WO2021148032A1 - 胺基脲敏感性胺氧化酶抑制剂制备及其应用 - Google Patents
胺基脲敏感性胺氧化酶抑制剂制备及其应用 Download PDFInfo
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- WO2021148032A1 WO2021148032A1 PCT/CN2021/073649 CN2021073649W WO2021148032A1 WO 2021148032 A1 WO2021148032 A1 WO 2021148032A1 CN 2021073649 W CN2021073649 W CN 2021073649W WO 2021148032 A1 WO2021148032 A1 WO 2021148032A1
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- KCNVRDMLEGUSND-UHFFFAOYSA-N C(Cc1ncncc1)c1ncccc1 Chemical compound C(Cc1ncncc1)c1ncccc1 KCNVRDMLEGUSND-UHFFFAOYSA-N 0.000 description 1
- QMNJSMRSQLRXNV-KPKJPENVSA-N C/C(/COc1cnc(N(CC2)CCC2(COC)O)nc1)=C\F Chemical compound C/C(/COc1cnc(N(CC2)CCC2(COC)O)nc1)=C\F QMNJSMRSQLRXNV-KPKJPENVSA-N 0.000 description 1
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- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to the technical field of medicine, and more specifically, to a amine urea-sensitive amine oxidase inhibitor.
- Semicarbazide-sensitive amine oxidase is a type of amine oxidase containing dopamine quinone groups. It belongs to the semicarbazide-sensitive amine oxidase family and is also called vascular adhesion protein. -1, VAP-1 (vascular adhesion protein 1). It is mainly encoded by the AOC3 gene in animals. Mammalian smooth muscle cells, adipocytes, and endothelial cells are rich in SSAO content, and are also expressed in various organs such as the vascular system, cartilage, and kidney. In mammals, SSAO is divided into two types, membrane-bound and soluble.
- SSAO can catalyze the metabolism of endogenous or food amines into aldehydes, with the accompanying production of hydrogen peroxide and ammonia.
- the natural metabolic substrates in the body are mainly aliphatic amines and aromatic amines, among which methylamine (MA) and aminoacetone (Aminoacetone) are recognized as the physiological substrates of SSAO, which are catalyzed to formaldehyde and pyruvaldehyde, respectively.
- MA methylamine
- Amoacetone aminoacetone
- SSAO exists in the form of vascular adhesion protein-1, which mediates the adhesion and exudation process of leukocytes and endothelial cells.
- SSAO and its metabolites are related to atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, retinopathy, chronic obstructive pulmonary disease (COPD), autoimmune diseases, multiple sclerosis, etc.
- COPD chronic obstructive pulmonary disease
- SSAO/VAP-1 plays an important role in cancer biology
- SSAO/VAP-1 small molecule inhibitors reduce the number of angiogenesis factor bone marrow cells in melanoma and lymphoma.
- SSAO dysfunction plays a role in the occurrence and development of liver diseases such as fatty liver disease. Fatty liver disease combined with inflammation will develop into non-alcoholic fatty liver after progression, and a certain proportion of patients will further develop into liver fibrosis, cirrhosis and even liver cancer after a period of time.
- the purpose of the present invention is to provide a new type of SSAO inhibitor and its preparation method and application.
- A is selected from the following group: substituted or unsubstituted 5-12 membered heteroaromatic ring;
- R 1 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted -(CH 2 ) m -O-C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkane Base, -C(O)NR 4 R 5 ;
- n is selected from the following group: 1, 2, 3 or 4;
- R 4 and R 5 are each independently selected from the following group: H, -OH, substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted -C6- C10 aryl, substituted or unsubstituted -C1-C4 alkyl (C6-C10 aryl), substituted or unsubstituted -C1-C4 alkyl (C3-C8 cycloalkyl); or R 4 , R 5 and the same The connected nitrogen atoms together form a substituted or unsubstituted 3-8 membered heterocyclic group;
- the above-mentioned groups together form a chemically stable structure; unless otherwise specified, the above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl include any form of monocyclic, fused ring, bridged ring or spiro ring;
- substitution means that the above group is substituted by a group selected from the group consisting of C1-
- the ring A is a substituted or unsubstituted 5-7 membered heteroaromatic ring.
