WO2014086104A1 - Activateur d'ampk et son application dans la préparation de médicaments pour le traitement du diabète et/ou de complications du diabète - Google Patents

Activateur d'ampk et son application dans la préparation de médicaments pour le traitement du diabète et/ou de complications du diabète Download PDF

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WO2014086104A1
WO2014086104A1 PCT/CN2013/070166 CN2013070166W WO2014086104A1 WO 2014086104 A1 WO2014086104 A1 WO 2014086104A1 CN 2013070166 W CN2013070166 W CN 2013070166W WO 2014086104 A1 WO2014086104 A1 WO 2014086104A1
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diabetes
hsd
compound
ampk
formula
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Chinese (zh)
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程坚
敖桂珍
贾佳
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苏州大学
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    • 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
    • A61K31/435—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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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

Definitions

  • the present invention relates to the field of medicine, and in particular to an AMPK activator and its preparation in therapy and
  • Diabetes is a disease process caused by multiple causes, affecting 6% of the world's population. It is estimated that by 2025, the number of patients will double to 300 million. The most important clinical pathological feature of diabetes is an increase in plasma glucose (blood sugar) concentrations. Increased blood glucose levels are the leading cause of various clinical symptoms of diabetes. Uncontrolled hyperglycemia causes many complications of diabetes, such as increased risk of microvascular and macrovascular disease, including kidney disease, neuropathy, retinopathy, hypertension, cerebral ischemia, and coronary heart disease. Therefore, lowering blood sugar is the key to treating and preventing diabetes and its complications.
  • Type I diabetes is diabetes caused by various causes of insulin deficiency.
  • Type II diabetes is also called non-insulin-dependent diabetes, accounting for the total number of diabetics.
  • the basic factors of the disease are relative insulin deficiency and/or insulin resistance (ie, the body's ability to respond to insulin decreases).
  • islet ⁇ cells initially compensate for excessive insulin secretion due to insulin resistance, and then lead to insulin deficiency and blood glucose increase due to islet ⁇ cell failure over time. Therefore, type 2 diabetes is not caused by the absolute lack of insulin, but because the body's ability to respond to insulin stimuli is insufficient, resulting in a decrease in the body's ability to metabolize and utilize glucose, leading to hyperglycemia.
  • Insulin is the most important promotion in Portugal Glucose utilization and metabolism of endogenous hormones. Insulin is more effective for type 1 diabetes, that is, diabetes due to various causes of insulin deficiency. However, for type 2 diabetes, if exogenous insulin is administered inappropriately, tolerance to glucose can be irreparable, further aggravating the condition. Therefore, an important strategy for the treatment of type 2 diabetes is to improve the body's ability to respond to insulin.
  • AMPK is involved in a variety of metabolic processes as an important protein kinase. AMPK plays a major role in regulating the balance of energy metabolism in the body. In muscle and liver, activation of AMPK enhances glucose uptake, fatty acid oxidation and insulin sensitivity, and reduces the production of glucose, cholesterol and triglycerides. Therefore, AMPK and its signaling pathway are targets for effective drugs for type II diabetes.
  • biguanide hypoglycemic agents such as diterpene, phenformin and butylformin, which are currently widely used clinically, are AMPK activators.
  • Dioxin is the most widely used first-line anti-diabetic drug in clinical practice. It is not only the first choice for diabetes treatment, but also has no effect on normal blood sugar. This suggests that AMPK is a key target for the treatment of type 2 diabetes.
  • Lactic acidosis is a serious class of metabolic diseases that can be life-threatening if they occur. It is precisely because it can cause lactic acidosis, bismuth AMPK activators such as phenformin have been discontinued in clinical applications in Europe and the United States. Although diazepam is less likely to cause lactic acidosis than phenformin, it has the highest number of clinical reports of severe toxic and side effects and deaths in oral hypoglycemic agents. Therefore, the development of novel, non-biguanide AMPK activation As a therapeutic drug for diabetes, it has important clinical significance.
  • the 3H-1 , 2-dithiol-3-thione compound has the structure shown in Formula I, and such compounds have the same pharmacophore: i.e., 5-p-hydroxyphenyl-3H-1, 2-Dithiocyclopentene-3-thione, but does not contain a biguanide group.
  • R is selected from -CH 3 , -H,
  • R is -CH 3
  • the compound is named 5-p-methoxyphenyl-3H-1 , 2-dithiolen-3-indolone (HSD);
  • R When R is -H, the compound is named 5-p-hydroxyphenyl-3H-1,2-dithiolene-3-thione (HSD-OH for short; when R is, the compound is named pyridine- 3-decanoic acid 4- ( 3H-1 , 2-disulfide
  • Heterocyclic pentene -3-thione -5-yl)-phenyl ester ester of nicotinic acid, abbreviated as HSD-3;
  • HSD-4 2, -Dithiazine-3-thione-5-yl)-phenyl ester (ester of aspirin, abbreviated as HSD-4).
  • HSD-OH is an in vivo metabolite of HSD.
  • HSD is a clinical drug for the treatment of cholestasis and acute and chronic hepatitis.
  • the pharmacological effects of HSD are currently known to be: 1) promote bile excretion, significantly increase the secretion of solid components such as bile acid, bile pigment and cholesterol, especially increase bile pigment secretion; 2) significantly enhance glutamylcysteine Acid synthase, glutathione reductase and other activities, thereby enhancing liver glutathione levels, liver cell viability; 3) stimulating digestive action, anti-psychotic drug-induced saliva reduction is particularly effective; can promote gastrointestinal motility And gas discharge in the intestine can eliminate the symptoms of dyspepsia; 4) Detoxification; It can promote the rapid metabolism of alcohols in the body and eliminate it, and has good detoxification and anti-allergic effects on alcohol, drugs, food and other poisoning, 5 Reduce blood cholesterol levels and prevent them from sinking or adhering to the inner wall of blood vessels.
  • the 3H-1,2-dithiocyclopentene-3-thione compound does not contain a biguanide group; wherein HSD is a clinical drug for treating cholestasis and acute and chronic hepatitis. HSD has never been found to cause lactic acidosis in long-term clinical applications. Therefore, compared with the currently widely used biguanide AMPK activators, 3H-1, 2-dithiocyclopentene-3-thione compounds are used as AMPK activators, as well as therapeutic and/or preventative preparations. Drugs for diabetes and its complications are safer.
  • the present invention provides the use of a compound having the structure of Formula I as an AMPK activator
  • R is selected from -CH 3 , -
  • the compound having the structure of Formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein HSD is currently used as a drug for treating cholestasis and acute hepatitis, but HSD, HSD-OH, The role of HSD-3 and HSD-4 in activating AMPK and lowering blood glucose has never been reported.
