WO2024046323A1 - Composés cycliques azotés à cinq chaînons benzo, leur procédé de préparation et leurs utilisations médicales - Google Patents

Composés cycliques azotés à cinq chaînons benzo, leur procédé de préparation et leurs utilisations médicales Download PDF

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WO2024046323A1
WO2024046323A1 PCT/CN2023/115543 CN2023115543W WO2024046323A1 WO 2024046323 A1 WO2024046323 A1 WO 2024046323A1 CN 2023115543 W CN2023115543 W CN 2023115543W WO 2024046323 A1 WO2024046323 A1 WO 2024046323A1
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compound
alkyl
pharmaceutically acceptable
prodrug
isomer
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武大雷
黄牛
宋淳
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山东大学
济南成城生物技术有限公司
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
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    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants

Definitions

  • This application relates to the field of medicinal chemistry, specifically to a benzo five-membered nitrogen ring compound, its preparation method and medicinal use.
  • the kidney is an important organ of the human body. In addition to the basic functions of the urinary system, the kidney can also secrete erythropoietin (EPO) to promote red blood cell production and is the main place for EPO production.
  • EPO erythropoietin
  • the main treatment for renal anemia is injection of recombinant human EPO (recombinant human EPO, rhEPO) and its related products, namely erythropoiesis-stimulating agents (ESAs).
  • ESAs can increase the hemoglobin level of patients with renal anemia, reduce the patient's need for blood transfusion, and greatly improve the patient's quality of life.
  • clinical studies have shown that injecting rhEPO into CKD patients can lead to a higher risk of cardiovascular disease and mortality, and rhEPO is expensive and has limitations in its application. Therefore, it is of great significance to find ESAs that are easily absorbed orally, are cheap, and have low side effects.
  • Another strategy for treating renal anemia is to inhibit the ubiquitination pathway of hypoxia-inducible factor (HIF) 2 ⁇ through small molecule inhibitors of prolyl hydroxylase domain proteins (PHD). Promote the expression of EPO.
  • HIF activity in CKD patients may be inhibited by factors such as oxidative stress and uremia, leading to renal anemia.
  • PHD inhibitors such as Roxadustat, Vadadustat and Daprodustat can effectively increase the level of hemoglobin in patients' blood.
  • Roxadustat has been approved for marketing as a Class I new drug.
  • the reported HIF-2 ⁇ agonist (Wu DL et al. Nat. Chem. Biol. 2019, 15, 367) can directly act on the HIF-2 ⁇ target, activate the HIF-2 pathway, and positively regulate the protein expression of the downstream gene EPO. level. But agonists are known to activate the HIF-2 pathway only at higher concentrations of the compounds. Therefore, it is necessary to develop products with better activity and more rationality.
  • the ideal HIF-2 ⁇ agonist has important clinical value and significance.
  • the present application provides benzo five-membered nitrogen ring compounds represented by Formula I, or their pharmaceutically acceptable salts, isomers, isotope-labeled compounds, prodrugs, polymorphs or solvates and preparation methods thereof.
  • the compound can activate the HIF-2 ⁇ signaling pathway and has a significant regulatory effect on the transcription or expression of HIF-2 ⁇ downstream genes (for example, EPO, VGEF, Glut1, NDRG1).
  • the present application provides a benzo five-membered nitrogen ring compound shown in formula I, or a pharmaceutically acceptable salt, isomer, isotope-labeled compound, prodrug thereof, Polymorphs or solvates:
  • R and R' are each independently selected from hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3- 8- cycloalkyl and 3-8-membered heterocyclyl;
  • R 2 is selected from H, D, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy and halogenated C 1-6 alkoxy;
  • R 3 is absent or selected from H, D, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl and 6-10 membered aryl-C 1-4 alkylene;
  • n 1, 2, 3, 4 or 5.
  • X in Formula I is N.
