 shows that compound (II) inhibits programmed necrosis of Jurkat-FADD-/-cells.
  • a novel compound can be used as a highly effective RIP1 inhibitor.
  • Such inhibitor compounds can effectively inhibit RIP1 activity, can also effectively reduce the interaction between RIP1 and RIP3, and effectively inhibit cells.
  • Programmed necrosis, improve cell viability; can also effectively degrade TDP25 protein and NLRP3 protein, etc., thereby preventing and treating various diseases.
  • These compounds can quickly cross the blood-brain barrier and have the function of promoting nerve cell proliferation. The present invention has been completed on this basis.
  • C 1-6 alkyl is a straight or branched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, tert-butyl, n-pentyl, n-hexyl and the like. C 1-3 alkyl is preferred.
  • C 6-10 aryl is an aryl group having 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • 5-membered to 10-membered heteroaryl is a heteroaryl group having 5 to 10 ring atoms, wherein one or more (eg, 1, 2, 3, or 4) ring atoms each It is independently a heteroatom selected from nitrogen, sulfur, or oxygen.
  • 5- to 6-membered heteroaryl or 6- to 10-membered heteroaryl for example, furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline.
  • NLRP3 protein is an important part of NLRP3 inflammatory bodies, and as an important component of innate immunity plays an important role in the body's immune response and disease development.
  • NLRP3 protein-related diseases are diseases mediated by (or at least partially mediated by) NLRP3 protein, including, but not limited to: Alzheimer's disease, systemic lupus erythematosus, inflammatory bowel disease, atherosclerosis Sclerosis, type 2 diabetes, gout, obesity, malignancy.
  • TDP25 protein is a C-terminal fragment of TDP-43 with a molecular weight of 25 kD found in the brain regions of ALS patients. Studies have found that TDP25 protein can promote the formation of TDP-43 inclusion bodies, have toxic effects on motor neurons, cause neuron degeneration, and play an important role in the pathogenesis of disease. TDP25 protein related diseases are diseases mediated by (or at least partially mediated by) TDP25 protein, such as ALS.
  • the compound of the present invention is a compound of formula (A), and its structure is as follows:
  • the compound according to the present invention is a compound of formula (I), and its structure is as follows:
  • the active ingredient according to the present invention is a compound of formula (A) or a derivative thereof.
  • the active ingredient according to the present invention is a compound of formula (I) or a derivative thereof.
  • the derivative of the compound according to the present invention is any derivative of the compound, for example, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, stereoisomer or stereo Mixtures of isomers and the like.
  • pharmaceutically acceptable salt or “physiologically acceptable salt” includes, for example, salts of the compounds of the present invention with inorganic acids and salts with organic acids.
  • the free base can be obtained by basifying a solution of the acid addition salt.
  • the product if the product is a free base, it can be prepared according to a conventional method for preparing an acid addition salt from a basic compound by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Addition salts are obtained, especially pharmaceutically acceptable addition salts.
  • Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • Salts derived from inorganic acids include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like.
  • Salts derived from organic acids include acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, Tartrate, citrate, benzoate, cinnamate, mandelate, mesylate, ethanesulfonate, p-toluenesulfonate, salicylate, etc.
  • hydrate refers to a complex formed by combining a compound of the invention and water.
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.
  • compounds of the invention may exist as tautomers. Tautomers are in equilibrium with each other. For example, the carbonyl moiety may exist in the enol form. Regardless of which tautomer is displayed and regardless of the nature of the equilibrium between the tautomers, those of ordinary skill in the art understand that the compounds include both keto and enol tautomers.
  • stereoisomer refers to a compound composed of the same atoms bonded by the same bond, but with different three-dimensional structures, which are not interchangeable.
  • the “stereoisomers” in the present invention encompass various stereoisomers and mixtures of the compounds of the present invention and include “enantiomers”, which refer to two stereoisomers whose molecules are non-overlapping with each other.
  • enantiomers which refer to two stereoisomers whose molecules are non-overlapping with each other.
  • “Diastereomers” are stereoisomers with at least two asymmetric atoms, but they are not mirror images of one another.
  • prodrug means any compound that releases the active parent drug in vivo in accordance with the compound structure of the invention when said prodrug is administered to a subject.
  • the prodrug can be prepared by modifying any functional group present in a compound of the invention, such that the modification can be cleaved in vivo to release the parent compound.
  • Prodrugs can be prepared by modifying functional groups present in a compound in a manner that cleaves the modification into the parent compound in routine manipulations or in vivo.
  • the prodrug according to the present invention includes a group such as an amino group in the compound of the present invention and any group which can be cleaved in vivo to regenerate a free amino group respectively. Prodrug preparation, selection, and use are discussed in T.
  • the compound of the present invention can be prepared according to a conventional method in the art, and can also be prepared according to the following method (the method shown in the following reaction formula).
  • the preparation method of the present invention includes the steps of reacting Compound 2 and R 3 -LX to obtain a compound of formula (A).