  • the invention also provides the use of a compound having the structure of formula I for the manufacture of a medicament for the treatment and/or prevention of diabetes and/or diabetic complications
  • R is selected from -CH 3 , -H,
  • the diabetes having the structural compound of formula I which is treatable and/or preventable is type II diabetes.
  • the compound having the structure shown in Formula I to treat and / or prevention of complications of diabetes include hypertension, cardiovascular disease, obesity, neuropathy, retinopathy, diabetic nephropathy or ovarian syndrome t
  • the structural compound represented by the formula I has an AMPK activating activity and a hypoglycemic action, and thus has a therapeutic and/or preventive effect on diabetes. Because the complications of diabetes are mainly caused by hyperglycemia, lowering blood glucose is also a key measure for the treatment and prevention of diabetic complications. In addition, excessive activation of inflammatory cells is also an important cause of complication and development, and AMPK activation is an inhibitor of inflammatory cells. The key mechanism of activation. Since the structural compound of the formula I provided by the present invention has the effect of lowering blood glucose and activating inflammatory cell AMPK, the compound of the structure of formula I can treat and/or prevent diabetic complications associated with type 2 diabetes, such as hypertension. , cardiovascular and cerebrovascular diseases, obesity, neuropathy, retinal diseases, diabetic nephropathy or polymorphous ovarian syndrome, and symptoms caused by type 2 diabetes, including insulin resistance, glucose intolerance, hyperinsulinemia, and the like.
  • 3H-1,2-dithiocyclopentene-3-thione compounds can significantly reduce blood glucose levels in STZ-induced type 2 diabetic mice.
  • the experimental data of the present invention also showed that 3H-1,2-dithiocyclopentene-3-thione compounds can activate inflammatory cells AMPK in a cell inflammatory model induced by LPS. Because the complications of diabetes are mainly caused by hyperglycemia, lowering blood glucose is a key measure to treat and prevent diabetes complications. In addition, excessive activation of inflammatory cells is also an important factor leading to complications, and AMPK activation is an inhibitor of excessive activation of inflammatory cells. Key mechanism.
  • 3H-1,2-dithiocyclopentene-3-thione compounds have hypoglycemic effects and inhibit inflammation by activating AMPK, and thus it can be inferred that such compounds have therapeutic and/or therapeutic complications for diabetes. Preventive effect.
  • the present invention further exemplifies cerebral ischemia, indicating that 1,2-dithiocyclopentane Alkenyl-3-thione compounds have significant brain protective effects on cerebral ischemia in patients with type II diabetes And can effectively reduce the mortality of type 2 diabetic mice after cerebral ischemia.
  • the invention also provides a medicament for the treatment and/or prevention of diabetes and/or diabetic complications, comprising a compound of the structure of formula I and a pharmaceutically acceptable excipient
  • R is selected from -CH 3 , -
  • the adjuvant added to the medicament for treating and/or preventing diabetes and/or diabetic complications provided by the present invention is a disintegrant, a lubricant, an emulsifier, a binder.
  • the present invention provides a pharmaceutical composition for treating and/or preventing diabetes and/or diabetic complications having a mass fraction of 0.05% to 99% of the compound of formula I.
  • the medicament for the treatment and/or prevention of diabetes and/or diabetic complications provided by the present invention is administered by topical administration, digestive administration or parenteral administration.
  • the administration of the medicament for treating and/or preventing diabetes and/or diabetic complications provided by the present invention includes oral administration, injection, input, rectal administration, nasal administration, oral administration, sublingual administration. medicine.
  • the dosage form of the medicament for treating and/or preventing diabetes and/or diabetic complications provided by the present invention includes an oral preparation, an injection, a suppository or an inhalation.
  • oral preparations are capsules, micro-pills, pills, tablets, decoctions, granules, ointments, dispersible powders, lotions, oral liquids, pills, liposomes.
  • the injection is a powder injection or an injection.
  • the present invention provides an injection for treating and/or preventing diabetes and/or diabetic complications for subcutaneous injection or input, intravenous injection or input, monthly injection or input, intraperitoneal injection or input, Intrathecal injection or input, intraventricular injection or input, intrasternal injection or loss Intravenous, intracranial injection or input or use of an explanted reservoir.
  • the amount of the medicament for treating and/or preventing diabetes and/or diabetic complications provided by the present invention is 0.005 mg/kg/day to 5000 mg/kg/based on the amount of the structural compound represented by formula I.
  • the dosage of the compound having the structure of I per kilogram of animal body weight per day is 0.005 mg to 5000 mg.
  • the present invention provides the use of a compound having the structure of formula I as an AMPK activator, wherein the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, which does not contain a biguanide group.
  • HSD is currently used as a drug for the treatment of cholestasis and acute and chronic hepatitis. HSD has never been found to cause lactic acidosis in long-term clinical applications. Therefore, compared with the currently widely used biguanide AMPK, 3H-1, 2-dithiocyclopentene-3-thione compounds are used as AMPK activators, and the prepared drugs for treating diabetes have higher Security.
  • 3H-1,2-dithiocyclopentene-3-thione compounds can effectively activate AMPK on cell models, and the activation efficiency is higher than that of the first-line antidiabetic drug diterpene, which is widely used in clinical practice.
  • 3H-1,2-dithiocyclopentene-3-thione compounds can be significantly reduced blood sugar.
  • 3H-1,2-dithiocyclopentene-3-thione compounds significantly reduced mortality and cerebral infarction volume in diabetic mice in STZ-induced ICR mice with type 2 diabetes and cerebral ischemia. It is indicated that 3H-1,2-dithiocyclopentene-3-thione compounds also have therapeutic and/or prophylactic effects on complications of diabetes.
  • Figure 1 shows the level of activation of AMPK in 3H-1,2-dithiocyclopentene-3-thione compounds in LPS-stimulated macrophage cells; wherein, Figure 1 (a) shows that HSD is not added.
  • the level of activation of AMPK in LPS-stimulated macrophage cells P-AMPK indicates the level of AMPK activation (the deeper the band indicates the higher degree of activation), AMPK indicates total AMPK, ⁇ -actin indicates internal reference, and 0 indicates no addition.
  • Macrophage of HSD-4 1 shows the macrophage pack after 30 min of 50 ⁇ /L HSD treatment, 2 lists the macrophage pack after 60 min of 50 ⁇ /LHSD treatment, 3 lists Macrophage was collected after 120 min of HSD treatment, and 4 macrophages after treatment with 50 ⁇ /L HSD for 240 min;
  • the level of activation of AMPK in phagocytes indicates AMPK activation level
  • AMPK indicates total AMPK
  • ⁇ -actin indicates internal reference
  • 0 indicates macrophages without HSD-OH
  • 1 indicates addition of 50 ⁇ /L Macrophages after 30 min treatment with HSD-OH
  • Figure 1 (c) shows the activation level of AMPK in HSD-3 in LPS-stimulated macrophage cells
  • P-AMPK shows AMPK activation level
  • AMPK shows total AMPK
  • ⁇ -actin shows internal reference
  • 0 shows no HSD-3 macrophages were added
  • 1 shows the macrophage packs treated with 50 ⁇ /L HSD-4 for 30 min
  • 2 lists the macrophage after 60 min of 50 ⁇ /L HSD-3 treatment.