  • X in Formula I is N;
  • R 3 is selected from H, D, C 1-4 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl and 6-10 membered aryl- C 1-2 alkylene, preferably, R 3 is selected from H, D, C 1-2 alkyl, C 3-6 cycloalkyl, phenyl and benzyl, preferably, R 3 is selected from H, D , methyl, cyclopropyl and phenyl, preferably, R 3 is selected from H, D and cyclopropyl, preferably, R 3 is H or D.
  • -X( R3 )- in Formula I is -NH-.
  • halogen e.g., fluorine, chlorine, bromine
  • R2 is selected from H, D, halogen (eg, fluorine, chlorine, bromine), C 1-4 alkyl, and C 1-4 alkoxy.
  • halogen eg, fluorine, chlorine, bromine
  • R2 is selected from H, D, fluorine, chlorine, bromine, C 1-2 alkyl, and C 1-2 alkoxy.
  • R is selected from H, D, fluorine, chlorine, bromine, and methoxy.
  • R is selected from H, D, fluoro, and bromine.
  • R is selected from H and bromine.
  • R2 is H or D.
  • R2 is fluorine
  • the compound has the structure of Formula II:
  • each group is as defined in any of the preceding items.
  • X is selected from N, S, and O;
  • Each R 1 is independently selected from H, D, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy and halo C 1-6 alkoxy;
  • R 2 is selected from H, D, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy and halogenated C 1-6 alkoxy;
  • R 3 is selected from H, D, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl and 6-10 membered aryl-C 1-4 alkylene;
  • n 1, 2, 3, 4 or 5.
  • the compound of Formula II wherein X is N.
  • halogen e.g., fluorine, chlorine, bromine
  • cyano e.g., cyano, haloC 1-4 alkyl, and C 1-4 alkoxy
  • n 1, 2, 3, 4 or 5.
  • each R1 in the compound of Formula II is trifluoromethyl and n is 2.
  • R2 in the compound of Formula II is selected from the group consisting of H, D, halogen (eg, fluorine, chlorine, bromine), C 1-4 alkyl, and C 1-4 alkoxy.
  • R2 in the compound of Formula II is selected from H, D, fluorine, chlorine, bromine, C 1-2 alkyl, and C 1-2 alkoxy.
  • R2 in the compound of Formula II is selected from H, D, fluorine, chlorine, bromine, and methoxy.
  • R2 is H or D in the compound of Formula II.
  • R3 in the compound of Formula II is selected from H, D, C 1-4 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, and 6-10 membered aryl-C 1- 2 alkylene.
  • R3 in the compound of Formula II is selected from H, D, C 1-2 alkyl, C 3-6 cycloalkyl, phenyl, and benzyl.
  • R3 in the compound of Formula II is selected from H, D, methyl, cyclopropyl, and phenyl.
  • R3 is H or D in the compound of Formula II.
  • the compound has the structure of Formula III:
  • R2 is halogen, preferably fluorine.
  • R and R' are each independently selected from hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3- 8- cycloalkyl and 3-8-membered heterocyclyl;
  • n 1, 2 or 3.
  • C 1-2 alkylene preferably, R 3 is selected from H, D, C 1-2 alkyl, C 3-6 cycloalkyl, phenyl and benzyl, preferably, R 3 is selected from H, D , methyl, cyclopropyl and phenyl, preferably, R 3 is selected from H, D and cyclopropyl, preferably, R 3 is H or D.
  • -X( R3 )- in Formula III is -NH-.
  • X is selected from N, S, and O;
  • Each R 1 is independently selected from H, D, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy and halo C 1-6 alkoxy;
  • R 3 is fluorine
  • R 3 is selected from H, D, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl and 6-10 membered aryl-C 1-4 alkylene;
  • n 1, 2, 3, 4 or 5.
  • the compound is selected from:
  • the present application provides the preparation of any of the foregoing benzazepine compounds, or pharmaceutically acceptable salts, isomers, isotopically labeled compounds, prodrugs, polymorphs or Solvate method.