  • R 1 , R 2 , R 3 , and L have the same definitions as above;
  • X is N (CH 3 ) 2 or halogen (for example, fluorine, chlorine, bromine, or iodine).
  • Compound 2 was prepared by following the method of Example 1 of WO2016094848A1 and using corresponding raw materials.
  • the reaction is performed in a solvent.
  • a solvent for example, DMF, DMSO, THF, etc.
  • This solvent is generally not involved in the reaction.
  • some solvents can also participate in the reaction as the reaction reagent R 3 -LX, such as when DMF is used as a solvent.
  • the reaction may be performed under basic conditions or acidic conditions.
  • Basic conditions are performed, for example, in the presence of a base.
  • the base include alkaline agents such as sodium hydride, potassium hydride, sodium hydroxide, and potassium hydroxide.
  • Acidic conditions are performed, for example, in the presence of an acid.
  • the acid is, for example, an acidic reagent such as phosphorus oxychloride.
  • the reaction can be performed under conventional conditions. For example, it is performed at a certain temperature (for example, -10 ° C to 30 ° C; preferably 0 ° C to 30 ° C) for a period of time (for example, 0.1 to 10 hours; preferably 0.1 to 5 hours).
  • a certain temperature for example, -10 ° C to 30 ° C; preferably 0 ° C to 30 ° C
  • a period of time for example, 0.1 to 10 hours; preferably 0.1 to 5 hours.
  • the compounds of the present invention have one or more of the following functions: inhibition of RIP1 kinase activity; reduction of RIP1 and RIP3 interactions; inhibition of programmed cell necrosis; degradation of TDP25 protein; degradation of NLRP3 protein, and so on.
  • the compound of the present invention or a derivative thereof and a pharmaceutical composition containing the compound or a derivative thereof as a main active ingredient can be used to treat, prevent, and alleviate diseases related to RIP1, diseases related to RIP1 and RIP3, diseases related to TDP25 protein, or NLRP3 Protein-related diseases.
  • diseases include, but are not limited to, various neurodegenerative diseases, autoimmune diseases, liver diseases such as liver injury, liver failure, gastroenteritis, and the like.
  • the pharmaceutical composition of the present invention contains an active ingredient in a safe and effective amount range and a pharmacologically acceptable excipient or carrier.
  • the “safe and effective amount” means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of active ingredient / dose, and more preferably, 5-200 mg of active ingredient / dose.
  • the "one dose” is a capsule or tablet.
  • the “pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition and the active ingredient can blend with each other without significantly reducing the efficacy of the active ingredient.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • Wetting agents such as sodium lauryl sulfate
  • the administration method of the active ingredient of the present invention or the medicine containing the active ingredient is not particularly limited, and representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration medicine.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerol; (d) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycerol, such
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as casings and other materials known in the art. They may contain opaque agents and the release of the active ingredient in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be in micro-encapsulated form with one or more of the aforementioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the active ingredients of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the active ingredient of the present invention is applied to a subject in need of treatment, such as a mammal (such as a human), wherein the dose when administered is a pharmaceutically considered effective dose for 60 kg body weight
  • the daily dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health, etc., which are all within the skill of a skilled physician.
  • treatment is a method for obtaining beneficial or desired results, including clinical results.
  • beneficial or required clinical results may include one or more of the following: a) Inhibition of a disease or condition (e.g., reduction of one or more symptoms caused by the disease or condition and / or reduction of the degree of the disease or condition) B) slow or prevent the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilize the disease or condition, prevent or delay the deterioration or progression of the disease or condition, and / or prevent or delay the spread of the disease or condition (E.g., metastasis); and / or c) alleviate the disease, i.e., cause the regression of clinical symptoms (e.g., improve the state of the disease, provide partial or total relief of the disease or condition, enhance the effect of another drug, delay the progression of the disease, Improve quality of life and / or prolong survival).
  • a disease or condition e.g., reduction of one or more symptoms caused by the disease or condition and / or reduction of the
  • prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • the active ingredient may be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • a "subject” refers to an animal, such as a mammal (including a human), that has been or will be the subject of a treatment, observation, or experiment.
  • the methods described herein can be used in human therapy and / or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • the compound of the present invention or its derivative can effectively inhibit RIP1 activity, and can be used as an effective RIP1 inhibitor, so as to prevent or treat RIP1-mediated diseases.
  • the compound of the present invention or its derivative can effectively reduce programmed cell necrosis of cells and improve cell viability.
  • the compounds of the present invention or their derivatives also have the ability to inhibit inflammation.
  • the compound of the present invention or its derivative can also degrade the NLRP3 protein and the TDP25 protein.
  • the compound of the present invention or a derivative thereof can also treat liver damage.
  • the compound of the present invention or a derivative thereof can be used for treating multiple diseases (such as RIP1-mediated diseases, NLRP3 protein-mediated diseases, or TDP25 protein-mediated diseases) with one drug and multiple targets.