  • FIG. 1 shows the activation level of AMPK in HSD-4 in LPS-stimulated macrophage cells, P-AMPK shows AMPK activation level, AMPK shows total A MPK, ⁇ -actin shows internal reference, 0 lists macrophage packets without HSD-4, 1 shows macrophage packets after 30 min of 50 mol/L HSD-4 treatment, and 2 shows 50 ⁇ /L HSD-4 treated macrophages after 60 min, 3 showed macrophages after 120 min treatment with 50 ⁇ /L HSD-4, and 4 showed addition of 50 ⁇ /L HSD-4 for 240 min.
  • Macrophage pack 5 lists macrophages treated with 50 ⁇ /L HSD-4 for 480 min;
  • Figure 2 shows the comparison of AMPK activation levels between 3H-1,2-dithiocyclopentene-3-thione and diterpene in the LPS-stimulated macrophage inflammatory cell model;
  • Figure 2 (a) The level of activation of AMPK by HSD at a final concentration of 50 ⁇ /L on a LPS-stimulated macrophage inflammatory cell model, P-AMPK indicates AMPK activation level, AMPK indicates total AMPK, ⁇ -actin indicates internal reference, and 0 indicates no Stimulated normal macrophages, 1 shows the results of 30 minutes after LPS inflammation treatment, 2 shows the results after 60 minutes of LPS inflammation treatment, and 3 shows the results after 120 minutes of LPS inflammation treatment, 4 Listed the results of LPS-induced inflammation after 240 min, 5 shows the results of LPS-induced inflammation after 480 min, and 6 shows LPS-induced conditions with 5 ( ⁇ mol/L of HSD for 30 min) 7 shows the results of HSD treatment with 50 ⁇ /L for 60 min under
  • FIG. 2 (b) shows the giant LPS stimulation.
  • Macrophages 1 showed the results after 30 minutes of LPS-induced inflammation treatment, 2 showed the results after 60 minutes of LPS-induced inflammation treatment, 3 showed the results after 120 minutes of LPS-induced inflammation treatment, and 4 showed LPS-induced inflammation treatment.
  • the results were detected after 240 min, 5 showed the results after 480 min of LPS-induced inflammation treatment, 6 showed the results of HSD-OH supplementation with 50 ⁇ /L for 30 min under LPS-induced conditions, and 7 ⁇ l showed LPS-induced inflammation. Under the condition of adding 50 ⁇ /L HSD-OH for 60 min, the results showed that 8 showed LPS-induced conditions to add 50 ⁇ /L HSD-OH for 120 min, and 9 showed LPS-induced conditions.
  • results were detected after 60 min of treatment with /L diterpene and sputum, and the results were detected after adding 1000 ⁇ /L diterpene for 120 min under LPS-induced conditions, and 9 were added for 1000 ⁇ /L dimers under LPS-induced conditions.
  • the results were detected after 240 min of double-twisting treatment, and 10 results showed that the results were obtained after adding 480 min of 1000 ⁇ /L diterpene in the LPS-induced conditions.
  • Figure 3 shows that HSD (5 ( ⁇ mol/L) activates AMPK in human cell KEK293T.
  • P-AMPK shows AMPK activation level
  • AMPK shows total AMPK
  • ⁇ -actin shows internal reference
  • 0 shows no HSD-treated control.
  • the cell group, 1 shows the test results after 30 minutes of administration in the experimental group
  • 2 shows the test results after 60 minutes of administration in the test group
  • 3 shows the test results after 120 minutes of administration in the test group, 4 columns.
  • the results of the test after 240 minutes of administration in the experimental group were shown, and 5 were shown after the administration of the experimental group for 480 minutes;
  • Figure 4 shows the effect of 3H-1,2-dithiocyclopentene-3-thione on blood glucose levels in mice in a low-dose STZ-induced type II diabetes ICR mouse model.
  • Figure 4 (a) shows the effect of HSD on non-fasting blood glucose levels in mice with STZ-induced ICR mouse model of type II diabetes, in which the ordinate is the non-fasting blood glucose level in mice, and the column 1 shows the mice in the solvent injection group.
  • Non-fasting blood glucose levels, column 2 showed non-fasting blood glucose levels in HSD-administered mice, * showed a significant difference at p ⁇ 0.05;
  • Figure 4 (b) shows STZ-induced type II diabetes ICR mouse models The effect of HSD on the fasting blood glucose level of mice, wherein the abscissa is the time after injection, the ordinate is the fasting blood glucose level of the mouse, the curve 1 shows the fasting blood glucose level of the mice in the solvent injection group, and the curve 2 indicates the small HSD administration group. Rat fasting blood glucose levels, * showed a significant difference at p ⁇ 0.05 level;
  • Figure 5 shows the incidence of cerebral infarction volume and mouse mortality in low-dose STZ-induced type 2 diabetes mellitus and ICR mouse animal models with cerebral ischemia in 3H-1,2-dithiocyclopentene-3-thione
  • Figure 5 (a) shows the effect of HSD on the volume of cerebral infarction in type I diabetes mellitus and ICR mouse models with cerebral ischemia, where the ordinate is the cerebral infarct volume, Ch ⁇ HSD administration group
  • the volume of cerebral infarction in mice, the area of cerebral infarction in mice showed that there was a significant difference at p ⁇ 0.05.
  • Column 1 showed cortical infarct size
  • column 2 showed striatum infarct volume
  • column 3 showed hemisphere.
  • Figure 5 (b) shows ICR mice with type 2 diabetes and cerebral ischemia The effect of HSD on mortality in mice on animal models, wherein the ordinate is mouse mortality, column 1 shows mortality in mice in the solvent-injected group, and column 2 shows mortality in mice in the HSD-administered group.
  • the present invention provides the use of a compound having the structure of Formula I as an AMPK activator, and in the preparation of a medicament for the treatment and/or prevention of diabetes and/or diabetic complications.
  • a compound having the structure of Formula I as an AMPK activator
  • Those skilled in the art can learn from the contents of this paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the present invention provides the use of a compound having the structure of Formula I as an AMPK activator
  • R is selected from -CH 3 , -H,
  • the compound having the structure of the formula I is a 3H-1,2-dithiocyclopentene-3-thione compound and does not contain a biguanide group.
