WO2022160138A1 - Composé de benzoxazine-4-one, son procédé de préparation et son utilisation médicale - Google Patents

Composé de benzoxazine-4-one, son procédé de préparation et son utilisation médicale Download PDF

Info

Publication number
WO2022160138A1
WO2022160138A1 PCT/CN2021/074002 CN2021074002W WO2022160138A1 WO 2022160138 A1 WO2022160138 A1 WO 2022160138A1 CN 2021074002 W CN2021074002 W CN 2021074002W WO 2022160138 A1 WO2022160138 A1 WO 2022160138A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbons
unsubstituted
acid
substituted
branched
Prior art date
Application number
PCT/CN2021/074002
Other languages
English (en)
Chinese (zh)
Inventor
张丽颖
Original Assignee
承德医学院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 承德医学院 filed Critical 承德医学院
Priority to PCT/CN2021/074002 priority Critical patent/WO2022160138A1/fr
Publication of WO2022160138A1 publication Critical patent/WO2022160138A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A61K31/536—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 ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/535—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
    • A61K31/537—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 spiro-condensed or forming part of bridged ring systems
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a benzoxazin-4-one compound as a glycogen phosphorylase inhibitor, a preparation method and medical use thereof.
  • the liver is an important organ that regulates blood sugar in the fasted state. It is estimated that after an overnight fast, 74% of fasting blood glucose is derived from hepatic glycogenolysis and the remainder from hepatic gluconeogenesis. In patients with type 2 diabetes, the rate of hepatic glucose production is significantly increased, and hepatic glucose production is on the high side. Therefore, inhibition of hepatic glucose production has become one of the important targets for the development of new antidiabetic drugs.
  • metformin the clinically preferred hypoglycemic drug
  • inhibition of hepatic glycogen degradation, thereby reducing their hepatic glucose output helps to reduce their fasting blood glucose.
  • Glycogen phosphorylase is a key enzyme that catalyzes glycogenolysis, which catalyzes the phosphorylation of glycogen, and the generated glucose-1-phosphate is converted into glucose- 6-phosphate, which is catalyzed by glucose-6-phosphatase to generate glucose, and blood sugar rises.
  • glycogen phosphorylase thereby inhibiting hepatic glycogen degradation.
  • CN103497181A discloses a benzazepine Ketones have good inhibitory activity on glycogen phosphorylase, but the problem is that their half-life in the body is too short, they will be metabolized by the body soon after taking the drug, and the bioavailability is low, which causes serious problems. affect the efficacy.
  • the present invention provides a benzoxazinone compound represented by formula (I) with glycogen phosphorylase inhibitory activity, a preparation method and medical use thereof. Since the compound of formula (I) of the present invention can inhibit glycogen phosphorylase, it can be used for the prevention and/or treatment of diseases related to abnormal glycogen metabolism. In particular, the compounds of the present invention have a long half-life in vivo, high bioavailability, and improved curative effect.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as follows:
  • X 1 , X 2 , X 3 and X 4 are all C or one of X 1 , X 2 , X 3 and X 4 is N and the other must be C;
  • R 1 and R 1 ' are each independently H, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, vinyl , ethynyl;
  • R 2 and R 2 ' are each independently H, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, vinyl , ethynyl;