  • multiple diseases such as RIP1-mediated diseases, NLRP3 protein-mediated diseases, or TDP25 protein-mediated diseases
  • cell viability (%) after drug treatment cell viability of drug-treated wells / cell viability of control wells * 100%; the higher the cell viability (%), the stronger the cell viability after drug treatment.
  • cell viability was determined by ATP-based viability measurement.
  • the conditions for cell culture and drug treatment are: stable temperature (37 ° C), stable CO 2 level (5%), constant pH (pH: 7.2-7.4), high relative saturation Humidity (95%).
  • experimental materials such as various cells
  • reagents used in the following examples can be obtained from commercial sources unless otherwise specified.
  • Jurkat FADD-/-cells represent FADD-/-knockout Jurkat cells.
  • Jurkat cells are commonly used to study acute T-cell leukemia.
  • Jurkat cells FADD-/-knockout Jurkat cells specifically induce the occurrence of programmed necrosis under the conditions induced by TNF ⁇ .
  • Jurkat FADD -/- cells in this experiment can be obtained by CRISPR technology.
  • U937 cells are human histiocyte lymphoma cells; purchased from Nanjing Kebai Cell Bank.
  • BV2 cells are mouse microglia; purchased from Nanjing Kebai Cell Bank. Since BV2 cells secrete TNF ⁇ by themselves under conditions induced by z-VAD-fmk, no additional TNF ⁇ is required for the induction conditions.
  • 293T cells were derived from 293 cells; purchased from Nanjing Kebai Cell Bank.
  • 293 cells are a human renal epithelial cell line transfected with the adenovirus E1A gene.
  • H4-TDP25 cells are H4 cells stably expressing TDP25; purchased from Nanjing Kebai Cell Bank.
  • HT-29 cells are human colon cancer cells; purchased from Nanjing Kebai Cell Bank.
  • BMDM cells are bone marrow-derived macrophages; purchased from Nanjing Kebai Cell Bank.
  • Compound 2 was prepared by following the method of Example 1 of WO2016094848A1. Under nitrogen protection and ice bath conditions, POCl 3 (0.4 mmol, 60 mg) was added dropwise to DMF (1 mL), and stirring was continued in the ice bath for 0.5 hours. Then, a DMF solution of compound 2 (0.2 mmol, 59 mg) was added to the reaction solution, and the temperature was raised to room temperature to continue the reaction for 5 hours. An appropriate amount of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate.
  • Example 1 ZJU-37 can inhibit Jurkat-FADD -/- programmed cell necrosis
  • TNF ⁇ purchased from Sigma, USA
  • Nec1 structure is (Selleck; purchased as a positive control).
  • Jurkat FADD -/- cells were plated on a 96-well white plate.
  • the medium used was 1640 medium (purchased from Nanmo Biological Company, the same below).
  • the plated density was 20,000 cells per well.
  • NEc1 hole with TNF [alpha] (final concentration effect of 30ng / ml) and different concentrations of the drug action NEc1 (final concentration effect of 10 -7 ⁇ M, 10 -6 ⁇ M, 10 -5 ⁇ M, 10 -4 ⁇ M, 10 -3 ⁇ M , 10-2 ⁇ M, 10 -1 ⁇ M, 1 ⁇ M, 10 ⁇ M) together;
  • ZJU-37 well use TNF ⁇ (final action concentration is 30ng / ml) and drugs with different action concentrations ZJU-37 (final action concentration is 10 -7 ⁇ M, 10 -6 ⁇ M, 10 -5 ⁇ M, 10 -4 ⁇ M, 10 -3 ⁇ M, 10 -2 ⁇ M, 10 -1 ⁇ M, 1 ⁇ M, 10 ⁇ M) together;
  • TNF ⁇ well treated with TNF ⁇ (30ng / ml) and DMSO with the same volume as the drug;
  • Figure 1 shows that Nec1 and ZJU-37 can inhibit the programmed necrosis of Jurkat-FADD-/-cells at a concentration of 10 ⁇ M, respectively.
  • Figure B shows that Nec1 and ZJU-37 can inhibit Jurkat-FADD- / at different concentrations, respectively.
  • -Inhibition of programmed necrosis of cells Panel C represents the EC50 of Nec1 inhibiting the programmed necrosis of Jurkat-FADD-/-cells
  • Panel D represents the EC50 of the programmed necrosis of Jurkat-FADD-/-cells by ZJU-37.
  • ZJU-37 can inhibit programmed necrosis of Jurkat-FADD-/-cells, and its inhibitory effect is similar to that of the positive control drug Nec1.
  • Example 2 ZJU-37 can inhibit programmed necrosis of U937 cells
  • TNF ⁇ (ibid.); Z-VAD-fmk (purchased from BioVision); Nec1 (ibid.).