  • the method includes the following steps:
  • Step 1 React compound 1a with hydroxylamine hydrochloride to obtain compound 1b;
  • Step 2 Halogenate compound 1b to obtain compound 1c;
  • Step 3 React compound 1c with compound B to obtain compound 1d;
  • Step 4 cyclize compound 1d to obtain the compound of formula II';
  • R 1 , R 2 , R 3 and n are as defined in any one of the first aspects of this application.
  • the present application provides the preparation of benzisoxazole compounds represented by formula I' (i.e., compounds of formula II when XR 3 is NH), or pharmaceutically acceptable salts, isomers, and isotopes thereof
  • Step 1 React compound 1a with hydroxylamine hydrochloride to obtain compound 1b;
  • Step 2 Halogenate compound 1b to obtain compound 1c;
  • Step 3 React compound 1c with compound B to obtain compound 1d;
  • Step 4 cyclize compound 1d to obtain the compound of formula I';
  • R 1 , R 2 and n are as defined in any one of the first aspects of this application.
  • step 1 includes the following operations:
  • step 2 includes the following operations:
  • step 3 includes the following operations:
  • Step 3 Dissolve compound 1c (4.6mmol) in anhydrous THF (14mL), then add substituted aniline (6.9mmol), reflux the reaction solution and stir. After about 48 hours, TLC monitors that no raw materials remain. After the reaction is completed, Add 60 mL of water to the reaction solution to dilute the reaction solution, and extract with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography to obtain solid compound 1d.
  • step 4 includes the following operations:
  • Step 4 Dissolve compound 1d (0.71mmol) in NMP (7mL), add potassium tert-butoxide, stir at 100°C, and complete the reaction in about 2.5 hours. After the reaction, add 40mL of water to the reaction solution to dilute the reaction solution. , and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure under vacuum, and separated by silica gel column chromatography to obtain solid compounds, namely benzisoxazole compounds.
  • Step 1 React compound 2a with sodium nitrate, copper chloride, and sulfur dioxide to obtain compound 2b;
  • Step 2 Amination of compound 2b to obtain compound 2c;
  • Step 3 Chlorine compound 2c to obtain compound 2d;
  • Step 4 react the compound of formula III' with compound 2d and compound B';
  • R 1 , R 3 and n are as defined in any of the preceding items.
  • step 1 includes the following operations:
  • step 2 includes the following operations:
  • step 3 includes the following operations:
  • step 4 includes the following operations:
  • the present application provides a pharmaceutical composition, which contains the benzo five-membered nitrogen ring compound described in any one of the first aspects or its pharmaceutically acceptable salts, isomers, isotopically labeled Compounds, prodrugs, polymorphs or solvates, and optional carriers and/or excipients.
  • the compound may be a single active ingredient or may be combined with other active ingredients to form a joint preparation.
  • the other active ingredients can be various other drugs that can be used for symptoms of chronic kidney disease, renal anemia, dyslipidemia and high cholesterol.
  • the content of active components in the composition is usually a safe and effective amount, which should be adjustable by those skilled in the art.
  • the pharmaceutical composition further contains a prolyl hydroxylase inhibitor.
  • the prolyl hydroxylase inhibitor is selected from the group consisting of roxadustat, valdustat, dadostat, ennadustat, and molidustat.
  • the present application provides a vaccine adjuvant, which contains the benzo five-membered nitrogen ring compound described in any one of the first aspects or its pharmaceutically acceptable salts, isomers, isotopically labeled Compound, prodrug, polymorph or solvate, or the pharmaceutical composition of any one of the third aspects.
  • the present application provides an immunogenic or immune stimulating composition, which contains any one of the fourth aspects The vaccine adjuvant described in the item.
  • the compounds of the present application, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof have significant enhancing activity on the expression of EPO, VGEF, Glut1, NDRG1 and other mRNA and proteins downstream of hypoxia-inducible factor HIF-2. Therefore, this application further provides the use of said compounds in medicine.