  • R 3 is H, unsubstituted or X-substituted linear or branched alkyl of 1-20 carbons, unsubstituted or X-substituted linear or branched alkenyl of 2-20 carbons, 2-20 unsubstituted or X-substituted straight or branched chain alkynyl, unsubstituted or X-substituted aryl, unsubstituted or X-substituted heteroaryl;
  • R 4 and R 5 are each independently H, unsubstituted or X-substituted linear or branched alkyl of 1-20 carbons, unsubstituted or X-substituted linear or branched alkene of 2-20 carbons base, 2-20 carbon unsubstituted or X-substituted linear or branched alkynyl, R 4 and R 5 can optionally form a ring;
  • Y is CHR 6 , NH, O, S;
  • R 6 is H, unsubstituted or X-substituted linear or branched alkyl of 1-20 carbons, unsubstituted or X-substituted linear or branched alkene of 2-20 carbons, 2-20 unsubstituted or X-substituted straight or branched chain alkynyl, phenyl, benzyl, naphthyl, nitrile groups of carbon atoms;
  • X is F, Cl , Br, I, CN, NO2, NH2 , CF3 , SH, OH, OCH3 , OC2H5 , COOH, straight or branched chain alkyl of 1-10 carbons, 2 - Linear or branched alkenyl of 10 carbons, linear or branched alkynyl of 2-10 carbons, aryl, heteroaryl.
  • X 1 , X 2 , X 3 and X 4 are all C or one of X 2 and X 3 is N and the other must be C;
  • R 1 and R 1 ' are each independently H, halogen, cyano, C 1-4 alkoxy;
  • R 2 and R 2 ' are each independently H;
  • R 3 is H, unsubstituted or X-substituted linear or branched alkyl of 1-20 carbons, unsubstituted or X-substituted C 6-14 aryl, unsubstituted or X-substituted C 5-10 hetero Aryl;
  • R 4 and R 5 are each independently H, unsubstituted or X-substituted linear or branched alkyl of 1-20 carbons, and R 4 and R 5 may optionally form a ring;
  • Y is CH 2 , NH, O;
  • X is F, Cl , Br, I, CN, NO2, NH2 , CF3 , SH, OH, OCH3 , OC2H5 , COOH, straight or branched chain alkyl of 1-10 carbons, 2 - Linear or branched alkenyl of 10 carbons, linear or branched alkynyl of 2 to 10 carbons, C6-14 aryl, C5-10 heteroaryl.
  • X 1 , X 2 , X 3 and X 4 are all C or one of X 2 and X 3 is N and the other must be C;
  • R 1 and R 1 ' are each independently H, F, Cl, Br, cyano, methoxy
  • R 2 and R 2 ' are each independently H;
  • R is H, unsubstituted or X-substituted straight or branched alkyl of 1-6 carbons;
  • R 4 and R 5 are each independently H, unsubstituted or X-substituted straight or branched chain alkyl of 1-6 carbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.
  • R 4 and R 5 can optionally form a ring, such as a five-membered ring (such as cyclopentyl), a six-membered ring (eg cyclohexyl), seven-membered ring (eg cycloheptyl), etc.;
  • Y is O
  • X is F, Cl , Br, I, CN, NO2, NH2 , CF3 , SH, OH, OCH3 , OC2H5 , COOH , straight or branched chain alkyl of 1-6 carbons.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • C 1-4 alkyl refers to straight or branched chain alkyl groups having 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary Butyl.
  • C 1-4 alkoxy refers to a straight or branched chain alkoxy having 1-4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy base, isobutoxy, tert-butoxy.
  • Aryl is eg phenyl, naphthyl, phenanthryl, anthracenyl and the like.
  • Heteroaryl has 1, 2 or 3 heteroatoms selected from S, O, N, eg, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyridyl azolyl, imidazolyl, thiazolyl, azolyl, iso azolyl, indolyl, benzo[b]thienyl, benzo[b]furanyl, quinolinyl, isoquinolinyl, quinazolinyl and the like.
  • the compounds of formula (I) and formula (II) are selected from the following compounds:
  • salts such as salts formed by compounds of formula (I) or formula (II) with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, etc.
  • Organic acids such as formic acid, acetic acid, propionic acid, valeric acid, diethylacetic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid , gluconic acid, ascorbic acid, niacin, isonicotinic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, etc.
