WO2021057680A1 - Application of 2,4-dihydroxybenzoic acid or isomer thereof in related diseases or conditions caused by iron overload - Google Patents

Application of 2,4-dihydroxybenzoic acid or isomer thereof in related diseases or conditions caused by iron overload Download PDF

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WO2021057680A1
WO2021057680A1 PCT/CN2020/116613 CN2020116613W WO2021057680A1 WO 2021057680 A1 WO2021057680 A1 WO 2021057680A1 CN 2020116613 W CN2020116613 W CN 2020116613W WO 2021057680 A1 WO2021057680 A1 WO 2021057680A1
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dihydroxybenzoic acid
iron
isomer
reduce
isomers
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张建国
任武贤
韩应兵
堐榜琴
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张建国
亚宝药业集团股份有限公司
任武贤
韩应兵
堐榜琴
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Definitions

  • the invention belongs to the field of iron-lowering drugs, and specifically relates to the application of 2,4-dihydroxybenzoic acid or its isomers in related diseases or conditions caused by iron overload.
  • Iron overload is a common phenomenon, which is determined by the way iron is metabolized. Iron has no obvious excretion mechanism in the human body, and it can be used repeatedly. It is mainly controlled by the absorption of intestinal mucosal epithelial cells to control the total amount of iron. Under normal circumstances, as we age, there will be more and more iron in the cells. Absolute iron deficiency is very rare in clinical practice, and it only occurs under conditions such as gastrointestinal resection, chronic bleeding, hemolysis, and pregnancy. Patients with general anemia also have iron overload, which is mainly due to a problem with the conversion mechanism of iron storage. The iron in hemoglobin and some functional enzymes is divalent iron, while the iron stored and transported is all trivalent iron. Therefore, iron overload is mainly for ferric iron.
  • trivalent iron overload will directly react with macromolecular compounds to form insoluble particles and cause iron deposition.
  • liver cirrhosis, pulmonary fibrosis, heart disease, etc. these are the serious consequences of trivalent iron deposition;
  • trivalent iron Iron overload directly induces the production of free radicals, which triggers lipid peroxidation and severely damages cell functions.
  • drugs used in clinical treatment of iron overload there are very few drugs used in clinical treatment of iron overload, and there are only three kinds of drugs: deferoxamine, deferiprone and snow deferox tablets. However, these three drugs can not enter the cell, but mainly decomplex and replace the ferric iron in the serum ferritin.
  • Insulin resistance in diabetic patients has been clearly known to be related to iron overload, but there is no iron remover available clinically. It can be seen that the treatment of diabetes and other related diseases by lowering iron is still a blank field in clinical practice.
  • iron overload is equivalent to "iron storage excess”.
  • concentration of ferritin in cells cannot be determined at present, but ferritin in blood is released by cells of various tissues, which is a collection of ferritin released by cells of various tissues. Therefore, under normal circumstances, the level of serum ferritin concentration can basically reflect the iron storage in the body.
  • iron ferritin as the main indicator to measure iron overload and at the same time as the only target to reduce iron overload.
  • concentration of ferritin in the blood When the concentration of ferritin in the blood is reduced, the cells will naturally re-release, thereby achieving the purpose of reducing the concentration of ferritin in the cells. This makes the dosage of the drug very large.
  • the iron complexing agent is more than 6g per day, and the time required is very long, generally more than one year; the second is that the ability of the drug to complex iron must be stronger than that of ferritin, only Only in this way can the iron in ferritin be removed. In this way, the complex iron in some major enzymes has also been removed, which will bring great side effects. It is precisely within the framework of this inertial thinking that there is no major breakthrough in the research and development of iron removal drugs.
  • the related diseases induced by iron overload are mainly free iron ions playing a leading role.
  • the trivalent iron in ferritin is inactive and will not induce free radical reactions.
  • the average load of human plasma ferritin is only 20%-30% of its capacity, so the free iron salt in the plasma is actually zero.
  • Ferritin is actually an antioxidant, and its presence inhibits the existence of free iron ions. Therefore, a high concentration of serum ferritin can only represent iron overload and will not cause damage to cells, but can cause damage to cells and trigger The disease can only be free iron ions. From this point of view, reducing the concentration of free iron ions by reducing the concentration of serum ferritin is a big circle, and even a very wasteful practice.