- the ring A is selected from the following group:
- the compound of formula I has a structure shown in the following formula:
- R 1 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted -(CH 2 ) m -O-C1-C8 alkyl, substituted or unsubstituted Substituted C3-C8 cycloalkyl, -C(O)NR 4 R 5 ;
- n 1, 2, 3, 4.
- the compound is selected from the following group:
- the second aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the compound according to the first aspect of the present invention or its stereoisomer or racemate or a pharmaceutically acceptable salt thereof, And pharmaceutically acceptable excipients.
- the pharmaceutical composition is used to prevent and/or treat diseases related to SSAO or regulated by SSAO/VAP-1 protein or activity; preferably, the disease is selected from the following group: inflammation Diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, mental disorders, ischemic diseases, vascular diseases, eye diseases, fibrosis, neuroinflammatory diseases, cancer, pain, fibrosis, or tissue transplant rejection.
- the inflammatory diseases and/or inflammation-related diseases are selected from the following group: arthritis (including juvenile rheumatoid arthritis) and pain caused by arthritis, Crohn’s disease, ulcerative colon Inflammation, inflammatory bowel disease (eg, irritable bowel syndrome), psoriasis, asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye disease, contact dermatitis, hepatitis, liver autoimmune disease , Autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, atherosclerosis, chronic heart failure, congestive heart failure, ischemic disease, stroke and its Complications, myocardial infarction and its complications, inflammatory cell destruction after stroke, synovitis, systemic inflammatory sepsis, etc.
- arthritis including juvenile rheumatoid arthritis
- Crohn’s disease ulcerative
- the inflammation is selected from the following group: arthritis (including juvenile rheumatoid arthritis) and pain caused by arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease ( For example, irritable bowel syndrome), psoriasis, asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye disease, contact dermatitis, hepatitis, liver autoimmune disease, autoimmune hepatitis, original Primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, atherosclerosis, chronic heart failure, congestive heart failure, ischemic disease, stroke and its complications, myocardial infarction and its complications Complications, inflammatory cell destruction after stroke, synovitis, systemic inflammatory sepsis, etc.
- arthritis including juvenile rheumatoid arthritis
- COPD chronic obstructive pulmonary disease
- the pain is selected from the group consisting of muscle pain, bone and joint pain, neuropathic pain, pain caused by tumor, low back pain, inflammatory pain and the like.
- the diabetes and/or diabetes-related diseases are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.
- the eye disease is uveitis or macular degeneration.
- the fibrosis is selected from the group consisting of cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, including non-alcoholic fatty liver diseases such as non-alcoholic fatty liver (NASH) and Alcohol-induced fibrosis leads to liver cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and complications caused by fibrosis.
- cystic fibrosis idiopathic pulmonary fibrosis
- liver fibrosis including non-alcoholic fatty liver diseases such as non-alcoholic fatty liver (NASH) and Alcohol-induced fibrosis leads to liver cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and complications caused by fibrosis.
- NASH non-alcoholic fatty liver
- the neuroinflammatory disease is selected from the group consisting of stroke, Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, chronic multiple sclerosis and the like.
- the cancer is selected from the following group: lung cancer: breast cancer: colorectal cancer: anal cancer: pancreatic cancer: prostate cancer: ovarian cancer: liver and bile duct cancer: esophageal cancer: non-Hodgkin Lymphoma: bladder cancer: uterine cancer: glioma, glioblastoma, medulloblastoma and other brain tumors: kidney cancer: head and neck cancer: stomach cancer: multiple myeloma: testicular cancer: germ cell tumor: neuroendocrine Tumors: cervical cancer: benign tumors of the gastrointestinal tract, breast and other organs: signet ring cell carcinoma: mesenchymal cell tumors including sarcoma, fibrosarcoma, hemangioma, hemangioma, hemangiopericytoma, pseudohemangioma Hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastoma, lipoma, ang
- the diabetes and/or diabetes-related diseases are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.
- the psychiatric disorder is severe depression, bipolar depression or attention deficit hyperactivity disorder.