  • the present invention provides the preparation method of the above-mentioned compound, comprising the following steps:
  • R 3 ' is an organic group, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl, etc.; preferably, the organic solvent is selected from Dioxane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform, toluene, n-hexane, cyclohexane, tert-butyl methyl ether, pyridine and mixtures of two or more thereof, more preferably dichloromethane oxane, tetrahydrofuran or mixtures thereof;
  • the organic solvent is selected from benzene, toluene, xylene, dioxane, DMF, DMSO, acetonitrile and mixtures of two or more thereof, more preferably dioxane, toluene, xylene and two or more thereof a mixture of one or more;
  • the metal catalyst is selected from palladium carbon, Raney nickel, iron powder, zinc powder, and stannous chloride;
  • the hydrogen source is selected from hydrogen, hydrazine hydrate, amine formate, formic acid, ammonium chloride, cyclohexene;
  • the organic solvent is selected from methanol, ethanol, n-butanol, tert-butanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform, toluene, n-hexane, cyclohexane , tert-butyl methyl ether and a mixture of two or more thereof, more preferably methanol, ethanol or a mixture thereof;
  • the organic solvent is an inert solvent, more preferably an aprotic solvent , and further preferably the organic solvent is selected from acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, toluene, n-hexane, cyclohexane, tetrahydrofuran, tert-butyl methyl ether and Wherein the mixture of two or more, further preferably the organic solvent is selected from dichloromethane, 1,2-dichloroethane or, N,N-dimethylformamide and the mixture of two or more thereof; preferably , the condensation reagent is
  • R 3 ' in the organic alcohol R 3 'OH is an organic group, further preferably, the organic alcohol R 3 'OH is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, benzyl alcohol and mixtures of two or more thereof, further preferably methanol, ethanol, isopropanol, tert-butanol and mixtures of two or more thereof; Fluoroacetic acid, methanesulfonic acid and mixtures of two or more thereof; preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid and mixtures thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the dosage forms of the pharmaceutical composition of the present invention include, but are not limited to, tablets, capsules, pills, suppositories, soft capsules, oral liquids, suspensions, injections and other commonly used pharmaceutical forms.
  • the present invention provides a method for preventing and/or treating a disorder associated with abnormal glycogen metabolism, comprising administering to an individual in need thereof an effective amount of formula (I) or formula (II) ) compound or a pharmaceutically acceptable salt thereof.
  • the dosage of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof will vary from formulation to formulation.
  • the total amount of the compound of formula (I) or formula (II) administered per kilogram per 24 hours is about 0.01-800 mg, preferably a total amount of 0.1-100 mg /kg. If necessary, it is administered in several single doses. However, it is also possible to deviate from the above-mentioned amounts if necessary, i.e. it depends on the type and weight of the subject to be treated, the behavior of the individual with the drug, the nature and severity of the disease, the type of formulation and administration, and the time of administration and interval.
  • the present invention provides a compound of formula (I) or formula (II) of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention in the preparation for use in the treatment and/or prevention of and Use in medicine for disorders associated with abnormal glycogen metabolism.