  • HSD is currently used as a drug for the treatment of cholestasis and acute and chronic hepatitis. HSD has never been found to cause lactic acidosis in long-term clinical applications. Therefore, compared with the currently widely used biguanide AMPK, 3H-1, 2-dithiocyclopentene-3-thione compounds are safer to use as AMPK activators and to prepare drugs for treating diabetes. .
  • the invention also provides the use of a compound having the structure of formula I for the preparation of a medicament for the treatment and/or prevention of diabetes and/or diabetic complications
  • R is selected from -CH 3 , -H,
  • Type II diabetes is non-insulin-dependent diabetes mellitus due to the relative deficiency of insulin. Therefore, diabetes having the structural compound represented by Formula I can be used for the treatment and/or prevention of type 2 diabetes.
  • diabetic complications which can be treated and/or prevented by the structural compound represented by Formula I include hypertension, cardiovascular and cerebrovascular diseases, obesity, neuropathy, retinal diseases, diabetic nephropathy or polymorphous ovarian syndrome.
  • the structural compound represented by the formula I has an AMPK activating activity and a hypoglycemic action, and thus has a therapeutic and/or preventive effect on diabetes. Because the complications of diabetes are mainly caused by hyperglycemia, lowering blood glucose is also a key measure for the treatment and prevention of diabetic complications. In addition, excessive activation of inflammatory cells is also an important cause of the development and progression of diabetic complications. AMPK activation is the inhibition of excessive inflammatory cells. The key mechanism of activation. Since the structural compound of the formula I provided by the present invention has the effect of lowering blood glucose and activating inflammatory cell AMPK, the compound of the structure of formula I can treat and/or prevent diabetic complications associated with type 2 diabetes, such as hypertension. , cardiovascular and cerebrovascular diseases, obesity, neuropathy, retinal diseases, diabetic nephropathy or polymorphic ovarian syndrome, and symptoms caused by type 2 diabetes, including insulin resistance, glucose intolerance, hyperinsulinemia, and the like.
  • 3H-1, 2-dithiocyclopentene-3-thione compounds can significantly reduce blood glucose levels in type 2 diabetic mice induced by low doses of STZ; and can also be achieved by lowering blood glucose and by activating AMPK Excessive activation of inflammatory cells to treat and/or prevent diabetic complications.
  • the invention also provides a medicament for the treatment and/or prevention of diabetes and/or diabetic complications, comprising a compound of the structure of formula I and a pharmaceutically acceptable excipient
  • R is selected from -CH 3 , -H,
  • excipients added in the medicament for treating and/or preventing diabetes and/or diabetic complications provided by the present invention are disintegrants, lubricants, emulsifiers, binders.
  • the present invention provides a pharmaceutical composition for treating and/or preventing diabetes and/or diabetic complications having a mass fraction of 0.05% to 99% of the compound of formula I.
  • the present invention provides a pharmaceutical composition for the treatment and/or prevention of diabetes and/or diabetic complications having a mass fraction of the structural compound of formula I of from 15% to 60%.
  • the medicament for the treatment and/or prevention of diabetes and/or diabetic complications provided by the present invention is administered by topical administration, digestive administration or parenteral administration.
  • the modes of administration of the medicaments for treating and/or preventing diabetes and/or diabetic complications provided by the present invention include oral administration. , injection, input, rectal administration, nasal administration, oral administration, sublingual administration.
  • Dosage forms for the treatment and/or prevention of diabetes and/or diabetic complications provided by the present invention include oral preparations, injections, suppositories or inhalants.
  • oral preparations are capsules, micro-pills, pills, tablets, decoctions, granules, ointments, dispersible powders, lotions, oral liquids, pills, liposomes.
  • the injection is a powder injection or an injection.
  • the present invention provides for the treatment and/or prevention of diabetes and/or diabetes Injectables for complication of the disease for subcutaneous injection or input, intravenous or enter, intramuscular or enteral, intraperitoneal or enteral, intrathecal or enteral, intraventricular injection or input, intrasternal injection or input, intracranial injection or Enter or use the explanted reservoir for medication.
  • the amount of the drug for treating and/or preventing diabetes and/or diabetic complications provided by the present invention is 0.005 mg/kg/day based on the amount of the compound of the formula I according to the therapeutic effect and the severity of the disease ⁇ 5000 mg/kg/day, that is, a dose of 0.005 mg to 5000 mg per kg of animal body weight per day using the compound of the structure shown by I.
  • a serious side effect of the presently widely used biguanide AMPK activators is lactic acidosis.
  • the 3H-1,2-dithiocyclopentene-3-thione compound provided by the present invention does not contain a biguanide group, and HSD is currently used as a clinical drug for treating cholestasis and acute and chronic hepatitis. HSD has never been found to cause lactic acidosis in long-term clinical applications. Therefore, 3H-1,2-dithiocyclopentene-3-thione compounds are more safe as AMPK activators and to prepare drugs for treating diabetes than the currently widely used biguanide AMPK.
  • 3H-1,2-dithiocyclopentene-3-thione compounds can effectively activate AMPK in cell models, and the activation efficiency is higher than that of the first-line antidiabetic drug diterpenoids currently widely used in clinical practice.
  • 3H-1,2-dithiocyclopentene-3-thione compounds can be significantly reduced blood sugar.
  • 3H-1,2-dithiocyclopentene-3-thione compounds significantly reduced diabetic mice in STZ-induced ICR mice with type 2 diabetes and cerebral ischemia.
  • Mortality and cerebral infarction volume indicate that 3H-1,2-dithiocyclopentene-3-thione compounds also have therapeutic and preventive effects on diabetic complications.
  • Example 1 Activation of macrophage cell AMPK by a compound of formula I
  • the mouse macrophage cell line was taken out from the liquid nitrogen tank and quickly thawed in warm water at 37 °C, centrifuged at 1000 rpm for 3 min, the supernatant was discarded, and the mass fraction of the cells in the FBS was 10%.
  • the medium was cultured in DMEM, and subcultured when the cells were covered in the culture Jnr at a rate of 60% to 70%. After passage of the cell coverage rate of 60% to 70%, the cells were harvested by centrifugation at 1000 rpm for 3 min, stained with trypan blue, and counted under a microscope using a hemocytometer. The counted cells were diluted to a concentration of 150,000 / mL to 200,000 / mL, and a 96-well plate was plated, 15,000 / hole ⁇ 2.0 million / hole.