- the ischemic disease is stroke and/or its complications, myocardial infarction and/or its complications, or damage to tissues by inflammatory cells after stroke.
- the vascular disease is atherosclerosis, chronic heart failure or congestive heart failure.
- the arthritis is osteoarthritis, rheumatoid arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.
- systemic inflammatory syndrome is systemic inflammatory sepsis.
- the inflammatory bowel disease is irritable bowel disease.
- the liver disease is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic Fatty liver disease.
- the respiratory disease is asthma, acute lung injury, acute respiratory distress syndrome, lung inflammation, chronic obstructive pulmonary disease, bronchitis or bronchiectasis.
- the eye disease is uveitis, ulcerative colitis, rhinitis, retinitis, autoimmune ocular inflammation, inflammation caused by angiogenesis and/or lymphogenesis, or macular degeneration.
- the skin disease is contact dermatitis, skin inflammation, psoriasis or eczema.
- the neuroinflammatory disease is Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.
- the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related causative cirrhosis, or primary liver cancer .
- the third aspect of the present invention provides a compound according to the first aspect of the present invention or its stereoisomer or racemate or its pharmaceutically acceptable salt or the drug according to the second aspect of the present invention
- the use of the composition is to prepare a medicine for preventing and/or treating diseases related to SSAO or regulated by SSAO/VAP-1 protein or activity.
- the disease related to SSAO or regulated by SSAO/VAP-1 protein or activity is selected from the group consisting of inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, mental disorders, Ischemic disease, vascular disease, eye disease, fibrosis, neuroinflammatory disease, cancer, fibrosis or tissue transplant rejection.
- the disease is a diabetes-induced disease selected from diabetic nephropathy, glomerulosclerosis, diabetic retinopathy, non-alcoholic fatty liver disease, and choroidal neovascularization.
- the disease is a neuroinflammatory disease.
- the disease is selected from liver fibrosis, liver cirrhosis, renal fibrosis, idiopathic pulmonary fibrosis, and radiation-induced fibrosis.
- the disease is cancer.
- the term "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “substantially consisting of” or “consisting of”.
- alkyl refers to a fully saturated straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms and connected to the rest of the molecule by a single bond; having, for example, 1 to 12 ( Preferably 1 to 8, more preferably 1 to 6) carbon atoms, for example including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary Butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl Wait.
- C1-C6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms.
- alkoxy refers to alkyloxy.
- the alkyl group is as defined above.
- cycloalkyl refers to a cyclic alkyl group consisting only of carbon atoms and hydrogen atoms.
- the cycloalkyl group may optionally have a condensed ring, spiro ring or bridged ring structure.
- C3-C5 cycloalkyl refers to a cyclic alkyl group having 3 to 5 carbon atoms
- C5-C6 cycloalkyl refers to a cyclic alkyl group having 5 to 6 carbon atoms.
- the term "5-12 membered heterocyclic group” or “5-12 membered heterocyclic group” means a carbon atom and 1 to 3 selected from nitrogen and oxygen. It is a stable 5- to 12-membered non-aromatic cyclic group composed of heteroatoms of sulfur.
- the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; in the heterocyclic group Nitrogen, carbon or sulfur atoms can be optionally oxidized; nitrogen atoms can be optionally quaternized; heterocyclic groups can be partially or fully saturated.
- the heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
- heterocyclic groups containing fused rings one or more rings may be aryl or heteroaryl groups as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
- heterocyclic groups include, but are not limited to: tetrahydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7- Group, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl , Pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl
- 5-6 membered heterocyclic ring containing 1 nitrogen atom refers to a 5- or 6-membered heterocyclic ring containing only one nitrogen atom in the ring.
- 4-6 membered heterocyclic ring containing 1 oxygen atom refers to a 4-membered, 5-membered or 6-membered heterocyclic ring containing only one oxygen atom in the ring.
- 5-6 membered aromatic ring refers to a 5- or 6-membered aromatic ring.
- 5-6 membered heteroaromatic ring refers to a 5- or 6-membered aromatic ring having 1-3 heteroatoms selected from nitrogen, sulfur, and oxygen.