  • diseases related to abnormal glycogen metabolism include diabetes (especially type 2 diabetes) or its complications (such as diabetic nephropathy, diabetic foot, diabetic neuropathy, cardiovascular and cerebrovascular diseases complicated by diabetes, etc.), hyperlipidemia disease, obesity, ischemic cardiovascular and cerebrovascular diseases (especially myocardial infarction, angina pectoris, myocardial ischemia, myocardial ischemia-reperfusion, arrhythmia, coronary heart disease, cerebral ischemia, stroke, cerebral infarction or ischemic neurodegeneration disease, etc.), hyperinsulinemia, insulin resistance, fasting hyperglycemia, hypertension or its complications, atherosclerosis, metabolic syndrome or tumors.
  • diabetes especially type 2 diabetes
  • complications such as diabetic nephropathy, diabetic foot, diabetic neuropathy, cardiovascular and cerebrovascular diseases complicated by diabetes, etc.
  • hyperlipidemia disease especially obesity, ischemic cardiovascular and cerebrovascular diseases (especially myocardial infarction, angina pectoris, myocardial ischemia, myo
  • the present invention provides a compound of formula (I) or formula (II) of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention in the preparation of a glycogen phosphorylase inhibitor the use of.
  • Figure 1 shows the preparation process of some compounds of the present invention.
  • R 3 ' is an organic group, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl and the like.
  • Figure 2 is a mouse echocardiographic evaluation of the effect of compound treatment of Example 8 on myocardial ischemia-reperfusion injury
  • (A) is a representative image of small animal M-mode ultrasound;
  • (B) is a statistical map of small animal ultrasound EF, FS, EDV and ESV (*p ⁇ 0.05)
  • 5-Chloroindole-2-carboxylic acid (0.29 g, 1.48 mmol) was dissolved in dry DMF (7.4 mL), and HATU (0.38 g, 1 mmol, 0.4 mol/L of dry DMF) was slowly added under stirring.
  • 5-Chloroindole-2-carboxylic acid (0.14 g, 0.72 mmol) was dissolved in dry DMF (3.6 mL), and HATU (0.253 g, 0.665 mmol, 0.4 mol/L) was slowly added under stirring.
  • 5-Chloroindole-2-carboxylic acid (0.302 g, 1.549 mmol) was dissolved in dry DMF (7.75 mL), and HATU (0.4 g, 1.052 mmol, 0.4 mol/L) was slowly added with stirring.
  • 5-Chloroindole-2-carboxylic acid (0.131 g, 0.668 mmol) was dissolved in dry DMF (3.34 mL), and HATU (0.17 g, 0.447 mmol, 0.4 mol/L) was slowly added with stirring.
  • 5-Chloroindole-2-carboxylic acid (0.255 g, 1.307 mmol) was dissolved in dry DMF (6.5 mL), and HATU (0.435 g, 1.144 mmol, 0.4 mol/L) was slowly added under stirring.
  • 5-Chloroindole-2-carboxylic acid (0.1 g, 0.513 mmol) was dissolved in dry DMF (2.56 mL), and HATU (0.147 g, 0.387 mmol, 0.4 mol/L) was slowly added under stirring.
  • 5-Chloroindole-2-carboxylic acid (0.063 g, 0.323 mmol) was dissolved in dry DMF (1.65 mL), and HATU (0.083 g, 0.218 mmol, 0.4 mol/L) was slowly added under stirring.
  • 5-Chloroindole-2-carboxylic acid (0.067 g, 0.342 mmol) was dissolved in dry DMF (1.71 mL), and HATU (0.087 g, 0.2288 mmol, 0.4 mol/L) was slowly added under stirring.
  • 5-Chloroindole-2-carboxylic acid (0.22 g, 1.12 mmol) was dissolved in dry DMF (5.6 mL), and HATU (0.394 g, 1.036 mmol, 0.4 mol/L) was slowly added under stirring.
  • Preparation of reagents 1) Preparation of color developing solution: Weigh 5g of ammonium molybdate, dissolve it in 500ml of 1M HCl, stir with a stirrer, add 190mg of malachite green after it is completely dissolved, continue to stir until it is completely dissolved, and use tin foil Protect from light; 2) Preparation of buffer solution: 1 Precisely weigh Hepes 0.5958g, dissolve it in 5ml H 2 O, adjust the pH to 7.2 with 10M NaOH, and prepare Hepes with a final concentration of 0.5M; 2 Precisely weigh KCl 0.3728 g, dissolved in 5ml H 2 O to prepare KCl with a final concentration of 1M; 3Precisely weigh 0.0255g of MgCl 3 , dissolve in 1ml H 2 O, and prepare a final concentration of 125mM MgCl 2 ; 4Precisely weigh EGTA 0.0476g, dissolve in 5ml