  • U937 cells were plated on a 96-well white plate, the medium used was 1640 medium, the plate density was 20,000 cells per well, and the cells were plated for 2-4 hours and then subjected to the following processing:
  • Nec1 wells TZ (TNF ⁇ (final action concentration: 30ng / ml) and z-VAD-fmk (final action concentration: 40 ⁇ M)) and Nec1 (final action concentration: 0.0001 ⁇ M, 0.0005 ⁇ M, 0.001 ⁇ M, 0.005 ⁇ M, 0.01 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 5 ⁇ M, 10 ⁇ M) together;
  • ZJU-37 wells TZ (TNF ⁇ (final action concentration: 30ng / ml) and z-VAD-fmk (final action concentration: 40 ⁇ M)) and ZJU-37 (final action concentration: 0.0001 ⁇ M, 0.0005 ⁇ M) , 0.001 ⁇ M, 0.005 ⁇ M, 0.01 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 5 ⁇ M, 10 ⁇ M) together;
  • TZ well treated with TZ (TNF ⁇ (final action concentration: 30ng / ml) and z-VAD-fmk (final action concentration: 40 ⁇ M)) and DMSO with the same volume as the drug
  • FIG. 2 The experimental results are shown in Figure 2.
  • A shows that Nec1 and ZJU-37 can inhibit the programmed necrosis of U937 cells at a concentration of 10 ⁇ M, respectively.
  • Figure B shows that Nec1 and ZJU-37 can inhibit the programmed necrosis of U937 cells at different concentrations;
  • C The figure shows that Nec1 inhibits the EC50 of U937 cells;
  • the figure D shows that ZJU-37 inhibits the EC50 of U937 cells.
  • ZJU-37 can inhibit programmed necrosis of U937 cells, and its inhibitory effect is similar to that of the positive control drug Nec1.
  • Example 3 ZJU-37 can inhibit programmed necrosis of BV2 cells
  • BV2 cells were plated on a 96-well white plate.
  • the medium used was DMEM medium (purchased from Thermo Fisher Scientific, the same below).
  • the plated density was 8000 thousand cells per well. After the cells were plated for 1 day, the following treatment was performed:
  • Nec1 well use z-VAD-fmk (final action concentration of 70 ⁇ M) and Nec1 (final action concentration of 0 ⁇ M, 0.0001 ⁇ M, 0.0005 ⁇ M, 0.001 ⁇ M, 0.005 ⁇ M, 0.01 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M) , 10 ⁇ M) processing together;
  • ZJU-37 well use z-VAD-fmk (final action concentration of 70 ⁇ M) and ZJU-37 (final action concentration of 0 ⁇ M, 0.0001 ⁇ M, 0.0005 ⁇ M, 0.001 ⁇ M, 0.005 ⁇ M, 0.01 ⁇ M, 0.5 ⁇ M , 1 ⁇ M, 5 ⁇ M, 10 ⁇ M) together;
  • Z-VAD well treated with z-VAD-fmk (final effect concentration: 70 ⁇ M) and DMSO with the same volume as the drug;
  • Figure 3 shows that Nec1 and ZJU-37 can inhibit the programmed necrosis of BV2 cells at a concentration of 10 ⁇ M respectively;
  • Figure B shows that Nec1 and ZJU-37 can inhibit the programmed necrosis of BV2 cells at different concentrations;
  • C The figure shows that Nec1 inhibits the EC50 of programmed necrosis of BV2 cells;
  • the figure D shows that ZJU-37 inhibits the EC50 of programmed necrosis of BV2 cells.
  • ZJU-37 can inhibit programmed necrosis of BV2 cells, and its inhibitory effect is similar to that of the positive control drug Nec1.
  • Example 4 ZJU-37 can effectively inhibit RIP1 kinase activity
  • Flag-RIP1 purchased from Vitrus Bio
  • LPS purchased from Sigma
  • Nec1 ibid.
  • 293T cells were plated in six-well plates using DMEM medium with a plate density of 500,000 cells per well; after plated for 24 hours, the following treatments were performed:
  • Flag + LPS wells Transfect 1 ⁇ g Flag-RIP1, and treat with LPS (final action concentration 100ng / ml) and DMSO with the same volume as the drug 24 hours after transfection;
  • Nec1-10 wells transfect 1 ⁇ g Flag-RIP1, and treat with LPS (final action concentration of 100 ng / ml) and Nec1 (final action concentration of 10 ⁇ M) 24 hours after transfection;
  • ZJU37-5 wells transfect 1 ⁇ g Flag-RIP1, and treat with LPS (final action concentration: 100 ng / ml) and ZJU-37 (final action concentration: 5 ⁇ M) 24 hours after transfection;
  • ZJU37-10 wells transfect 1 ⁇ g Flag-RIP1, and treat with LPS (final action concentration of 100 ng / ml) and ZJU-37 (final action concentration of 10 ⁇ M) after transfection for 24 hours
  • ZJU37-20 wells transfect 1 ⁇ g Flag-RIP1, and treat with LPS (final action concentration: 100ng / ml) and ZJU-37 (final action concentration: 20 ⁇ M) 24 hours after transfection;
  • Control well blank control without adding inducer and drug.