- halo refers to fluoro, chloro, bromo or iodo.
- the compound of the present invention is a compound represented by formula I or a stereoisomer or racemate or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention may contain one or more chiral carbon atoms, and therefore can produce enantiomers, diastereomers and other stereoisomeric forms.
- Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
- the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
- racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
- Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
- pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
- Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
- organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
- “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
- Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
- Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
- Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
- Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethyl
- reaction scheme exemplarily illustrates the method for preparing the compound represented by formula I or its stereoisomer or racemate or its pharmaceutically acceptable salt, wherein each group is as described above. It should be understood that in the following reaction schemes, combinations of substituents and/or variables in the general formulae are permissible only when such combinations result in stable compounds. It should also be understood that other general formulas can be prepared by those skilled in the art of organic chemistry by the methods disclosed herein (by applying appropriately substituted starting materials and modifying the synthesis parameters as required by methods known to those skilled in the art) or known methods.
- the functional group of the intermediate compound may need to be protected by an appropriate protecting group.
- Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
- Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl, etc.
- Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
- Suitable protecting groups for mercapto include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
- Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
- Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
- the protecting group can also be a polymer resin.
- the compound of the present invention has excellent SSAO inhibitory activity and can be used in a pharmaceutical composition with the compound of the present invention as an active ingredient for the prevention and/or treatment of diseases related to SSAO or regulated by SSAO/VAP-1 protein, such as arteries Atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, chronic obstructive pulmonary disease (COPD), autoimmune disease, multiple sclerosis, rheumatoid arthritis, pain caused by arthritis, Alzheimer's Murder disease, eye disease, liver disease (such as fatty liver, hepatitis, liver fibrosis, liver cirrhosis, liver cancer).
- diseases related to SSAO or regulated by SSAO/VAP-1 protein such as arteries Atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, chronic obstructive pulmonary disease (COPD), autoimmune disease, multiple sclerosis, rheumatoid arthritis, pain caused by arthritis, Alzheimer's Murder disease, eye disease, liver disease (such
- the term "pharmaceutical composition” refers to a preparation of the compound of the present invention and a medium generally accepted in the art for the delivery of a biologically active compound to a mammal (such as a human).
- the medium includes a pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, which is conducive to the absorption of the active ingredient and thus the biological activity.
- the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing Undesirable biological reactions or interactions with any components included in the composition in an undesirable manner.
- the term "pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, Sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
- prevention includes reducing the likelihood of the occurrence or exacerbation of a disease or condition in a patient.
- treatment and other similar synonyms include the following meanings:
- an "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
- the terms “administration”, “administration”, “administration”, etc. refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
- parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
- topical administration and rectal administration.
- Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceuticals (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
- the compounds and compositions discussed herein are administered orally.
- drug combination refers to drugs obtained by mixing or combining more than one active ingredient Treatment, which includes fixed and non-fixed combinations of active ingredients.
- fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
- non-fixed combination refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
- the relative inhibitory potency of a compound can be determined by the amount required to inhibit the amine oxidase activity of SSAO/VAP-1 in a variety of ways, for example, using recombinant human proteins in in vitro tests or using recombinant non-human enzymes, in expressing normal rodents In cell tests of enzymes, in cells that have been transfected with human proteins, in vivo tests in rodents and other mammalian species, etc.
- the present invention also discloses methods for inhibiting SSAO/VAP-1 in patients suffering from inflammatory diseases and methods for treating inflammatory diseases using the compounds described by formulas I and II.
- Human inflammatory diseases include arthritis and pain caused by arthritis, Crohn's disease, irritable bowel syndrome, psoriasis, asthma, chronic obstructive pulmonary disease, bronchiectasis, joint sclerosis, inflammation caused by diabetes, and post-stroke inflammation Sex cell destruction.
- the present invention relates to a method of inhibiting amine oxidase in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of formula I or formula II to produce a positive therapeutic response.
- the present invention relates to a method of treating diseases associated with amine oxidase, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I or Formula II.
- the present invention relates to a method of treating diseases modulated by SSAO/VAP-1, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I or Formula II.