  • the present application provides the benzo five-membered nitrogen ring compound described in any one of the first aspects or its pharmaceutically acceptable salts, isomers, isotope-labeled compounds, prodrugs, and polymorphs. Or solvate, or the use of the pharmaceutical composition according to any one of the third aspects in the preparation of medicines, which are used as hypoxia-inducible factor HIF-2 agonists, immunomodulators, or for treatment and/or Prevent the following diseases and/or symptoms:
  • the diseases related to abnormalities in the HIF-2 signaling pathway are selected from chronic kidney disease, dyslipidemia, high cholesterol, or are related to EPO or low activity of EPO receptors, or are based on EPO Diseases and/or conditions characterized by deficiency or lack or deficiency of red blood cells; preferably, the diseases and/or conditions associated with low activity of EPO or EPO receptors, or characterized by lack of EPO or lack or deficiency of red blood cells are ischemia Diseases, such as renal anemia, chronic renal anemia, hypoerythropoiesis anemia, stroke caused by ischemia, or myocardial ischemia;
  • the present application provides a method for activating the HIF-2 signaling pathway in subject cells, including combining the cells with the benzo five-membered nitrogen ring compound described in any one of the first aspects or its pharmaceutical properties.
  • the present application provides an immunomodulatory method, which includes administering to a subject in need an effective amount of the benzo five-membered nitrogen ring compound or a pharmaceutically acceptable compound thereof according to any one of the first aspects.
  • the present application provides a method for treating and/or preventing diseases and/or symptoms, comprising administering an effective amount of the benzo five-membered nitrogen ring according to any one of the first aspects to a subject in need thereof.
  • compounds or their pharmaceutically acceptable salts, isomers, isotopically labeled compounds, prodrugs, polymorphs or solvates, or the pharmaceutical compositions of any one of the third aspects, the diseases and/or Or the symptoms are as mentioned above.
  • the present application provides the benzo five-membered nitrogen ring compound described in any one of the first aspects or its pharmaceutically acceptable salts, isomers, isotope-labeled compounds, prodrugs, and polymorphs.
  • the compound, or a pharmaceutically acceptable salt, isomer, isotopically labeled compound, prodrug, polymorph or solvate thereof stimulates (e.g., primes or enhances) immunity in a subject answer.
  • the immune response is a non-specific immune response.
  • the immune response is an antigen-specific immune response.
  • the immune response includes activation of B cells, activation of T cells, production of antibodies, and/or release of cytokines.
  • the present application provides use of the immunogenic or immunostimulatory composition of any one of the fifth aspects for use as a vaccine or in the preparation of a vaccine.
  • salt shall be understood to mean any form of an active compound used by the present invention, wherein the compound may be in ionic form or charged or coupled to a counterion (cation or anion) or in in solution.
  • pharmaceutically acceptable salt generally refers to any salt that is physiologically tolerated when used therapeutically in an appropriate manner, particularly when applied or used in humans and/or mammals.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include hydrochloride, trifluoroacetate and other similar salts.
  • isomers refers to compounds with the same molecular formula but different structures, including structural isomers, stereoisomers and electronic tautomers. It should be understood that the scope of the present invention encompasses all proportions (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) the isomers or mixtures thereof.
  • the present invention also includes pharmaceutically acceptable isotopically labeled compounds of said compounds that are identical to the compounds of the present invention except that one or more atoms are substituted with the same atomic number but an atomic mass or mass number different from that which predominates in nature. Atomic substitution for atomic mass or mass number.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ) ; Isotopes of chlorine (e.g. 36 Cl); Isotopes of fluorine (e.g.
  • Isotopes of iodine e.g. 123 I and 125 I
  • Isotopes of nitrogen e.g. 13 N and 15 N
  • Isotopes of oxygen e.g. 15 O , 17 O and 18 O
  • isotopes of phosphorus such as 32 P
  • isotopes of sulfur such as 35 S.
  • the invention further includes within its scope prodrugs of the compounds, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity when administered into or onto the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrug is used in its broadest sense and includes those derivatives which can be converted in vivo to the compounds of the invention. Typically such prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention may be prepared, for example, by using certain moieties known to those skilled in the art as "pro-moiety” (e.g. described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds, which may be single polymorphs or mixtures of more than one polymorph in any proportion.