  • This part of iron plays a vital role in cell growth, development and metabolism. At the same time, this part of iron is also most closely related to diseases, or it is the main reason for the decline of cell function.
  • the treatment of diseases by removing iron is mainly to remove this part of iron.
  • the presence of this complexed iron has been identified in the synovial fluid of rheumatoid arthritis, which may be the main reason why the disease is difficult to cure.
  • Non-protein complexed iron also has a very important role. It can complex with iron regulatory protein to make its activation and conformation change, and finally induce the expression of ferritin and transferrin genes. In turn, ferritin can further compete for non-ferritin. The protein complexes the trivalent iron in the iron to further reduce its concentration. Therefore, there is a balance between ferritin and non-protein complexed iron, and it is this balance that maintains the normal function of cells. By reducing the concentration of serum ferritin, the goal of reducing non-protein complexed iron can eventually be achieved, but this method is far faster and easier than entering the cell to directly complex this part of iron. Aspirin can specifically induce the expression of ferritin gene and has time and dose effects.
  • aspirin has the effect of removing non-protein complexed iron and can be used for the treatment of cardiovascular and cerebrovascular diseases.
  • its iron removal method is indirect, it promotes the binding of free iron to regulatory proteins, so its effect is very limited, and it is only suitable for the elderly with high free iron.
  • With the increase of age there are more and more insoluble macromolecular compounds in the cytoplasm, and the fluidity of non-protein complexed iron is getting worse and worse.
  • a higher concentration of non-protein complex is required Combine iron to stimulate. Therefore, the more aging cells are, the higher the concentration of non-protein complexed iron, which is not based on people's will, but is also the essence of aging.
  • the present invention provides the application of 2,4-dihydroxybenzoic acid or its isomers in foods, health products or medicines for treating or preventing diseases or conditions related to iron overload.
  • the present invention also provides the application of 2,4-dihydroxybenzoic acid or its isomers in the preparation of foods, health products or medicines for treating or preventing diseases or conditions related to iron overload.
  • the present invention also provides a method for treating or preventing diseases or conditions related to iron overload, which comprises administering 2,4-dihydroxybenzoic acid or an isomer thereof to a patient in need.
  • the patient is preferably a mammal, more preferably a human, such as an adult or a minor.
  • the total dose of 2,4-dihydroxybenzoic acid and/or its isomers can be 0.5-3 g per day, for example, it can be divided into three doses per day.
  • the dose administered to them can be reduced based on their body weight.
  • the disease or condition includes one or more selected from the group consisting of diabetes, hypertension, hyperlipidemia, liver cirrhosis, pulmonary fibrosis, hyperuric acid, gout, rheumatoid arthritis, Heart disease, vascular sclerosis, cerebral infarction, senile dementia, tumor, hepatitis B virus, depression, aging, blood disease, etc.
  • the present invention also provides a food, health care product or pharmaceutical composition comprising at least one selected from 2,4-dihydroxybenzoic acid or its isomers, wherein the composition can be used for treatment or prevention
  • a food, health care product or pharmaceutical composition comprising at least one selected from 2,4-dihydroxybenzoic acid or its isomers, wherein the composition can be used for treatment or prevention
  • One or more of the following diseases or conditions : diabetes, hypertension, hyperlipidemia, liver cirrhosis, pulmonary fibrosis, hyperuric acid, gout, rheumatoid arthritis, heart disease, vascular sclerosis, cerebral infarction, old age Dementia, tumors, hepatitis B virus, depression, aging, blood diseases, etc.
  • the disease or condition may be the above-mentioned disease or condition related to iron overload, for example, the above-mentioned related disease or condition caused by iron overload.
  • the composition may be in the form of a preparation, for example, one selected from oral agents, injections or other dosage forms.
  • the disease or condition is diabetes.
  • the isomer of 2,4-dihydroxybenzoic acid is preferably a positional isomer of 2,4-dihydroxybenzoic acid, for example selected from 2,3-dihydroxybenzoic acid , 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid.
  • the 2,4-dihydroxybenzoic acid, its isomers or a combination thereof are used to reduce the ferric iron in the non-protein complexed iron in the cell.
  • the 2,4-dihydroxybenzoic acid, its isomers or a combination thereof are used to reduce free iron in cells.
  • the 2,4-dihydroxybenzoic acid, its isomers or a combination thereof are used to reduce the concentration of serum ferritin.