- inflammation includes various indications, including arthritis (including juvenile rheumatoid arthritis), Crohn's disease, ulcerative colitis, inflammatory bowel disease (e.g., irritable bowel syndrome).
- psoriasis asthma, pneumonia, chronic obstructive pulmonary disease (COPD), bronchiectasis, skin inflammation, eye disease, contact dermatitis, hepatitis, liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, Sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, atherosclerosis, chronic heart failure, congestive heart failure, ischemic disease, stroke and its complications, myocardial infarction and its complications, post-stroke inflammation Cell destruction, synovitis, systemic inflammatory sepsis, etc.
- COPD chronic obstructive pulmonary disease
- the above method is also applicable where the disease is type I diabetes and its complications, type II diabetes and its complications, and the like.
- the above method is also applicable where the disease is macular degeneration and/or other eye diseases.
- fibrosis includes such diseases as cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, including non-alcoholic fatty liver diseases such as non-alcoholic fatty liver (NASH) and alcohol-induced Fibrosis leads to liver cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and other diseases in which excessive fibrosis contributes to the pathology of the disease.
- non-alcoholic fatty liver diseases such as non-alcoholic fatty liver (NASH) and alcohol-induced Fibrosis leads to liver cirrhosis, renal fibrosis, scleroderma, radiation-induced fibrosis, and other diseases in which excessive fibrosis contributes to the pathology of the disease.
- NASH non-alcoholic fatty liver
- neuroinflammatory diseases includes various indications, including stroke, Parkinson's disease, Alzheimer's disease, vascular dementia, multiple sclerosis, chronic multiple sclerosis, and the like.
- the above method is also applicable to pain-related diseases selected from but not limited to the following group: muscle pain, bone and joint pain, neuropathic pain, pain caused by tumor, low back pain, inflammatory pain and the like.
- the cancer is selected from lung cancer: breast cancer: colorectal cancer: anal cancer: membranous adenocarcinoma: prostate cancer: ovarian cancer: liver and bile duct cancer: esophageal cancer: non-Hodgkin’s lymphoma: bladder cancer : Uterine cancer: glioma, glioblastoma, medulloblastoma and other brain tumors: kidney cancer: head and neck cancer: stomach cancer: multiple myeloma: testicular cancer: germ cell tumor: neuroendocrine tumor: cervical cancer : Benign tumors of the gastrointestinal tract, breast and other organs: Signet ring cell carcinoma: Mesenchymal cell tumors including sarcoma, fibrosarcoma, hemangioma, hemangioma, hemangiopericytoma, pseudohemangioma stromal hyperplasia, myofibroblast Cell tumor, fibromatos
- Triethylamine (545.1 g, 5344.0 mmol) was slowly dropped at -78 degrees Celsius. After dripping, the reaction solution was raised to room temperature, the reaction was continued to stir for 1 hour, and the reaction was monitored by TLC. When the reaction solution has no raw materials remaining, add water (1000 mL) to the reaction solution, separate the organic layer, extract the aqueous layer with dichloromethane (200 mL ⁇ 2), combine the organic layers, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product .
- the crude product was dissolved in 3 liters of n-heptane, washed with 3% brine until no triethylamine remained, and then concentrated to obtain the crude product, which was purified by distillation to obtain the title compound A2 (225.0 g, 70.1%) as a colorless oil.
- This detection method is used to evaluate the in vitro inhibitory activity of the compounds of the present invention on SSAO/VAP-1 of different species.
- recombinant human SSAO protein or mouse SSAO protein or rat SSAO protein (provided by Eli Lilly) is used.
- the enzyme activity detection kit MAO-Glo Assays kit (V1402) was purchased from Promega. Formulating an enzyme reaction buffer (50mM HEPES, 120mM NaCl, 5mM KCl, 2mM CaCl 2, 1.4mM MgCl 2, 0.001% Tween-20, pH7.4). The test compound was dissolved in DMSO and diluted by a 3-fold concentration gradient.
- the final concentration of the test compound in a 10 ⁇ l reaction system was 1 ⁇ M to 0.05 nM.
- the content of DMSO in the detection reaction is 1%.