  • Determination of the dose-response curve of rabbit muscle glycogen phosphorylase activity by reading the OD value at 655nm after adding different concentrations of GPa to the chromogenic solution, the dose-response curve was measured.
  • the amount of GPa can be selected as 250ng from the dose-response curve.
  • test results show that most of the compounds in the examples have IC 50 ⁇ 1 ⁇ M, which are proved to be effective, as shown in Table 1 below.
  • the pharmacological data show that the compound of the general formula (I) of the present invention has an inhibitory effect on glycogen phosphorylase, and the activity is similar to that of the known compound (the compound of Example 1 of CN103497181A).
  • the compound of formula (I) of the present invention has the activity of inhibiting glycogen phosphorylase, so it can be used to treat various diseases related to abnormal glycogen metabolism.
  • Plasma sample 0.2mL, add 0.4mL acetonitrile solution, vortex for 5min, centrifuge at 10000r ⁇ min -1 for 10min, take the supernatant, centrifuge at 10000r ⁇ min -1 for 10min, then take the supernatant, and use HPLC to determine the drug concentration in plasma .
  • the pharmacokinetic parameters are listed in Table 2:
  • the compound of the present invention has a longer half-life, higher Cmax and better bioavailability than the prior art compound (the compound in Example 1 of CN103497181A), thereby improving the curative effect.
  • mice After 4-week-old male C57 BL/6J mice were adaptively fed for 5 days, 10 mice were randomly selected as normal control group, fed with low-fat diet, and the remaining mice were fed with high-fat diet. Mice were housed in a cage of 5 mice with free access to food and water, a light-dark cycle of 12 hours, and a room temperature of 22°C to 26°C. After the mice were continuously fed for 12 weeks, fasting and glucose tolerance were measured to evaluate insulin resistance, which showed that the modeling was successful.
  • the high-fat feeding group was randomly divided into the following experimental groups according to 10 animals/group: model control group, metformin group (400 mg/kg, gavage) and Example 8 compound group (high, medium and low dose groups, respectively For 50, 25, 12.5 mg/kg, gavage, once a day).
  • model control group metformin group (400 mg/kg, gavage)
  • Example 8 compound group high, medium and low dose groups, respectively For 50, 25, 12.5 mg/kg, gavage, once a day.
  • the patients were given continuous administration for 4 weeks, and they fasted overnight before the last administration.
  • the blood glucose levels of the model control group on the 0, 7, 14, 21, and 27 days of administration were significantly higher than those of the normal control group ( ## p ⁇ 0.01).
  • the metformin 400mg/kg group showed significant differences in blood glucose, which were lower than those in the model control group ( ** p ⁇ 0.01);
  • the compound of Example 8 of the present invention 50mg/kg group showed significant differences on the 7th, 21st, and 27th days of administration.
  • the blood glucose values on the 14th, 21st, and 27th days were significantly lower than those in the model control group ( * p ⁇ 0.05, ** p ⁇ 0.01), and the blood glucose values in the 25mg/kg and 12.5mg/kg groups were significantly lower on the 21st and 27th days of administration compared with the model control group ( ** p ⁇ 0.01).
  • Table 3 The effect of the compound of Example 8 of the present invention on the blood glucose of the C57BL/6 hyperglycemia mouse model induced by high-fat diet
  • mice 8-week-old SPF grade C57 BL/6J mice, weighing 20-25g, were randomly divided into the following experimental groups, 10 mice/group: sham operation group (Sham), I/R model group (I.R Model) and Example 8 Compound group high dose group (HD 100mg/kg), middle dose group (MD 50mg/kg) and low dose group (LD 30mg/kg).