  • Jurkat FADD-/-cells were plated on a six-well plate, the medium used was 1640 medium, and the plate density was 1.5 million cells per well; after the plate was plated for 2 hours, the following treatment was performed:
  • TNF ⁇ well treated with TNF ⁇ (final effect concentration 30ng / ml) and DMSO with the same volume as the drug;
  • Nec1 wells treated with TNF ⁇ (final action concentration 30ng / ml) and Nec1 (final action concentration 10 ⁇ M);
  • ZJU-37 wells treated with TNF ⁇ (final action concentration 30ng / ml) and ZJU-37 (final action concentration 10 ⁇ M);
  • Control well blank control without adding inducer and drug.
  • Example 5 ZJU-37 can effectively inhibit RIP1 kinase activity
  • 293T cells were plated in a 10 cm culture dish using DMEM medium with a plate density of 3 million cells per dish; 24 hours after plating, 6 ⁇ g of pCMV-Flag (System 1) or Flag-RIP1 (System 2-System 5) was transfected. ). ATP was added to System 1, System 3 to System 5, and ATP was not added to System 2.
  • DMSO was added to System 2 and System 3; 50 ⁇ M of Nec1 was added to System 4; and 50 ⁇ M of ZJU-37 was added to System 5.
  • the 5 systems were added to the centrifuge tube of each sample, and then placed in a metal bath at 30 ° C for 30 minutes.
  • the beads were collected and immunoblot hybridized with the corresponding antibodies.
  • Example 6 ZJU-37 can reduce the interaction of RIP1 and RIP3 in cells
  • TNF ⁇ ibid.
  • Z-VAD-fmk ibid.
  • SMAC purchased from Selleck
  • Nec1 ibid.
  • EGFP-RIP1 purchasedd from Weizhen Bio
  • Flag-RIP3 purchased from Weiwei
  • HT-29 cells were plated in a 10cm culture dish, the medium used was 1640 medium; the plating density was 2 million cells per dish; after plating for 24h, the following treatment was performed:
  • TZS well treated with TZS (TNF ⁇ (final action concentration: 30ng / ml), z-VAD-fmk (final action concentration: 20 ⁇ M) and SMAC (final action concentration: 100nM)) and DMSO with the same volume as the drug;
  • Nec1 wells treated with TZS (TNF ⁇ (final action concentration: 30 ng / ml), z-VAD-fmk (final action concentration: 20 ⁇ M) and SMAC (final action concentration: 100 nM)) and Nec1 (final action concentration: 10 ⁇ M);
  • ZJU-37 wells TZS (TNF ⁇ (final action concentration 30ng / ml), z-VAD-fmk (final action concentration 20 ⁇ M) and SMAC (final action concentration 100nM)) and ZJU-37 (final action concentration is 10 ⁇ M) processing;
  • Control well blank control without adding inducer and drug.
  • 293T cells were plated in a 10 cm culture dish, the medium used was DMEM medium; the plate density was 4 million cells per dish; after the plate was plated for 24 h, the following treatment was performed:
  • EGFP-RIP1 + Flag-RIP3 wells transfect 2 ⁇ g each of EGFP-RIP1 and Flag-RIP3, and add and treat with the same volume of DMSO as the drug;
  • Nec1 wells transfect 2 ⁇ g each of EGFP-RIP1 and Flag-RIP3, and add Nec1 (final action concentration is 10 ⁇ M) at the same time;
  • ZJU-37 well transfection with 2 ⁇ g each of EGFP-RIP1 and Flag-RIP3, and add ZJU-37 (final action concentration: 10 ⁇ M) at the same time;
  • Control well blank control without adding inducer and drug.
  • Panel B In 293T cells, both Nec1 and ZJU-37 can reduce the interaction between RIP1 and RIP3, and the effect of ZJU-37 is better than Nec1.
  • Example 7 ZJU-37 can effectively degrade the level of TDP25 protein
  • Raw material Compound B3 (structure is ); Nec1 (ibid.).
  • H4-TDP25 cells were plated in a six-well plate, the medium used was DMEM medium, and the plate density was 200,000 cells per well; after the plate was plated for 12 hours, the following treatment was performed:
  • Well B3 cells are treated with compound B3 (final action concentration 10 ⁇ M) for 6 hours, and then the solution is changed, and then treated with the same volume of DMSO as the drug;
  • Nec1-10 wells cells were treated with compound B3 (final effect concentration 10 ⁇ M) for 6 hours, and then the solution was changed, and then treated with Nec1 (final effect concentration 10 ⁇ M);
  • ZJU37-1 well cells were treated with compound B3 (final action concentration: 10 ⁇ M) for 6 hours, and then the solution was changed, and then treated with ZJU-37 (final action concentration: 1 ⁇ M);
  • ZJU37-5 wells cells were treated with compound B3 (final action concentration 10 ⁇ M) for 6 hours, and then the solution was changed, and then treated with ZJU-37 (final action concentration 5 ⁇ M);
  • ZJU37-10 wells cells were treated with compound B3 (final action concentration 10 ⁇ M) for 6 hours, and then the solution was changed, and then treated with ZJU-37 (final action concentration 10 ⁇ M);
  • ZJU37-20 wells cells were treated with compound B3 (final action concentration 10 ⁇ M) for 6 hours, and then the solution was changed, and then treated with ZJU-37 (final action concentration 20 ⁇ M);
  • Control well blank control without adding inducer and drug.
