WO2021012694A1 - Malate d'éthyle méthyle hydroxypyridine ou composition pharmaceutique de celui-ci, et utilisation dans la prévention et/ou le traitement du diabète de type ii - Google Patents

Malate d'éthyle méthyle hydroxypyridine ou composition pharmaceutique de celui-ci, et utilisation dans la prévention et/ou le traitement du diabète de type ii Download PDF

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Publication number
WO2021012694A1
WO2021012694A1 PCT/CN2020/080782 CN2020080782W WO2021012694A1 WO 2021012694 A1 WO2021012694 A1 WO 2021012694A1 CN 2020080782 W CN2020080782 W CN 2020080782W WO 2021012694 A1 WO2021012694 A1 WO 2021012694A1
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WO
WIPO (PCT)
Prior art keywords
malate
ethyl methyl
pharmaceutical composition
diabetes
compound
Prior art date
Application number
PCT/CN2020/080782
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English (en)
Chinese (zh)
Inventor
基谢列娃·阿娜丝塔熙娅
萨玛莉娜·娜达莉娅
卡林琴科·斯维特兰娜
沃尔斯洛夫·列昂尼德
Original Assignee
北京克诺腾达贸易有限公司
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Publication of WO2021012694A1 publication Critical patent/WO2021012694A1/fr

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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
    • A61K31/435—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
    • 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
    • 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