  • the mice were anesthetized with isoflurane, and after observing that they had no righting response, they were fixed in the supine position on the operation board.
  • the surgical site on the front of the mouse chest was disinfected with 75% alcohol, and an incision of about 1 cm was cut along the third and fourth intercostal space.
  • the pectoralis major and minor muscles were bluntly separated, and a curved hemostat was used to penetrate the intercostal muscle. Deep into the chest cavity, with its power, quickly squeeze the heart out of the intercostal space.
  • the left anterior descending coronary artery was ligated with a suture needle, causing myocardial ischemia in the mouse, and the anterior wall of the left ventricle was observed to turn pale.
  • the heart was quickly returned to the thoracic cavity for repositioning, the end of the ligation slip-knot was exposed outside the body, and the skin incision was sutured with a suture needle. The timing of the ligation was started.
  • the ligature was gently pulled by hand to loosen the knot to restore blood supply to the heart.
  • the mice were placed on a 37°C insulation pad until they recovered their automatic crawling ability.
  • the I/R model was established 24 hours after the blood supply to the heart was restored.
  • the high, medium and low dose groups of the compound of Example 8 were administered by tail vein injection after I/R modeling, once a day, for 7 consecutive days.
  • EF ejection fraction
  • FS short-axis shortening
  • EDV end-diastolic volume
  • ESV end-systolic volume
  • LVEF left ventricular ejection fraction (Left Ventricular Ejection Fractions), refers to: the percentage of stroke volume in ventricular end-diastolic volume.
  • the ventricular diastolic volume is about 125mL for the left ventricle, about 137mL for the right ventricle, and the stroke volume is 60-80mL, that is, ejection of blood.
  • the percentage of the stroke volume in the diastolic volume of the ventricle is called the ejection fraction.
  • the ejection fraction of the human body is about 55% to 65% at rest.
  • the ejection fraction is related to the contractility of the myocardium. The stronger the myocardial contractility, the greater the stroke volume and the greater the ejection fraction.
  • the left ventricular ejection fraction is ⁇ 50%; the right ventricular ejection fraction is ⁇ 40%. If it is less than this value, it means cardiac insufficiency.
  • LVFS Left Ventricular Fractional shortening (Left Ventricular Fractional shortening), refers to: the left ventricular end-diastolic diameter minus the left ventricular end-systolic diameter, the percentage of the left ventricular end-diastolic diameter, this value reflects the contraction of the heart and diastolic function.
  • LVEDV Left Ventricular End-diastolic volume, literally, refers to the volume within the left ventricle at end-diastolic, used to calculate LVEF and LVFS.
  • LVESV Left Ventricular End-systolic volume, literally, refers to the volume in the ventricle at the end of systolic left ventricle, used to calculate LVEF and LVFS.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de benzoxazine-4-one représenté par la formule (I) qui agit en tant qu'inhibiteur de la glycogène phosphorylase, son procédé de préparation et son utilisation dans un médicament pour le traitement et/ou la prévention de maladies associées à des anomalies du métabolisme du glycogène.
PCT/CN2021/074002 2021-01-27 2021-01-27 Composé de benzoxazine-4-one, son procédé de préparation et son utilisation médicale WO2022160138A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/074002 WO2022160138A1 (fr) 2021-01-27 2021-01-27 Composé de benzoxazine-4-one, son procédé de préparation et son utilisation médicale