  • solvate generally refers to any form of an active compound according to the present invention combined by non-covalent bonds with another molecule (usually a polar solvent), which may in particular be Including but not limited to hydrates and alcoholates, such as methoxide.
  • alkyl generally refers to saturated aliphatic hydrocarbon radicals, which may be straight or branched.
  • C 1-6 alkyl generally refers to an alkyl group including 1, 2, 3, 4, 5 or 6 carbon atoms, including C 1-4 alkyl, C 1-2 alkyl wait.
  • Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, and the like.
  • haloalkyl generally refers to an alkyl group as described above that is replaced by one or more (e.g., 1, 2, 3, 4, 5 or 6, etc.) halogens (e.g. , fluorine, chlorine, bromine or iodine) substituted group.
  • halogens e.g. , fluorine, chlorine, bromine or iodine
  • Specific examples of the haloalkyl group include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, and the like.
  • alkoxy refers to a group having the structure alkyl-O-, where alkyl is as defined above.
  • alkyl is as defined above.
  • C 1-6 alkoxy group C 1-4 alkoxy group, C 1-2 alkoxy group, etc.
  • Specific examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, etc.
  • haloalkoxy generally refers to an alkoxy group as described above substituted by one or more (e.g., 1, 2, 3, 4, 5 or 6, etc.) halogens. (e.g., fluorine, chlorine, bromine, or iodine).
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon radical.
  • C 3-6 cycloalkyl Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocyclyl refers to a saturated or unsaturated cyclic structure whose ring atoms consist of carbon atoms and at least one (eg, 1, 2, or 3) heterocyclic ring selected from nitrogen, oxygen, and sulfur. Atomic composition.
  • 3-8 membered heterocyclyl refers to a heterocyclyl with 3 to 8 ring atoms, including 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl
  • One-membered heterocyclic group or 8-membered heterocyclic group includes nitrogen heterocyclic group, oxygen heterocyclic group, etc.
  • Specific examples include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, butyrolactamyl, succinimidyl, 4H-[1,2,4]triazolyl or 1,3-oxynitrogen Heterohexane-2-one, etc.
  • aryl refers to a group formed by the loss of one hydrogen atom of a monocyclic or fused polycyclic aromatic hydrocarbon.
  • aryl group a group formed by the loss of one hydrogen atom of a monocyclic or fused polycyclic aromatic hydrocarbon.
  • 6-10 membered aryl group Specific examples include, but are not limited to, phenyl or naphthyl.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than The atoms specified have normal valences in the current situation and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds. If a substituent is described as “optionally substituted,” the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the substituent lists, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together any choice Replace with selected substituents.
  • nitrogen of a substituent is described as optionally substituted with one or more of the substituents listed, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected as optional. substitution of substituents. If a substituent is described as being "independently selected from” a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • the term "pharmaceutically acceptable carrier or excipient” refers to a carrier and/or excipient that is pharmacologically and/or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and include, but are not limited to: pH adjusters, surfactants, ionic strength enhancers, maintenance osmosis Pressure reagents, reagents that delay absorption, diluents, adjuvants, preservatives, etc.
  • pH adjusting agents include, but are not limited to, phosphate buffer.
  • Surfactants include, but are not limited to, cationic, anionic or nonionic surfactants such as Tween-80.
  • Ionic strength enhancers include, but are not limited to, sodium chloride.
  • Agents that maintain osmotic pressure include, but are not limited to, sugar, NaCl, and the like.
  • Agents that delay absorption include, but are not limited to, monostearate and gelatin.
  • Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), and the like.
  • Adjuvants include, but are not limited to, aluminum adjuvants (such as aluminum hydroxide), Freund's adjuvant (such as complete Freund's adjuvant), and the like.
  • Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc.
  • the pharmaceutically acceptable carrier or excipient is a sterile isotonic aqueous or non-aqueous solution (eg, balanced salt solution or physiological saline), dispersion, suspension, or emulsion.