  • a solution of 3H-1,2-dithiocyclopentene-3-thione compound was prepared, and the compound of the formula I was weighed and dissolved in DMSO so that the final concentration of the solution was 100 mmol/L in terms of mass concentration.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected From -C3 ⁇ 4, -H, when R is -CH 3 , the compound is HSD,
  • HSD solution HSD-OH solution
  • HSD-3 solution HSD-4 solution
  • HSD-4 solution were added to make the final concentration in the cells 50 ⁇ /L, and an equal volume of DMSO was added to the control cells.
  • the cells were sampled and extracted with RIPA lysate by adding 40 L of RIPA lysate, repeatedly blowing the cells, and blowing the cells.
  • the slurry was placed in a 50 ( ⁇ L) centrifuge tube and allowed to stand on ice for 30 min to fully lyse the cells.
  • the centrifuge tube was transferred to a high-speed centrifuge, and centrifuged at 13200 rpm for 20 min to 25 min at 4 ° C for aspiration.
  • the supernatant was also (containing cell proteins) into another centrifuge tube and stored in a -80 ° C refrigerator.
  • the extracted cell protein was measured for protein concentration using diquinolinic acid (BCA).
  • SDS-poly(propylene) protein electrophoresis gel was prepared. After gel polymerization, 30 mg of cell protein sample was added to each well, and electrophoresis was carried out at a constant pressure of 60 V. After the protein molecular weight marker runs away, use a constant voltage of 100V. After the electrophoresis was completed, the protein on the SDS-poly(propylene) protein electrophoresis gel was transferred to the PVDF fiber membrane at a constant current of 350 mA, and the membrane was continuously transferred for 115 min. After the transfer was completed, the PVDF membrane was taken out and blocked with a volume fraction of 5% IxTBST blocking solution for 2 hours.
  • the PVDF membrane was washed 3 times with IxTBST for 10 min/time, and the AMPK antibody was incubated separately [1000 times with IxTBST diluted solution containing 0.5% BSA (mass fraction)], anti-AMPK 172 Thr phosphorylation ( Phospho) antibody [diluted 1000 times with IxTBST dilution containing 0.5% BSA (mass fraction)], overnight at 4 °C.
  • the PVDF membrane was washed 3 times with IxTBST, and after 10 min/time, the HRP horseradish peroxidase-conjugated anti-rabbit IgG antibody was incubated.
  • Figure 1 shows the level of activation of AMPK by HSD in macrophage cells without LPS stimulation
  • Figure 1 (b) shows the giant HSD-OH stimulated without LPS The level of activation of AMPK in phagocytes
  • Figure 1 (c) shows the level of activation of AMPK by HSD-3 in macrophage cells without LPS stimulation
  • Figure 1 (d) shows that HSD-4 is stimulated without LPS
  • the level of activation of AMPK in macrophage cells, P-AMPK indicates the level of AMPK activation.
  • HSD was added at a final concentration of 50 ⁇ /L compared to the control cells (0 min) added [Fig. 1 (a)], HSD-OH [Fig.
  • mouse macrophage AMPK172Thr phosphorylation
  • the level increased significantly, while the total AMPK internal standard ⁇ -actin remained unchanged. Since the phosphorylation level of AMPK172Thr represents the level of activation of AMPK kinase, this result indicates that 3H-1,2-dithiocyclopentene-3-thione significantly activates AMPK on a cell model. --actin is an internal reference, indicating that the total amount of detected protein is the same.
  • Example 2 Activation of macrophage AMPK by a compound of formula I under LPS-induced conditions
  • the mouse macrophage cell line was taken out from the liquid nitrogen tank and quickly thawed in warm water at 37 ° C, centrifuged at 1000 rpm for 3 min, the supernatant was discarded, and the cells were in DMEM medium with a mass fraction of FBS of 10%.
  • Medium culture subculture when cells cover 60% to 70% of culture Jnr. After passage of the cell coverage rate of 60% to 70%, the cells were harvested by centrifugation at 1000 rpm for 3 min, stained with trypan blue, and counted under a microscope using a hemocytometer. The counted cells were diluted to a concentration of 150,000 / mL to 200,000 / mL, and a 96-well plate was plated, 15,000 / hole ⁇ 2.0 million / well.
  • a solution of 3H-1,2-dithiocyclopentene-3-thione compound was prepared, and the compound of the formula I was weighed and dissolved in DMSO so that the final concentration of the solution was 100 mmol/L in terms of mass concentration.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • HSD solution and HSD-OH solution respectively to make the final concentration in the cells 50 ⁇ /L, or add diterpene guanidine to make the final concentration in the cells 500 ⁇ /L and ⁇ /L;
  • LPS was added to a final concentration of 100 ng/mL in the cells, and DMSO and physiological saline were added to the control cells to make the volume equal to the control group.
  • the cells were sampled and extracted with RIPA lysate by adding RIPA lysate 40 ⁇ , repeatedly pipetting the cells, and blowing the cells down.
  • the slurry was placed in a 500-centrifuge tube, allowed to stand on ice for 30 min to fully lyse the cells, and then the centrifuge tube was transferred to a high-speed centrifuge, centrifuged at 13200 rpm for 20 min to 25 min at 4 ° C, and the supernatant was aspirated. (containing cell proteins) into another centrifuge tube and stored in a -80 ° C refrigerator.
  • the extracted cellular protein was measured for protein concentration using diquinolinic acid (BCA).
  • SDS-poly(propylene) protein electrophoresis gel was prepared. After gel polymerization, 30 mg of cell protein sample was added to each well, and electrophoresis was carried out at a constant pressure of 60 V. After the protein molecular weight marker runs away, use a constant voltage of 100 V. After electrophoresis, SDS-poly(propylene) protein electrophoresis was performed at a constant current of 350 mA. The protein on the gel was transferred to the PVDF fiber membrane and the membrane was continuously transferred for 115 min. After the transfer was completed, the PVDF membrane was taken out and blocked with 5% milk (1 x TBST) blocking solution for 2 hours.
  • the PVDF membrane was washed 3 times with lxTBST for 10 min/time, and the AMPK antibody was incubated separately [1000 times with 1 x TBST diluted solution containing 0.5% BSA (mass fraction)], anti-AMPK 172 Thr phosphorylation ( Phospho ) antibody [diluted 1000 times with 1 x TBST dilution containing 0.5% BSA (mass fraction)], overnight at 4 °C.
  • the PVDF membrane was washed 3 times with lxTBST, and after 10 min/time, the HRP horseradish peroxidase-conjugated anti-rabbit IgG antibody was diluted with a dilution of lxTBST containing 0.5% BSA (mass fraction) 2000. Double], incubate for 2 hours at room temperature.
  • the PVDF membrane was washed 3 times with lxTBST for 10 min/time, then ECL developer was added and developed with a Koda gel imaging system.