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/074002 WO2022160138A1 (fr) 2021-01-27 2021-01-27 Composé de benzoxazine-4-one, son procédé de préparation et son utilisation médicale

Publications (1)

Publication Number Publication Date
WO2022160138A1 true WO2022160138A1 (fr) 2022-08-04

Family

ID=82654000

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/074002 WO2022160138A1 (fr) 2021-01-27 2021-01-27 Composé de benzoxazine-4-one, son procédé de préparation et son utilisation médicale

Country Status (1)

Country Link
WO (1) WO2022160138A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1452526A1 (fr) * 2001-10-29 2004-09-01 Japan Tobacco Inc. Compose indolique, et utilisation a des fins therapeutiques
WO2006059164A2 (fr) * 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
CN1826340A (zh) * 2003-05-21 2006-08-30 普罗西迪恩有限公司 作为糖原磷酸化酶抑制剂的吡咯并吡啶－2－甲酸酰胺
CN101622231A (zh) * 2007-02-28 2010-01-06 艾德维纳斯医疗私人有限公司 作为葡糖激酶激活剂的2,2,2-三取代的乙酰胺衍生物、它们的制造方法和药学应用
CN103497181A (zh) * 2013-09-30 2014-01-08 承德医学院 作为糖原磷酸化酶抑制剂的苯并氮杂卓酮类化合物、其制备方法及医药用途
WO2014097188A1 (fr) * 2012-12-21 2014-06-26 C4T S.C. A.R.L. Composés de 2,3-dihydro-4h-1,3-benzoxazine-4-one, procédé pour leur préparation et forme pharmaceutique comprenant ceux-ci
CN112442022A (zh) * 2019-09-02 2021-03-05 承德医学院 苯并嗪-4-酮类化合物、其制备方法及医药用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1452526A1 (fr) * 2001-10-29 2004-09-01 Japan Tobacco Inc. Compose indolique, et utilisation a des fins therapeutiques
CN1826340A (zh) * 2003-05-21 2006-08-30 普罗西迪恩有限公司 作为糖原磷酸化酶抑制剂的吡咯并吡啶－2－甲酸酰胺
WO2006059164A2 (fr) * 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
CN101622231A (zh) * 2007-02-28 2010-01-06 艾德维纳斯医疗私人有限公司 作为葡糖激酶激活剂的2,2,2-三取代的乙酰胺衍生物、它们的制造方法和药学应用
WO2014097188A1 (fr) * 2012-12-21 2014-06-26 C4T S.C. A.R.L. Composés de 2,3-dihydro-4h-1,3-benzoxazine-4-one, procédé pour leur préparation et forme pharmaceutique comprenant ceux-ci
CN103497181A (zh) * 2013-09-30 2014-01-08 承德医学院 作为糖原磷酸化酶抑制剂的苯并氮杂卓酮类化合物、其制备方法及医药用途
CN112442022A (zh) * 2019-09-02 2021-03-05 承德医学院 苯并嗪-4-酮类化合物、其制备方法及医药用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 7 February 2012 (2012-02-07), ANONYMOUS : "1H-Indole-2-carboxamide, 6-ethoxy-N-(1,2,3,4-tetrahydro-1-oxo-7- isoquinolinyl)-(CA INDEX NAME) ", XP055954994, retrieved from STN Database accession no. 1355639-22-3 *

Similar Documents

Publication Publication Date Title
JP6238908B2 (ja) リシン構造を有するｌｓｄ１選択的阻害薬
EP1404653B1 (fr) Indoles substitues par triamide, benzofuranes et benzothiophenes utiles comme inhibiteurs de la proteine de transfert triglyceride microsomale (mtp) et/ou de la secretion de l'apolipoproteine b (apo b)
JP4196678B2 (ja) 複素環化合物
US9650380B2 (en) Difluoromethylene compound
EA012204B1 (ru) Три(цикло)замещённые амидные соединения
KR20030015390A (ko) 지질 풍부 플라크 퇴축제
WO2018157843A1 (fr) Inhibiteur fto de formiate aromatique 2-(matrice de benzène substitué), son procédé de préparation et ses applications
TW200942239A (en) Phenylacetamide derivatives
CN113993845A (zh) 作为治疗cns障碍例如多发性硬化的gpr17调节剂的n-(苯基)-吲哚-3-磺酰胺衍生物和相关化合物
JP2013537240A (ja) 糖尿病および脂質異常症の処置のための方法および組成物
TW201536722A (zh) 新穎化合物
JP2020520949A (ja) 組成物、並びにミトコンドリア脱共役剤を調製及び使用する方法
CA2931836C (fr) Urees asymetriques p-substituees et utilisations medicales de celles-ci
CA2232497A1 (fr) Derives d'acryloylguanidine a substitution heteroaryle et leurs composition medicinale
TW479058B (en) 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives
UA120389C2 (uk) Нові сполуки піридинію
WO2022143574A1 (fr) Dérivé de 2-pyridone, son procédé de préparation et son application pharmaceutique
WO2019096089A1 (fr) Dérivés d'indolizine et son application en médecine
WO2022160138A1 (fr) Composé de benzoxazine-4-one, son procédé de préparation et son utilisation médicale
JP7531506B2 (ja) アクリル含有核輸送モジュレーターおよびその使用
WO2002006249A1 (fr) Procede de fabrication d'un derive de 1,2,3 triasol substitue en position 1
CN112442022B (zh) 苯并嗪-4-酮类化合物、其制备方法及医药用途
WO2017016523A1 (fr) Composé antitumoral ciblant la mutation de idh2 et son procédé d'utilisation
Robertson et al. Imidazole-pyridine bioisosterism: comparison of the inotropic activities of pyridine-and imidazole-substituted 6-phenyldihydropyridazinone cardiotonics
WO2018205928A1 (fr) Dérivés d'indolizine et leur application en médecine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21921758

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21921758

Country of ref document: EP

Kind code of ref document: A1