  • TDP25 After H4-TDP25 cells were induced by compound B3, the expression of TDP25 increased. After treatment with ZJU-37, the expression of TDP25 protein in the cells decreased significantly. It can be seen that ZJU-37 can effectively degrade TDP25 protein, and its inhibitory effect is better than that of the positive control drug Nec1 (while TDP25 protein aggregation can induce a series of diseases, such as ALS).
  • Example 8 ZJU-37 can effectively weaken the binding of RIP1 / RIP3 proteins in mouse brain tissue
  • Raw materials C57BL / 6 male mice (purchased from Shanghai Nanmo Biological); LPS (ibid.); Nec1 (ibid.).
  • mice C57BL / 6 male mice were treated as follows:
  • Control group blank control, without adding inducers and drugs
  • LPS group intraperitoneal injection treatment with LPS (final effect concentration 100ng / kg) and DMSO with the same volume as the drug;
  • Nec1 group intraperitoneal injection treatment with LPS (final effect concentration 100ng / kg) and Nec1 (final effect concentration 5mg / kg);
  • ZJU-37 group intraperitoneal injection treatment with LPS (final action concentration: 100ng / kg) and ZJU-37 (final action concentration: 5mg / kg);
  • mice were dissected to take out the brain, 1/2 of the brain tissue was added and RIPA lysate was ground for 1 min, and the supernatant was centrifuged for 20 min at 12000 rpm. This step was repeated three times. Finally, the supernatants were combined and beads and antibodies were added for incubation. Finally, the proteins were collected and used for immunoblot hybridization.
  • Example 9 ZJU-37 can effectively inhibit LPS-induced acute liver injury in mice
  • mice C57BL / 6 male mice were treated as follows:
  • Control group blank control, without adding inducers and drugs
  • LPS group intraperitoneal injection treatment with LPS (final effect concentration 100ng / kg) and DMSO with the same volume as the drug;
  • LPS + ZJU-37 group intraperitoneal injection treatment with LPS (final action concentration 100ng / kg) and ZJU-37 (final action concentration 5mg / kg);
  • liver HE staining section is generally to observe whether the liver cell morphology is complete, whether the nucleus is enlarged, whether the liver lobular morphology is intact, and whether inflammation occurs to detect the damaging effects of drugs and other stimulating factors on the liver.
  • Example 10 ZJU-37 can effectively degrade NLRP3 protein induced by inflammation
  • TNF ⁇ (ibid.); Z-VAD-fmk (ibid.); SMAC (ibid.); Nec1 (ibid.).
  • HT-29 cells were plated in a six-well plate using 1640 medium and a plate density of 700,000 cells per well; after plated for 24 hours, the following treatments were performed:
  • TZS well treated with TZS (TNF ⁇ (final action concentration: 30ng / ml), z-VAD-fmk (final action concentration: 20 ⁇ M) and SMAC (final action concentration: 100nM)) and DMSO with the same volume as the drug;
  • Nec1 wells treated with TZS (TNF ⁇ (final action concentration: 30 ng / ml), z-VAD-fmk (final action concentration: 20 ⁇ M) and SMAC (final action concentration: 100 nM)) and Nec1 (final action concentration: 10 ⁇ M);
  • ZJU-37 wells TZS (TNF ⁇ (final action concentration 30ng / ml), z-VAD-fmk (final action concentration 20 ⁇ M) and SMAC (final action concentration 100nM)) and ZJU-37 (final action concentration is 10 ⁇ M) processing;
  • Jurkat FADD-/-cells were plated on a six-well plate, the medium used was 1640 medium, and the plate density was 1.5 million cells per well; after the plate was plated for 2 hours, the following treatment was performed:
  • TNF ⁇ well treated with TNF ⁇ (final effect concentration 30ng / ml) and DMSO with the same volume as the drug;
  • Nec1 wells treated with TNF ⁇ (final effect concentration 30ng / ml) and Nec1 (final effect concentration 10 ⁇ M);
  • ZJU-37 well treated with TNF ⁇ (final action concentration 30ng / ml) and ZJU-37 (final action concentration 10 ⁇ M);
  • Figure A In the case that NLRP3 is induced to increase by TTZ, ZJU-37 can effectively degrade the NLRP3 protein induced by inflammation, and the effect is better than that of the positive drug Nec1.
  • Panel B In the case that NLRP3 is induced to increase by TNF ⁇ , ZJU-37 can effectively degrade the NLRP3 protein induced by inflammation, and the effect is better than that of the positive drug Nec1.