  • Fig. 2 shows the activation level of AMPK by HSD-OH at a final concentration of 50 ⁇ /L on the LPS-stimulated macrophage inflammation model
  • FIG. 2 (b) shows Activation of AMPK by HSD-OH at a final concentration of 50 ⁇ /L on a LPS-stimulated macrophage inflammatory cell model
  • Figure 2 (c) shows a final concentration of 500 ⁇ /L on a LPS-stimulated macrophage inflammatory cell model The level of activation of AMPK by diterpenoids
  • Figure 2(d) shows the level of activation of AMPK by diterpene in a final concentration of 1000 ⁇ /L on a LPS-stimulated macrophage inflammatory cell model.
  • ⁇ -actin is an internal reference, indicating that the total amount of detected protein is the same, only cells treated with LPS, at different time points (30 min, 60 min, 120 min, 240 min or 480 min) AMPK
  • the 172Thr phosphorylation level was significantly lower.
  • AMPK phosphorylation (P-AMPK) levels in macrophages with both LPS and 50 ⁇ /L HSD or HSD-OH were significantly increased at each time point compared to control cells supplemented with LPS only, while total AMPK
  • the level (AMPK) is essentially unchanged, indicating that HSD or HSD-OH at 50 ⁇ /L can also activate AMPK in the case of LPS:.
  • the results showed that 50 ⁇ /L HSD [Fig. 2(a)] and HSD-OH [Fig. 2(b)] significantly increased AMPK phosphorylation (activation) levels in LPS-stimulated macrophage inflammatory cell models.
  • the KEK293T cells were taken out from the liquid nitrogen tank and quickly thawed in warm water at 37 ° C, centrifuged at 1000 rpm for 3 min, the supernatant was discarded, and the cells were cultured in DMEM medium with a FBS mass fraction of 10%. The cells were subcultured when the coverage of the cultured Jnr reached 60% to 70%. After passage of the cell coverage rate of 60% - ⁇ 70%, the cells were harvested by centrifugation at 1000 rpm for 3 min, stained with trypan blue, and counted 150,000/mL to 200,000/mL under a microscope using a hemocytometer. Board, 15,000 / hole ⁇ 2.0 million / hole.
  • a solution of 3H-1,2-dithiocyclopentene-3-thione compound was prepared, and the compound of the formula I was weighed and dissolved in DMSO so that the final concentration of the solution was 50 mmol/L by mass concentration.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected From -C3 ⁇ 4, -H, .
  • R is -CH 3
  • the compound is HSD
  • the compound is HSD-4.
  • HSD-OH solution was added to give a final concentration of 50 ⁇ /L in the cells, and cells with only an equal volume of DMSO were used as controls.
  • the cells were cultured in an incubator. At 30 min, 60 min, 120 min, 240 min, and 480 mim, the cells were sampled and extracted with RIPA lysate by adding RIPA lysate 40 ⁇ . The cells were repeatedly beaten, and the blown cell pellet was placed in a 500-centrifuge tube, allowed to stand on ice for 30 min to fully lyse the cells, and then the centrifuge tube was transferred to a high-speed centrifuge at 4 ° C, 13200 rpm, 20 min to 25 min. Aspirate the supernatant (containing cell proteins) into another centrifuge tube and store in a -80 ° C refrigerator. The extracted cellular protein was measured for protein concentration using diquinolinic acid (BCA).
  • BCA diquinolinic acid
  • SDS-poly(propylene) protein electrophoresis gel was prepared. After gel polymerization, 30 mg of cell protein sample was added to each well, and electrophoresis was carried out at a constant pressure of 60 V. After the protein molecular weight marker runs away, use a constant voltage of 100 V. After the electrophoresis was completed, the protein on the SDS-poly(propylene) protein electrophoresis gel was transferred to the PVDF fiber membrane at a constant current of 350 mA, and the membrane was continuously transferred for 115 min. After the transfer was completed, the PVDF membrane was taken out and blocked with 5% milk (1 x TBST) blocking solution for 2 hours.
  • the PVDF membrane was washed 3 times with lxTBST for 10 min/time, and the AMPK antibody was incubated separately [1000 times with 1 x TBST diluted solution containing 0.5% BSA (mass fraction)], anti-AMPK 172 Thr phosphorylation ( Phospho ) antibody [1000 times diluted with 1 x TBST solution containing 0.5% BSA (mass fraction)], overnight at 4 °C.
  • the PVDF membrane was washed 3 times with lxTBST, and after 10 min/time, the HRP horseradish peroxidase-conjugated anti-rabbit IgG antibody was diluted with a dilution of lxTBST containing 0.5% BSA (mass fraction) 2000. Double], incubate at room temperature 2 hour. After the incubation of the secondary antibody, the PVDF membrane was washed 3 times with lxTBST for 10 min/time, then ECL developer was added and developed with a Koda gel imaging system.
  • AMPK phosphorylation was added to macrophages at a final concentration of 50 ⁇ /L HSD-OH at the time of detection (30 min, 60 min, 120 min, 240 min, 480 min) compared to the control cells to which the solvent was added. The level is significantly increased, while the total AMPK level (AMPK) is basically unchanged. Indicates that HSD-OH activates human AMPK:. In combination with Examples 1 to 2, it was shown that HSD-OH has no species specificity for the activation of AMPK.
  • mice The purchased ICR mice were placed in the animal room to adjust to the environment for 24 hours, the food was removed, and the water was taken. After 15 hours, the STZ was intraperitoneally injected. The injection amount was 90 mg/kg according to the weight of the mice, and the feeding was resumed. , induces type 2 diabetes in mice.
  • mice after STZ injection were randomly divided into two groups, a solvent injection group and an HSD administration group, and 7 mice were randomly selected from each group.
  • the solvent injection group was only injected with the solvent for dissolving HSD, and the HSD-administered group was injected with the prepared HSD solution at a dose of 50 mg/kg/day (50 mg per kilogram of animal body weight per day).
  • After 6 hours of STZ administration they were administered separately in groups, for a total of 4 weeks.
  • the preparation method of HSD solution is as follows: 12 mg of HSD is first dissolved in 80 ⁇ DMSO, and then diluted with 920 ⁇ corn oil to a solution with a final solubility of 12 mg/mL.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • the fasting blood glucose of the mice was measured on the 3rd, 7th, 14th, 21st, and 28th days after the injection of the HSD solution.
  • the method is as follows: the food of the mice was removed the night before the blood glucose measurement, only for water. After 15 hours, the mice were fixed with a mouse holder (avoid the mouse cage to prevent other mice from being frightened by blood sugar) ), use a blood collection needle to puncture the tail to a hemorrhage of about 10 microliters, then drop the blood on the test paper that has been inserted into the blood glucose meter, and record the degree after 5 seconds.
  • the non-fasting blood glucose was measured.
  • the blood was not removed one night before the blood glucose measurement, the normal water supply was performed, and the blood glucose was measured.