  • the term “vaccine” is a composition administered to produce or artificially increase immunity to a specific antigen.
  • the terms “immunogenic composition” and “immunostimulatory composition” are compositions capable of generating an immune response in the body when administered to an individual. Therefore, the terms “immunogenic composition,” “immunostimulatory composition,” and “vaccine” are understood to be synonymous terms.
  • the subject is preferably a mammal, more preferably a human, but may also be other mammals.
  • the composition may be administered to a cattle (including cow), sheep, goat or horse. Induced immunity in pets, such as dogs or cats.
  • the terms "vaccine adjuvant” and “adjuvant” refer to substances capable of modifying or enhancing the immune response to an antigen.
  • the immune response to the antigen may be higher or different in the presence of the adjuvant than in the absence of the adjuvant (including when the response is modified, e.g., a subset of T cells are activated in the presence of the adjuvant versus in the absence of the adjuvant activated subsets are different).
  • prevention includes inhibiting and delaying the onset of disease and includes not only the development Prevention before the disease also includes preventing the recurrence of the disease after treatment.
  • treating means reversing, alleviating or eliminating the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition.
  • the term "effective amount” refers to an amount sufficient to achieve the desired preventive or therapeutic effect, for example, an amount that reduces one or more symptoms associated with the disease to be treated.
  • Dosage regimens can be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as the exigencies of the therapeutic situation indicate. It is noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular subject, specific dosage regimens will be adjusted over time based on the needs of the subject and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount administered will depend on the subject treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50 mg per kg of body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day.
  • dosage levels no higher than the lower end of the foregoing ranges may be sufficient, while in other cases, larger dosages may still be employed without causing any deleterious side effects, provided that the larger dosage is first
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the term "subject” includes humans or non-human animals.
  • exemplary human subjects include human subjects (referred to as patients) suffering from a disease, such as a disease described herein, or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.).
  • the compounds provided by the present invention can be adapted to any form of administration, which can be oral or parenteral administration, for example, via pulmonary, nasal, rectal and/or intravenous injection, and more specifically, intradermal administration. , subcutaneous, intramuscular, intraarticular, intraperitoneal, pulmonary, oral, sublingual, nasal, transdermal, vaginal, oral or parenteral administration.
  • the benzo five-membered nitrogen ring compound Compared with the control compound, the benzo five-membered nitrogen ring compound has better HIF-2 agonistic activity, and has significant enhancing activity on the expression of EPO, VGEF, Glut1, NDRG1 and other mRNA and proteins downstream of HIF-2, It has good industrialization prospects.
  • Figure 1 shows the effect of the compounds of the present invention on the transcription of the HIF-2 ⁇ downstream gene NDRG1 in the 786-O cell line.
  • Figure 2 shows the effect of the compounds of the present invention on the transcription of the HIF-2 ⁇ downstream gene VEGFA in the 786-O cell line.
  • FIG. 3 shows the effect of the compounds of the present invention on the expression of HIF-2 ⁇ downstream gene EPO.
  • Example 16 to Example 46 are the same as the general synthesis method of formula III'.
  • step 4 Use 3-chloro-4-fluorobenzo[d]isothiazole-1,1-dioxide and 2-(pyrrolidin-1-yl)-3-methylaniline as raw materials.
  • step 4 obtain N-(2-(pyrrolidin-1-yl)-3-methylphenyl)-4-fluorobenzo[d]isothiazole-1,1-dioxide-3 -amine.
  • step 4 Synthetic method to obtain N-(2-(pyrrolidin-1-yl)-3,5-dimethylphenyl)-4-fluorobenzo[d]isothiazole-1,1-dioxide-3- amine.
  • N- was obtained through the synthesis method in step 4. (3-(pyrrolidin-1-yl)pyridin-4-yl)-4-fluorobenzo[d]isothiazole-1,1-dioxide-3-amine.