  • Example 11 ZJU-37 can effectively suppress RIP1-dependent coke death
  • Mouse BMDM cells Mice were purchased from Nanmo Biological; BMDM extraction method: Take the femur of the mouse, cut the two ends of the leg bone, wash the inside of the leg bone with a needle suction PBS to wash out the cells, the obtained cells are 1000rpm, 4 Centrifuge for 5 min. Discard the supernatant, add appropriate amount of ACK to lyse red blood cells, and add PBS to neutralize after 3-5min. Centrifuge at 1000 rpm for 5 min at 4 degrees. That is, the medium can be resuspended to count and plate.
  • LPS ibid.
  • Nec1 ibid.
  • 5z-7 structure is: CAS: 66018-38-0.
  • the mouse BMDM cells were spread on a six-well plate, and the medium used was 1640 medium (purchased from Nanmo Biological Co., Ltd .; 10% FBS--56 ° C fire extinguishing for 30 minutes + M-CSF-20ng / ml + 1% double antibody)
  • the plating density is 2 million cells per well, which is 10 6 / ml.
  • the cells are exchanged after 3 days of plating, and the following treatment is performed after 5 days:
  • Control group blank control, without adding inducers and drugs
  • LPS + 5z-7 wells add coke death inducer (LPS (final action concentration: 10ng / ml) and 5z-7 (final action concentration: 125nM)) and DMSO with the same volume as the drug
  • Nec1 well add coke death inducer (LPS (final action concentration: 10ng / ml) and 5z-7 (final action concentration: 125nM)), and add Nec1 (final action concentration: 10 ⁇ M);
  • ZJU-37 well add coke death inducer (LPS (final action concentration: 10ng / ml) and 5z-7 (final action concentration: 125nM)), and add ZJU-37 (final action concentration: 10 ⁇ M);
  • LPS final action concentration: 10ng / ml
  • 5z-7 final action concentration: 125nM
  • Example 12 ZJU-37 can alleviate multiple sclerosis (MS) in mice
  • Raw materials 6-8 week old male C57 mice (purchased from Nanmo Biological); conventional feed (purchased from Hangzhou Siluojin Biotechnology Co., Ltd.); 0.2% Cuprizone feed (purchased from Hangzhou Siluojin Biotechnology Co., Ltd., In order to add 0.2% Cuprizone to conventional feed); Nec1 (same as above).
  • group one and group two are each divided into the following four groups:
  • the first group blank control group
  • the second group Cup group (Cuprizone feed can induce the occurrence of MS in mice);
  • the third group Cup + Nec1 group (Cuprizone feed + Nec1);
  • the fourth group Cup + ZJU-37 group (Cuprizone feed + ZJU-37)
  • Group 1 Mice in the first group were fed with conventional feed from the first day, and brain tissue was perfused after 6 weeks of feeding. Mice in the second, third or fourth group were fed with 0.2% Cuprizone feed from the first day. After 6 weeks of feeding, brain tissue was perfused.
  • the third group started intraperitoneal injection of drugs (Nec1, effective concentration of 5mg / kg) from the first day; the fourth group started intraperitoneal injection of drugs (ZJU-37, effective concentration of 5mg / kg) from the first day;
  • the solvent was injected intraperitoneally from the first day (solvent formula: 2% DMSO + 30% PEG400 + 68% ddH2O).
  • Group 2 Four groups of mice were fed with 0.2% Cuprizone feed from the first day to the 30th day and then fed with conventional feed from the 31st to the 45th day, and the drugs were injected intraperitoneally from the 31st day. After 6 weeks, brain tissue was perfused. Among them, the third group started to inject drugs at the 31st day (Nec1, with an effective concentration of 5mg / kg), and the fourth group started to inject drugs at the same time from the 31st day (ZJU-37, with an effective concentration of 5mg / kg) ), The second group started to inject the solvent from the 31st day (solvent formulation: 2% DMSO + 30% PEG400 + 68% ddH2O).
  • A Mouse brain slices were fixed with 4% glutaraldehyde and the carcass part was observed under electron microscopy. The electron microscopy results showed that the cup group showed partial demyelination, with loose myelin sheaths and lower g-ratio values ( The g-ratio is the inner diameter of the myelin sheath than the outer diameter of the myelin sheath. A lower value indicates that the myelin sheath is more loose.) However, after intraperitoneal injection of two drugs, the myelin sheath is less demyelinated and the myelin sheath is more compact.
  • Panel B The brain slices of each group were stained with elechroman blue (the normal myelin sheath shows blue, and the demyelination site disappears to be white). From the figure we can see that the cup group showed partial demyelination, but after the two drugs were injected intraperitoneally, the demyelination phenomenon was improved, and the effect of ZJU-37 was better than that of Nec1.
  • Example 13 ZJU-37 can pass through the blood-brain barrier of mice
  • mice Seven BALB / c Nude mice were divided into two groups (drug treatment group and solvent group):
  • mice were intraperitoneally injected with 4 mg / kg ZJU37; the drug treatment components were divided into two groups:
  • 0.5h group 0.5 hours after intraperitoneal injection of ZJU37, samples were taken for analysis.
  • Group 1h Samples were taken for analysis one hour after intraperitoneal injection of ZJU37.