- the test compound DMSO solution was diluted in the enzyme reaction buffer at a volume ratio of 1:25, 2.5 ⁇ l was added to each well of the detection plate, with two replicate wells for each concentration.
- Add 2.5 ⁇ l of enzyme reaction buffer diluted reaction substrate to each well, and the final concentration in a 10 ⁇ l reaction system is 10 ⁇ M.
- 10 ⁇ l of detection reagent was added to each well. Incubate at room temperature for 20 minutes, and read the Synergy Neo 2 plate for detection. The value is converted into inhibition rate by the following formula
- Inhibition rate (Signal positive -Signal test )/(Signal positive -Signal negative ) ⁇ 100%
- Signal positive is a positive control without detection compound
- Signal negative is a negative control without detection compound and SSAO
- Signal test is the detection value of each concentration of different compounds. 4 parameter curve fitting calculation IC50 data. For compounds with an inhibition rate of less than 50% in the compound test range, the IC50 value is reported as higher than the highest test concentration.
- the compounds of the examples of the present invention can effectively inhibit the enzyme activity of different species of SSAO/VAP-1, and the results are shown in Table 1.
- Recombinant human MAO-A and MAO-B proteins were purchased from Sigma (M7316, M7441). Other reagents are the same as biological test example 1.
- the final concentration of the test compound in a 10 ⁇ l reaction system is 100 ⁇ M to 5 nM.
- the final concentrations of MAO-A and MAO-B proteins in a 10 ⁇ l reaction system were 70 nM and 300 nM, respectively.
- Other reaction conditions are the same as in Biological Test Example 1.
- the data analysis and IC50 calculation method are the same as the biological test example 1. For compounds with an inhibition rate of less than 50% within the test range of the compound, the IC50 value is reported as higher than the highest tested concentration. The results are shown in Table 1.
- Recombinant human AOC1/DAO protein was purchased from R&D systems (Cat: 8298-AO). Amplex UltraRed was purchased from Thermo scientific (Cat: A36006). HRP (Cat: P8250) and Putrescine (Cat: V900377) were purchased from Sigma. Formulating an enzyme reaction buffer (50mM HEPES, 120mM NaCl, 5mM KCl, 2mM CaCl 2, 1.4mM MgCl 2, 0.001% Tween-20, pH7.4). The test compound was dissolved in DMSO and diluted by a 3-fold concentration gradient. When detecting AOC1, the final concentration of the test compound in a 10 ⁇ l reaction system was 100 ⁇ M to 5 nM.
- the content of DMSO in the detection reaction is 1%.
- DMSO solution was diluted in the enzyme reaction buffer at a volume ratio of 1:25, 10 ⁇ l was added to each well of the detection plate.
- Prepare 4 ⁇ substrate mixture (containing 400 ⁇ M Putrescine, 4U/ml HRP, 4 ⁇ M Amplex UltraRed) with enzyme reaction buffer, and add 10 ⁇ l to each well.
- Synergy Neo 2 plate reading detection the instrument is set to temperature 30°C, excitation wavelength 530nm, sending wavelength 590nm, detection once every minute, continuous detection for 30 minutes.
- the enzyme activity was calculated based on the increase from the 10th minute to the 30th minute of each well. The value is converted into inhibition rate by the following formula
- Inhibition rate (Signal positive -Signal test )/(Signal positive -Signal negative ) ⁇ 100%
- Signal positive is a positive control without detection compound
- Signal negative is a negative control without detection compound and AOC1
- Signal test is the detection value of each concentration of different compounds. 4 parameter curve fitting calculation IC50 data. For compounds with an inhibition rate of less than 50% in the compound test range, the IC50 value is reported as higher than the highest test concentration.
- Recombinant human AOC2 protein (provided by Eli Lilly). Other reagents are the same as biological test example 1.
- the final concentration of the test compound in a 10 ⁇ l reaction system is 100 ⁇ M to 5 nM.
- the final concentration of AOC2 protein in a 10 ⁇ l reaction system is 10nM.
- Other reaction conditions are the same as in Biological Test Example 1.
- the data analysis and IC50 calculation method are the same as the biological test example 1. For compounds with an inhibition rate of less than 50% within the test range of the compound, the IC50 value is reported as higher than the highest tested concentration. The results are shown in Table 1.