  • the other methods were the same as the fasting blood glucose measurement.
  • Fig. 4(a) and Fig. 4(b) show the results of non-fasting blood glucose measurement of the mice 28 days after the injection of the HSD solution
  • Fig. 4(b) shows the results after the injection of the HSD solution.
  • Fasting blood glucose was significantly reduced in type 2 diabetic mice 14 and 28 days after HSD injection [Fig. 4(b)].
  • * indicates a significant difference at the p ⁇ 0.05 level.
  • HSD has the same pharmacophores as HSD-OH, HSD-3, HSD-4, and the data provided by Example 1 of the present invention and Example 2 of the present invention indicate HSD and HSD-OH, HSD-3 and HSD- 4 has the same pharmacological effects: that is, both can activate AMPK, and AMPK activation is the key mechanism of action of diabetes drugs for hypoglycemic.
  • mice The purchased ICR mice were placed in the animal room to adjust to the environment for 24 hours, the food was removed, and the water was taken. After 15 hours, the STZ was intraperitoneally injected. The injection amount was 90 mg/kg according to the weight of the mice, and the feeding was resumed. , induces type 2 diabetes in mice.
  • mice injected with STZ were randomly divided into two groups, the solvent injection group and the HSD administration group, and 7 mice were randomly selected from each group.
  • the solvent injection group only injected the solvent for dissolving HSD;
  • the HSD administration group injected the prepared HSD solution at a dose of 50 mg/kg/day (50 mg per kilogram of animal body weight per day).
  • After 6 hours of STZ administration they were administered separately in groups, for a total of 4 weeks. These mice were subjected to middle cerebral artery embolization 4 weeks later.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected From -C3 ⁇ 4, -H, when R is -CH 3 , the compound is HSD,
  • the compound is HSD-4.
  • the HSD solution was prepared by dissolving 12 mg of HSD first in 80 ⁇ DMSO and then diluting it into 920 ⁇ of corn oil to a final solubility of 12 mg/mL in O CM.
  • mice model of middle cerebral artery occlusion was made by Longa method and other improved suture method. The procedure is as follows: After the mice are anesthetized with isoflurane. The anesthetized mice were fixed in the upright position and routinely broke the wine to disinfect the skin of the neck and the skin of the head. The laser Doppler cerebral blood flow measurement probe was fixed at the midpoint of the right ear line of the mouse to monitor the blood flow of the cerebral cortex in real time.
  • the internal carotid artery was temporarily clamped with a type of blood vessel clamp, and the carotid sheath was not opened, and the pterygopalatine artery was not separated and ligated.
  • a suture was ligated between the common bifurcation of the common carotid artery and the distal ligature of the external carotid artery. The suture was not tightened, and then a small opening was made inside the distal ligature of the external carotid artery with an ophthalmic scissors.
  • the external carotid artery enters the internal carotid artery through the bifurcation until there is light resistance and A sudden drop in blood flow in the cerebral cortex was observed on the laser Doppler cerebral blood flow tester (blood flow should drop below 25% of the baseline value), indicating that the head of the striate head has reached the beginning of the middle cerebral artery, Broken blood flow to the middle cerebral artery.
  • mice Animal mortality was counted 24 hours after reperfusion of the middle cerebral artery occlusion (MCAO) in mice. After anesthetizing the surviving mice, the brain was quickly decapitated, and the brain tissue was removed to remove the olfactory bulb, cerebellum and low brain stem. Five coronal sections were made at intervals of 1 mm and placed in a TTC solution with a volume fraction of 2%. °C away from the light bath, turn it every 15 minutes, and keep the bath for 30 minutes. The size of the cerebral infarction area was determined by TTC staining. TTC is reduced by mitochondrial catalase, which causes the normal brain tissue to stain red, while the ischemic infarct tissue is white.
  • MCAO middle cerebral artery occlusion
  • Figure 5(a) shows the statistical results of cerebral infarction volume indicating that non-insulin-dependent (type II) diabetic mice were induced in low-dose STZ (90 mg/kg) ICR mice.
  • Figure 5(a) shows the statistical results of cerebral infarction volume indicating that non-insulin-dependent (type II) diabetic mice were induced in low-dose STZ (90 mg/kg) ICR mice.
  • injection of HSD for 28 days (50 mg/kg/day) 24 hours after occlusion of the middle cerebral artery, injection of 50 mg/kg HSD significantly reduced cortex, striatum and cerebral hemisphere compared with type II diabetic mice injected only with the solvent control group.
  • Infarct volume indicating that HSD has a significant protective effect on cerebral ischemia complications of type II diabetes.
  • Figure 5 (b) shows the mortality of type 2 diabetic mice after middle cerebral artery occlusion.
  • the results showed that: low-dose STZ (90 mg/kg) induced non-insulin-dependent (type II) diabetes in ICR mice, HSD (50 mg/kg/day) was injected into the mice, and middle cerebral artery occlusion was performed 4 weeks later, HSD injection (50 mg/kg/day) reduced mortality in type 2 diabetic mice.
  • This example only detects the protective effect of HSD on cerebral ischemia in STZ-induced diabetic mice.
  • the results show that HSD has a significant protective effect on the cerebral ischemia of type II diabetes and can effectively reduce type II after middle cerebral artery occlusion. Mortality in diabetic mice.
  • HSD has the same pharmacophores as HSD-OH, HSD-3 and HSD-4, and inventive examples 1 and
  • inventive examples 1 and The data provided in Inventive Example 2 indicates that HSD, HSD-3, and HSD-4 and HSD-OH have the same pharmacological action, that is, both activate AMPK:.
  • AMPK activation is a key mechanism of action for diabetes drugs to reduce blood sugar, and lowering blood sugar is also a key measure to treat and prevent diabetes and its complications.
  • Example 6 A compound of formula I for use in the preparation of a tablet for the treatment and/or prevention of diabetes and/or diabetic complications
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected from -C3 ⁇ 4, -H,
  • a triterpene-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a tablet is obtained by a conventional method.
  • Example 7 A compound of formula I is used to prepare a capsule for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a capsule is prepared by a conventional method.
  • EXAMPLE 8 Micro-tanning agents for the treatment and/or prevention of diabetes and/or diabetes complications
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a micro-twisting agent is obtained by a conventional method.
  • Example 9 A compound of formula I for use in the preparation of granules for the treatment and/or prevention of diabetes and/or diabetic complications
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected from -C3 ⁇ 4, -H,
  • the granules are prepared by a conventional method by adding a conventional excipient to the 3H-1,2-dithiocyclopentene-3-thione compound.
  • Example 10 A compound of formula I for use in the preparation of a dispersion powder for the treatment and/or prevention of diabetes and/or diabetic complications
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a dispersed powder is obtained by a conventional method.