Definitions

  • the invention belongs to the field of pharmacology and medicine, and can also be applied to the field of endocrinology.
  • the present invention relates to the use of ethyl methyl hydroxypyridine malate or a pharmaceutical composition containing the compound and pharmaceutically acceptable excipients in the preparation of medicines for the prevention and/or treatment of disorders related to insulin resistance Diseases caused by or diseases caused by damage to pancreatic ⁇ cells, used to treat and/or prevent type 2 diabetes, to protect pancreatic ⁇ cells and reduce insulin resistance, to promote the secretory function of pancreatic ⁇ cells, and to regulate oxidation Stress reduces the risk of complications of type 2 diabetes.
  • Type II diabetes is mainly caused by the following: insulin resistance, relative lack of insulin, lack of insulin secretion function in the body or weak carbohydrate metabolism caused by this function. Therefore, type II diabetes is a heterogeneous carbohydrate metabolism disorder. This largely explains the lack of accepted theories about the etiology and pathogenesis of the disease. However, it is certain that there are two major defects in patients with type II diabetes: insulin resistance and impaired ⁇ -cell function. In most patients with type II diabetes, the decreased sensitivity of tissues to insulin is a primary (genetic) defect. If ⁇ cells cannot maintain high enough insulin secretion levels to inhibit insulin resistance, high blood sugar will be triggered.
  • insulin resistance refers to a decrease in the biological response of one or more actions of insulin.
  • the current understanding of insulin resistance is not limited to carbohydrate metabolism, but also includes changes in fat metabolism, protein metabolism, endothelial cell function and gene expression.
  • patients with dyslipidemia, hyperuricemia, and hypertension often develop insulin resistance.
  • the incidence of insulin resistance is also high, exceeding 25%, and its severity is comparable to that of type II diabetes patients.
  • Oxidative stress Another important change caused by oxidative stress is the decline in antioxidant defense capabilities. All tissues can form active oxygen, which contains a certain amount of enzymes and antioxidants to inactivate it.
  • antioxidants should be included in the treatment of diabetes complications.
  • the antioxidant mixture is used as the active ingredient, which includes ⁇ -sulfur Caprylic acid, N-acetyl-cysteine, ubiquinone, selenium, alpha-tocopherol or tocotrienol, L-arginine and tetrahydrobiopterin (US 2003077335 A1, published on 2003.04.24).
  • Each dose of the drug contains 50-120 mg of coenzyme Q10, 30-160 mg of dihydronaphthalene and 30-60 mg of alpha lipoic acid or 50-100 mg of coenzyme Q10 and 50-100 mg of dihydronaphthalene. 30-60 mg alpha-lipoic acid and 50-100 mg nicotinamide (RU 2535069 C2, published on 2014.12.10).
  • Mexiden (2-ethyl-6-methyl-3-hydroxypyridine succinic acid) as an insulin resistance corrector can be used as a similar drug with the closest function. Mexiden can improve the efficacy of hypoglycemic and hypolipidemic drugs because it has a direct effect on carbohydrate-lipid metabolism (RU 2158590 C1, published on 10.11.2000). Lipid metabolism disorders are the main cause of insulin resistance. Mexidola can correct lipid metabolism disorders, which is the premise and basis of its application.
  • mesidex can stimulate the direct oxidation of glucose in the pentose phosphate pathway, stabilize the glutathione-glutathione reductase system, and activate the endoplasmic reticulum
  • the metabolic process promotes the normalization of the metabolic levels of fatty acids, phospholipids and prostaglandins.
  • the purpose of the present invention is to find new drugs for treating type II diabetes and reducing insulin resistance.
  • This task is to use the known drug ethyl methyl hydroxypyridine malate for a new purpose, namely to reduce insulin resistance.
  • Ethyl methyl hydroxypyridine malate (ethyl methyl hydroxypyridine malate, 2-ethyl-6-methyl-3-hydroxypyridine hydroxysuccinic acid, Aethylmethylhydroxypyridini malatis) is an antioxidant and free radical Inhibitors have the effects of protecting the diaphragm, improving hypoxia, improving the mind, antispasmodic and anti-anxiety, and can enhance the body's anti-stress ability.
  • the compound has been found to be useful in the treatment of the following diseases: acute peritonitis, sympathetic nerve disease, endogenous poisoning and other endogenous poisoning, as well as many diseases such as ischemia and necrosis in the context of diabetes and oxidative stress. .
  • ethyl methyl hydroxypyridine malate or a pharmaceutical composition comprising the compound and pharmaceutically acceptable excipients in the preparation of a medicine, wherein the medicine is used for prevention and/ Or to treat diseases caused by disorders related to insulin resistance or diseases caused by impaired pancreatic ⁇ -cell function.
  • the medicament is used to treat and/or prevent type 2 diabetes.
  • the drug is used to protect pancreatic beta cells and reduce insulin resistance.
  • the drug is used to promote the secretory function of pancreatic beta cells, regulate oxidative stress, and reduce the risk of complications of type 2 diabetes.
  • ethyl methyl hydroxypyridine malate or a pharmaceutical composition containing the compound and pharmaceutically acceptable excipients for the prevention and/or treatment of disorders caused by insulin resistance related disorders The disease or disease caused by damage to the pancreatic beta cells.
  • the ethyl methyl hydroxypyridine malate or a pharmaceutical composition comprising the compound and pharmaceutically acceptable excipients is used to treat and/or prevent type 2 diabetes.
  • the ethyl methyl pyridine malate or a pharmaceutical composition comprising the compound and pharmaceutically acceptable excipients is used to protect pancreatic ⁇ cells and reduce insulin resistance.
  • the ethyl methyl hydroxypyridine malate or a pharmaceutical composition containing the compound and pharmaceutically acceptable excipients is used to promote the secretory function of pancreatic ⁇ cells, regulate oxidative stress, and reduce II Risk of complications from type diabetes.
  • a method for preventing and/or treating a disease caused by a disorder related to insulin resistance in a patient or a disease caused by damage to pancreatic ⁇ -cells is provided by administering ethyl methyl Hydroxypyridine malate or a pharmaceutical composition comprising the compound and pharmaceutically acceptable excipients.
  • a method for preventing and/or treating type 2 diabetes in a patient is provided by administering ethyl methyl hydroxypyridine malate or a drug containing the compound and pharmaceutically acceptable excipients to the patient combination.
  • the methods described above are used to protect pancreatic ⁇ cells and reduce insulin resistance.
  • the above method is used to promote the secretory function of pancreatic beta cells, regulate oxidative stress, and reduce the risk of complications of type 2 diabetes.
  • the daily dose of the ethyl methyl hydroxypyridine malate or the pharmaceutical composition containing the compound and pharmaceutically acceptable excipients to the subject is about 50 mg to 500 mg Ethyl methyl hydroxypyridine malate; preferably, the daily dose is about 100 mg.
  • the ethyl methyl hydroxypyridine malate or a pharmaceutical composition comprising the compound and pharmaceutically acceptable excipients is administered orally or intravenously; preferably, administered by intravenous injection.
  • insulin resistance refers to the decrease in the efficiency of insulin in promoting glucose uptake and utilization. Therefore, in order to maintain the stability of blood sugar, the body compensatively secretes excessive insulin, leading to hyperinsulinemia. Insulin resistance easily leads to metabolic syndrome and type 2 diabetes.
  • pancreatic ⁇ -cell refers to ⁇ -cells that produce insulin, which play a core regulatory role in glucose homeostasis.
  • pancreatic beta cells may eventually lead to type I and/or type II diabetes.
  • HbA1c glycosylated hemoglobin, which is a product of the combination of hemoglobin in red blood cells and sugars in serum. Its content depends on the blood glucose concentration and the contact time between blood glucose and hemoglobin, and can be used as a monitoring indicator for diabetes control.
  • HOMA also known as the HOMA steady-state model (Homeostasis model assessment)
  • HOMA steady-state model Homeostasis model assessment
  • the present invention confirms the new characteristics of ethyl methyl hydroxypyridine malate through experimental results, which can protect pancreatic ⁇ cells and reduce insulin resistance. This property makes it useful for the treatment of type II diabetes and related diseases.
  • the use of malate can produce curative effects and prolong the action time.
  • pancreatic ⁇ cell protective agent of the present invention can not only correct insulin resistance, thereby improving the treatment efficiency of type II diabetes patients, but also prevent its development.
  • the present invention has proved the feasibility of the new prescription through related pharmacological tests.
  • the material for this study is venous blood.
  • the serum insulin content was determined by enzyme-linked immunosorbent assay (Accubind, USA).
  • the glucose concentration was determined by the glucose oxidase method.
  • the degree of insulin resistance is measured by calculating the HOMA index (Homeostasis modelassessment):
  • HOMA-IR is an index used to evaluate the individual's insulin resistance level. The calculation method is as follows: fasting blood glucose level (FPG, mmol/L) ⁇ fasting insulin level (FINS, ⁇ U/mL)/22.5.
  • the HOMA-IR index of normal individuals is 1. As the level of insulin resistance increases, the HOMA-IR index will be higher than 1.
  • the content of glycosylated hemoglobin (HbA1c) in blood was determined by immunoturbidimetric method (Diasys, Germany).
  • the patients numbered 23 and 24 were injected with ethyl methyl hydroxy pyridine malate for 10 days, and then continued to inject ethyl methyl hydroxy pyridine malate until three months, the glycosylated hemoglobin level decreased and recovered normal.
  • ethyl methyl pyridine malate has a positive effect on the secretory function of pancreatic ⁇ cells, and can regulate oxidative stress and reduce the risk of diabetes complications.