  • mice were injected intraperitoneally with 2% DMSO + 30% peg400 + water; then samples were taken for analysis one hour after intraperitoneal injection of the solvent.
  • mice When sampling for analysis, mice were first injected intraperitoneally with a 4% aqueous solution of chloral hydrate, 200 ⁇ l / 20 g of body weight, and anesthetized. The plasma and brain drug concentrations were then analyzed separately.
  • Carotid blood was taken 300 ⁇ l into heparin tube. After mixing, 100 ⁇ l of the supernatant was centrifuged at 4000 rpm for 5 min, and 700 ⁇ l of acetonitrile was added. analysis.
  • HTRFkinEASESTK kit (Cat.62STKOPEC, Cisbio) and ADP-Glo Kinase kit (Cat.V6930, Promega) were used to detect the half inhibitory concentration (IC50) of ZJU-37 and Nec-1s on RIPK1 kinase.
  • Nec-1s The structure of Nec-1s is Purchased from Selleck;
  • 1 ⁇ enzyme buffer 1 mL of 1 ⁇ kinase buffer contains 200 ⁇ L 5 ⁇ enzyme buffer, 5 ⁇ L 1M MgCl 2 , 1 ⁇ L 1M MnCl 2 , 1 ⁇ L 1M DTT, 793 ⁇ L ddH2O.
  • STK-biotin substrate working solution The specific concentration of STK-biotin substrate is shown in Table 1. STK-biotin substrate was diluted to 5 times the reaction concentration with 1 ⁇ kinase buffer.
  • 5 ⁇ ATP working solution The specific concentration of ATP is shown in Table 1. Dilute ATP to 5 times the reaction concentration with 1x kinase buffer.
  • 5 ⁇ enzyme working solution See Table 1 for enzyme concentration.
  • a 5 ⁇ enzyme working solution of the enzyme was prepared with 1 ⁇ kinase buffer.
  • the RIPK1 enzyme reaction time is 180 minutes (see Table 1 for the corresponding ATP concentration and reaction time).
  • the inhibition rate of each well was calculated from the reaction well and the control well, and the average value of the duplicate wells was used to analyze the inhibitory activity of the test compound using the analysis software PRISM 5.0.
  • Inhibition rate (fluorescence signal from positive control well-fluorescence signal from dosing well) / (fluorescence signal from positive control well-fluorescence signal from negative control well) * 100%
  • Example 15 Compound (II) inhibits Jurkat-FADD -/- programmed cell necrosis
  • Example 1 The method of Example 1 was repeated, except that the compound ZJU37 was replaced by the compound (II), and the treatment time was 12 hours. The results are shown in Figure 15. It can be seen that in the case where TNF ⁇ specifically induces programmed necrosis, compound (II) can effectively inhibit programmed necrosis of Jurkat-FADD-/-cells.

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Abstract

L'invention concerne un inhibiteur de RIP1 et son utilisation en médecine. L'inhibiteur de RIP1 peut inhiber de manière efficace l'activité de la kinase RIP1, peut également réduire l'interaction entre RIP1 et RIP3, inhiber la nécrose cellulaire programmée, et dégrader la protéine NLRP3 et la protéine TDP25, et peut être utilisé pour prévenir ou traiter diverses maladies.
PCT/CN2019/097202 2018-07-25 2019-07-23 Inhibiteur de rip1 et son utilisation en médecine Ceased WO2020020119A1 (fr)

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WO2022027240A1 (fr) * 2020-08-04 2022-02-10 宜昌市第一人民医院（三峡大学人民医院） Application de primidone à titre d'inhibiteur de ripk1
CN112263576A (zh) * 2020-09-30 2021-01-26 浙江大学 化合物zju-37在制备肝脏疾病预防和/或治疗药物中的应用
CN113122538A (zh) * 2021-04-15 2021-07-16 遵义医科大学附属医院 一种靶向敲减Rip3基因表达的shRNA、重组载体及其应用

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WO2003042234A2 (fr) * 2001-11-14 2003-05-22 Novartis Ag Ligands non peptidiques du recepteur de la somatostatine
CN106619619A (zh) * 2017-01-06 2017-05-10 浙江大学 化合物hubin‑1在制备肝脏炎症性疾病预防和/或治疗药物中的用途
CN107530350A (zh) * 2014-12-11 2018-01-02 哈佛理事会 细胞坏死抑制剂及相关方法

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CN108191835A (zh) * 2018-01-09 2018-06-22 中国药科大学 一类新型的含吡咯环和吲哚啉结构rip1激酶抑制剂及其用途

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Publication number Priority date Publication date Assignee Title
WO2003042234A2 (fr) * 2001-11-14 2003-05-22 Novartis Ag Ligands non peptidiques du recepteur de la somatostatine
CN107530350A (zh) * 2014-12-11 2018-01-02 哈佛理事会 细胞坏死抑制剂及相关方法
CN106619619A (zh) * 2017-01-06 2017-05-10 浙江大学 化合物hubin‑1在制备肝脏炎症性疾病预防和/或治疗药物中的用途

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