  • N-(3-methoxybenzene is obtained through the synthesis method in step 4 methyl)-4-fluorobenzo[d]isothiazole-1,1-dioxide-3-amine.
  • N-(2-morpholinylbenzene is obtained through the synthesis method in step 4 methyl)-4-fluorobenzo[d]isothiazole-1,1-dioxide-3-amine.
  • step 4 Using 3-chloro-4-fluorobenzo[d]isothiazole-1,1-dioxide and 2-(4H-[1,2,4]-triazol-4-yl)aniline as raw materials, The synthesis method of step 4 obtains N-(2-(4H-[1,2,4]triazol-4-yl)phenyl)-4-fluorobenzo[d]isothiazole-1,1-di Oxide-3-amine.
  • N is obtained through the synthesis method in step 4 -(2-(pyrrolidine-2,5-dione)phenyl)-4-fluorobenzo[d]isothiazole-1,1-dioxide-3-amine.
  • Human renal clear cell carcinoma cell 786-O (Dingguochangsheng, CS0254), RPMI1640 medium (Keygen Biotech), trypsin-EDTA (0.25%, Gibco), fetal bovine serum (Cellmax, SA211.02); Trizol reagent ( Takara), reverse transcription kit (Takara), SYBR GREEN fluorescence quantification kit (Yisheng Biotech).
  • 786-O cells were cultured in a dish using RPMI1640 medium containing 10% fetal calf serum. When the growth reached 90%, they were seeded into a 12-well plate. When the cell density reaches about 60%, administer 10 ⁇ M PT2385 or 10 ⁇ M compound (final DMSO concentration 1 ⁇ ), and collect samples after culture.
  • Sample homogenization For adherent cells cultured in 12-well plates, remove the culture medium and wash the cells with PBS. Remove PBS, add Trizol reagent to each well, mix well by pipetting, then transfer to EP tube, let stand at room temperature for a while, until the nucleoprotein complex is completely dissociated;
  • Phase separation Add chloroform to the cell lysis solution, vortex to mix and let stand at room temperature. Centrifuge at 12,000 rpm for 10 minutes at 4°C. At this time, the sample is divided into three phases, the upper aqueous phase, the middle phase and the lower phenol-chloroform phase. At this time, all RNA is located in the upper aqueous phase, and the upper aqueous phase is transferred to a new EP tube;
  • Isolate RNA Add isopropyl alcohol to the EP tube, vortex to mix, and centrifuge at 4°C and 12,000 rpm for 10 minutes to collect the RNA precipitate. Discard the supernatant, wash the pellet twice with 75% ethanol, centrifuge at 12,000 rpm for 8 minutes at 4°C, discard the supernatant, open the EP tube cover and leave it at room temperature until the ethanol evaporates. The dried RNA is colorless and transparent. Add sterile water to dissolve the RNA and measure the concentration.
  • the ⁇ C T method was used to compare the target gene expression differences between groups with different treatments. Data processing is expressed as mean ⁇ SEM.
  • qPCR was used to detect the effects of compounds on the transcription of HIF-2 ⁇ downstream genes VEGFA and NDRG1 in the 786-O cell line.
  • the compounds of the present invention can significantly enhance the transcription of VEGFA and NDRG1, among which compounds 1, 2, 4, 5, 7, 8, 10, 12, 16, 17, 18, 19, 20, and 22 , 23, 27, 34, 35, 36, 37, and 38 have obvious effects.
  • Compounds 1, 5, 8, 10, 16, 17, 18, 19, 34, 35, 36, 37, and 38 have significantly better agonistic effects than the control compound. .
  • Hep3B cells Human hepatocellular carcinoma Hep3B cells (Dingguochangsheng, CS0172), DMEM medium (Keygen Biotechnology), trypsin-EDTA (0.25%, Gibco), fetal bovine serum (Cellmax, SA211.02); enzyme-linked immunosorbent assay kit (Hengyuan Biology).