Abstract

L'invention concerne l'utilisation d'un malate d'éthyle méthyle hydroxypyridine ou d'une composition pharmaceutique contenant ledit composé et un excipient pharmaceutiquement acceptable dans la préparation d'un médicament, ledit médicament étant utilisé pour prévenir et/ou traiter une maladie provoquée par un trouble lié à la résistance à l'insuline ou à une maladie provoquée par une lésion des cellules beta du pancréas, utilisé pour traiter et/ou prévenir le diabète de type II, utilisé pour protéger les cellules bêta du pancréas et réduire la résistance à l'insuline, et utilisé pour favoriser la fonction de sécrétion de cellules bêta pancréatiques, réguler le stress oxydatif, et réduire le risque d'apparition de diabète de type II et des maladies liées à ce dernier.
PCT/CN2020/080782 2020-03-13 2020-03-24 Malate d'éthyle méthyle hydroxypyridine ou composition pharmaceutique de celui-ci, et utilisation dans la prévention et/ou le traitement du diabète de type ii WO2021012694A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010173151.2 2020-03-13
CN202010173151.2A CN111228263A (zh) 2020-03-13 2020-03-13 乙基甲基羟基吡啶苹果酸盐或其药物组合物，预防和/或治疗ⅱ型糖尿病的用途

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WO2021012694A1 true WO2021012694A1 (fr) 2021-01-28

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CN (1) CN111228263A (fr)
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2158590C1 (ru) * 1999-11-10 2000-11-10 Российская медицинская академия последипломного образования Средство для коррекции инсулиновой резистентности
RU2377237C1 (ru) * 2008-04-10 2009-12-27 Закрытое акционерное общество "Медимэкс" (ЗАО "Медимэкс") 2-этил-6-метил-3-гидроксипиридинийгидроксибутандиоат, обладающий противоишемической, церебропротекторной, нейротропной и липидрегулируемой активностями, фармацевтические композиции и лекарственное средство

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2158590C1 (ru) * 1999-11-10 2000-11-10 Российская медицинская академия последипломного образования Средство для коррекции инсулиновой резистентности
RU2377237C1 (ru) * 2008-04-10 2009-12-27 Закрытое акционерное общество "Медимэкс" (ЗАО "Медимэкс") 2-этил-6-метил-3-гидроксипиридинийгидроксибутандиоат, обладающий противоишемической, церебропротекторной, нейротропной и липидрегулируемой активностями, фармацевтические композиции и лекарственное средство

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