  • Example 11 A compound of the formula I is used for the preparation of an injection for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected From -C3 ⁇ 4, -H,
  • the 3H-1,2-dithiocyclopentene-3-thione compound was added to a conventional excipient, and an injection solution was prepared by a conventional method.
  • Example 12 A compound of formula I is used to prepare liposomes for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected from -C3 ⁇ 4, -H,
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a liposome is obtained by a conventional method.
  • EXAMPLE 13 Compounds of formula I are used in the preparation of oral solutions for the treatment and/or prevention of diabetes and/or diabetes complications
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected Eight
  • the 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and an oral solution is prepared by a conventional method.
  • O CN Example 14 A compound of formula I is used to prepare a pill for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a pellet is obtained by a conventional method.
  • Example 15 A compound of formula I is used to prepare a decoction for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected from eight
  • a 3H-1,2-dithiocyclopenta-0 CN-enethione compound is added to a conventional excipient, and a decoction is prepared by a conventional method.
  • Embodiment 16 A compound of formula I is used for the preparation of a cream for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a paste is prepared by a conventional method.
  • Example 17 A compound of formula I is used to prepare a decoction for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected Eight
  • the 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a dew is prepared by a conventional method.
  • a dew is prepared by a conventional method.
  • a compound of formula I is used to prepare a pill for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • the 3 ⁇ -1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a dropping pill is prepared by a conventional method.
  • Example 19 A compound of formula I is used to prepare a powder for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected Eight
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a powder injection is prepared by a conventional method.
  • O CN Example 20 A compound of formula I is used to prepare a suppository for the treatment and/or prevention of diabetes and/or diabetes complications.
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected
  • a 3H-1,2-dithiocyclopentene-3-thione compound is added to a conventional excipient, and a suppository is prepared by a conventional method.
  • EXAMPLE 21 Compounds of formula I are useful in the preparation of inhalants for the treatment and/or prevention of diabetes and/or diabetes complications
  • the compound of formula I is a 3H-1,2-dithiocyclopentene-3-thione compound, wherein R is selected Eight

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Abstract

La présente invention concerne le domaine des médicaments, et plus particulièrement, un activateur d'AMPK et une application de celui-ci dans la préparation de médicaments pour le traitement et/ou la prévention du diabète et/ou de complications du diabète. La présente invention concerne une application d'un composé pentène-3-thione 3H-1,2-disulfohétérocyclique ayant la structure de la formule (I) comme activateur d'AMPK, et une application du composé pentène-3-thione 3H-1,2-disulfohétérocyclique dans la préparation de médicaments pour le traitement et/ou la prévention du diabète et/ou de complications du diabète. Ces composés ne contenant pas de groupe biguanide, pendant l'utilisation du composé comme activateur d'AMPK, le composé ne provoque pas d'acidose lactique, et les médicaments préparés pour le traitement et/ou la prévention du diabète et/ou de complications du diabète sont plus sûrs.
PCT/CN2013/070166 2012-12-05 2013-01-07 Activateur d'ampk et son application dans la préparation de médicaments pour le traitement du diabète et/ou de complications du diabète WO2014086104A1 (fr)

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Cited By (4)

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FR3063641A1 (fr) * 2017-03-07 2018-09-14 Olivier Petitjean Prevention des lesions cutanees dues aux uv et des melanomes a l'aide d'un inhibiteur selectif de la production d'especes reactives de l'oxygene d'origine mitochondriale
FR3063644A1 (fr) * 2017-03-07 2018-09-14 Gregoire Petitjean Prevention des effets adverses des statines a l'aide d'un inhibiteur specifique de la production de ros d'origine mitochondriale
WO2020244454A1 (fr) 2019-06-06 2020-12-10 中国药科大学 Utilisation médicale d'un composé de saponine triterpénoïde pentacyclique et composition pharmaceutique associée
RU2775597C2 (ru) * 2015-09-08 2022-07-05 Оп2 Дрэгс Ингибитор продукции реактивных форм кислорода для лечения заболеваний, связанных со свободными радикалами кислорода

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017042267A1 (fr) * 2015-09-08 2017-03-16 Orphan Partners 2 Composés pour le traitement de maladies liées à la production de formes réactives de l'oxygène (fro) mitochondriales
WO2018162581A1 (fr) * 2017-03-07 2018-09-13 OP2 Drugs Dérivés desméthylanethole trithione pour le traitement de maladies liées à la production de formes réactives de l'oxygène (fro) d'origine mitochondriale
CN110662535A (zh) 2017-03-07 2020-01-07 Op2药品公司 用于治疗与线粒体活性氧(ros)产生相关的疾病的去甲基茴三硫衍生物
CN108398549A (zh) * 2018-02-24 2018-08-14 苏州大学 获得具有线粒体解偶联作用的药物的方法
CN110339200A (zh) * 2019-08-23 2019-10-18 成都贝诺科成生物科技有限公司 一种茴三硫衍生物的应用
CN113101295A (zh) * 2020-03-20 2021-07-13 上海疆云医疗健康科技有限公司 二苯乙烯类似物在治疗糖尿病肾脏疾病中的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066894A1 (fr) * 2004-12-24 2006-06-29 Ctg Pharma S.R.L. Composes destines au traitement d'un syndrome metabolique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1244325C (zh) * 2001-05-11 2006-03-08 成都国嘉联合制药有限公司 胆维他在制药中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066894A1 (fr) * 2004-12-24 2006-06-29 Ctg Pharma S.R.L. Composes destines au traitement d'un syndrome metabolique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GE, BIN ET AL.: "AMPK acts as a new target for the treatment of type 2 diabetes", CHINESE PHARMACOLOGICAL BULLETIN, vol. 24, no. 5, 31 May 2008 (2008-05-31), pages 580 - 583 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2775597C2 (ru) * 2015-09-08 2022-07-05 Оп2 Дрэгс Ингибитор продукции реактивных форм кислорода для лечения заболеваний, связанных со свободными радикалами кислорода
FR3063641A1 (fr) * 2017-03-07 2018-09-14 Olivier Petitjean Prevention des lesions cutanees dues aux uv et des melanomes a l'aide d'un inhibiteur selectif de la production d'especes reactives de l'oxygene d'origine mitochondriale
FR3063644A1 (fr) * 2017-03-07 2018-09-14 Gregoire Petitjean Prevention des effets adverses des statines a l'aide d'un inhibiteur specifique de la production de ros d'origine mitochondriale
WO2020244454A1 (fr) 2019-06-06 2020-12-10 中国药科大学 Utilisation médicale d'un composé de saponine triterpénoïde pentacyclique et composition pharmaceutique associée

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