  • Enzyme-linked immunosorbent assay (ELISA);
  • Hep3B cells Human hepatocellular carcinoma Hep3B cells are cultured in a dish using DMEM medium containing 10% fetal bovine serum. When the growth reaches 90%, they are seeded into a 12-well plate;
  • ELISA was used to detect the expression of EPO protein.
  • the compounds of the present invention can significantly increase the protein expression of EPO.
  • compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 12 and 14 have particularly obvious agonistic activities.
  • Compounds 1, 2 , 5, 8 and 10 had better agonistic effects than the control compound.

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Abstract

L'invention concerne des composés cycliques azotés à cinq chaînons, leur procédé de préparation et leurs utilisations médicales. L'invention concerne plus précisément : des composés cycliques azotés à cinq chaînons, ou des sels pharmaceutiquement acceptables, des isomères, des composés marqués par un isotope, des promédicaments, des polymorphes ou des solvates de ceux-ci, un procédé de préparation associé, et leurs utilisations dans la prévention et/ou le traitement de maladies associées à une anomalie de la voie de signalisation du facteur HIF-2.
PCT/CN2023/115543 2022-08-29 2023-08-29 Composés cycliques azotés à cinq chaînons benzo, leur procédé de préparation et leurs utilisations médicales WO2024046323A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008011110A2 (fr) * 2006-07-20 2008-01-24 Amgen Inc. Composés hétérocycliques à bi-substitution amino et procédés d'utilisation
CN110121343A (zh) * 2016-09-12 2019-08-13 数值有限公司 用作gpr120调节剂的双环化合物
CN113200938A (zh) * 2021-05-20 2021-08-03 中国药科大学 苯并异噻唑类缺氧诱导因子2激动剂类化合物或其药学上可接受的盐、制备方法及应用
CN113264900A (zh) * 2021-06-07 2021-08-17 南京中医药大学 一种苯并异噻唑和苯并噻吩的制备方法及其医药用途
CN117143039A (zh) * 2022-08-29 2023-12-01 山东大学 一种苯并五元氮环类化合物、其制备方法及医药用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008011110A2 (fr) * 2006-07-20 2008-01-24 Amgen Inc. Composés hétérocycliques à bi-substitution amino et procédés d'utilisation
CN110121343A (zh) * 2016-09-12 2019-08-13 数值有限公司 用作gpr120调节剂的双环化合物
CN113200938A (zh) * 2021-05-20 2021-08-03 中国药科大学 苯并异噻唑类缺氧诱导因子2激动剂类化合物或其药学上可接受的盐、制备方法及应用
CN113264900A (zh) * 2021-06-07 2021-08-17 南京中医药大学 一种苯并异噻唑和苯并噻吩的制备方法及其医药用途
CN117143039A (zh) * 2022-08-29 2023-12-01 山东大学 一种苯并五元氮环类化合物、其制备方法及医药用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BÖSHAGEN HORST: "Über 3‐Chlor‐1.2‐benzisoxazole", CHEMISCHE BERICHTE, VCH, DE, vol. 100, no. 10, 1 October 1967 (1967-10-01), DE , pages 3326 - 3330, XP093143930, ISSN: 0009-2940, DOI: 10.1002/cber.19671001022 *
DATABASE REGISTRY 2 June 2016 (2016-06-02), ANONYMOUS: "Benzenamine, 2-(1,2-benzisoxazol-3-yloxy)​-4-chloro- (CA INDEX NAME)", XP093143920, retrieved from STNext Database accession no. 1923106-07-3 *
DATABASE Registry 28 November 2001 (2001-11-28), ANONYMUS: "1,2-Benzisoxazole, 3-[(4-chloro-2,3,5,6-tetrafluorophenyl)thio]- (CA INDEX NAME)", XP093143914, retrieved from STNext Database accession no. 372090-75-0 *
DATABASE Registry 4 December 2011 (2011-12-04), ANONYMOUS: "1,2-Benzisoxazol-3-amine, N-[3-(trifluoromethyl)phenyl]- (CA INDEX NAME)", XP093143911, retrieved from STNext Database accession no. 1348074-18-9 *

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