- Table 1 The in vitro inhibitory activity IC50 (nM) of the compounds of the invention against different species of SSAO and other amine oxidases
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Abstract
Description
人SSAO | AOC1 | AOC2 | MAO-A | MAO-B | |
1 | A | E | G | I | L |
2 | A | D | G | J | L |
Claims (10)
- 一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐:其中,A选自下组:取代或未取代的5-12元杂芳环;R 1选自下组:H、取代或未取代的C1-C8烷基、取代或未取代的-(CH 2) m-O-C1-C8烷基、取代或未取代的C3-C8环烷基、-C(O)NR 4R 5、;m选自下组:1、2、3或4;R 2、R 3各自独立地选自下组:H、F、-OH、=O、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-O-C1-C4烷基-C6-C10芳基、取代或未取代的-S-C1-C8烷基;或R 2、R 3单独或共同与其相连的碳原子共同构成3-8元的碳环,或3-8元的杂环(R 2、R 3与同一碳原子相连,或与不同碳原子相连);R 4、R 5各自独立地选自下组:H、-OH、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-C6-C10芳基、取代或未取代的-C1-C4烷基(C6-C10芳基)、取代或未取代的-C1-C4烷基(C3-C8环烷基);或R 4、R 5与其相连的氮原子共同构成取代或未取代的3-8元的杂环基;条件是上述各基团共同形成化学上稳定的结构;除非特别说明,上述的环烷基、杂环基、芳基和杂芳基包括单环、稠环、桥环或螺环的任意形式;除非特别说明,上述的“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:氧代(=O)、羟基、取代或未取代的C5-C6环烷基、取代或未取代的含1个氮原子的5-6元杂环、含1个氧原子的4-6元杂环、C1-C6烷基、C1-C6烷氧基、氟代C1-C6烷氧基、C1-C6烷氧基取代的C1-C6烷氧基、C1-C6烷基羰基、C2-C6酰胺基、C1-C6烷基NH-、(C1-C6烷基)(C1-C6烷基)N-;所述取代表示上述基团被选自下组的基团所取代:C1-C6烷氧基、C1-C6烷基羰基。
- 如权利要求1所述的化合物,或其立体异构体或外消旋体,或其药学上可接受的盐,其中,R 2、R 3各自独立地选自下组:H、F、=O、-CN、取代或未取代的C1-C8-烷基、取代或未取代的C3-C8环烷基、取代或未取代的-O-C1-C8烷基、取代或未取代的-O-C3-C8环烷基;或R 2、R 3单独或共同与其相连的碳原子共同构成3-8元的碳环,或3-8元的杂环(R 2、R 3与同一碳原子相连,或与不同碳原子相连)。
- 如权利要求1所述的化合物,或其立体异构体或外消旋体,或其药学上可接受的盐,其特征在于,所述的环A为取代或未取代的5-7元杂芳环。
- 一种药物组合物,其包含治疗有效量的权利要求1-6任一所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐,以及药学上可接受的赋形剂。
- 如权利要求7所述的药物组合物,其特征在于,所述的药物组合物用于预防和/或治疗与SSAO有关或由SSAO/VAP-1蛋白调节的疾病;优选地,所述的疾病选自下组:炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、缺血性疾病、血管疾病、眼部疾病、纤维化、神经炎性疾病,疼痛相关疾病、癌症或组织移植排斥。
- 权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐或权利要求7所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗与SSAO有关或由SSAO/VAP-1蛋白调节的疾病的药物。
- 如权利要求9所述的用途,其特征在于,所述与SSAO有关或由SSAO/VAP-1蛋白调节的疾病选自下组:炎症疾病和/或炎症相关疾病、糖尿病和/或糖尿病相关疾病、精神病症、疼痛相关疾病、缺血性疾病、血管疾病、眼部疾病、纤维化、神经炎性疾病,癌症、纤维化或组织移植排斥。
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US17/759,341 US20230066737A1 (en) | 2020-01-23 | 2021-01-25 | Preparation of semicarbazide-sensitive amine oxidase inhibitor and use thereof |
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