  • the main function of 2,4-dihydroxybenzoic acid and its isomers is to reduce intracellular non-protein complexed iron.
  • it is not possible to directly measure the non-protein complexed iron in cells, but it has a linear relationship with serum ferritin, which can be expressed indirectly by the level of serum ferritin. Therefore, in the absence of infection, inflammation, and alcohol abuse, by measuring the serum ferritin value, the changes in the intracellular non-protein complexed iron can be accurately determined.
  • the serum ferritin concentration is reduced, which can treat one or more of the following diseases or conditions formed by the intracellular non-protein complexed iron overload: diabetes, high Blood pressure, hyperlipidemia, liver cirrhosis, pulmonary fibrosis, hyperuric acid, gout, rheumatoid arthritis, heart disease, vascular sclerosis, cerebral infarction, senile dementia, tumor, hepatitis B virus, depression, aging, blood disease, etc.
  • the raw materials of the 2,4-dihydroxybenzoic acid and its isomers are derived from food additives, spices and medical raw materials, and are safe and non-toxic and side effects.
  • the inventors refined the conditions for removing iron into three conditions, that is, not only can it enter the cell, but its ability to complex iron is smaller than that of "ferritin", and at the same time, its ability to complex iron is better than that of cells.
  • the inner "non-protein complexed iron” is large. Only by meeting these three conditions can the goal of iron removal be achieved quickly, accurately and with little side effects.
  • Treatment of iron overload is essentially to enter the cell to reduce the trivalent iron in the "non-protein complexed iron", and then achieve the purpose of reducing the "intracellular free iron".
  • the invention has a reasonable design, and directly takes 2,4-dihydroxybenzoic acid and its isomers to achieve the purpose of directly reducing the "free iron" in the non-protein complexed iron in the cell, thereby quickly removing the excess iron in the body. So as to achieve the purpose of treating or preventing iron overload-related diseases or conditions (especially diabetes).
  • Figure 1 shows a schematic diagram of the control of fasting blood glucose (mmol/L) in a mouse experiment.
  • Figure 2 shows a schematic diagram of the control of serum ferritin value (ng/mL) in a mouse experiment.
  • Figure 3 shows a schematic diagram of the control of HBA1C [glycated hemoglobin value (mg/DL)] in a mouse experiment.
  • Iron overload will cause insulin resistance; 2. Iron overload will reduce the function of pancreatic ⁇ -cells and reduce insulin secretion.
  • the nature of insulin resistance has not yet been elucidated. Therefore, eliminating insulin resistance is only a clinical concept.
  • the mechanism of insulin's hypoglycemic effect is as follows: First, it binds to cell membrane receptors, and then transfers glucose from outside the cell to the cell under the action of glucose tolerance factors, which is the core function of insulin. In this process, the glucose tolerance factor plays a vital role, and the active center of the substance is the trivalent chromium ion. It has been proved that trivalent chromium ions in the blood of diabetic patients are always reduced, and people use a variety of methods to supplement chromium, but they have little clinical effect. The original trivalent chromium ions and trivalent iron ions use the same transport protein in the blood, that is, transferrin.
  • the saturation of transferrin does not exceed 35%.
  • the saturation of transferrin is Increase, or even exceed 50%, so that the transport of trivalent chromium ions will encounter difficulties, which will affect the quantum tolerance activity of glucose.
  • the iron overload problem is not solved, no more trivalent chromium will help, because difficulty in operation will affect the absorption of chromium ions, which is the essential cause of insulin resistance.
  • the clinical trials are as follows:
  • the inventor of the present application first selected a number of diabetic patients whose blood glucose level was still high after insulin injection, and then tested the serum ferritin value, and selected 10 patients whose serum ferritin exceeded the standard. By taking 2,4-Dihydroxybenzoic acid capsules (food grade), 3 times a day, 2 capsules each time (0.5g/capsule). Three months later, the serum ferritin, glycosylated hemoglobin and blood glucose levels were tested for comparison (see Table 1).
  • the normal value of serum ferritin for men is 15 to 130 ng/ml; the normal value for women is 15 to 80 ng/ml.
  • the inventor of the present application selected 10 diabetic patients with a medical history of less than two years, no signs of complications, and milder illnesses, by taking 2,4-dihydroxybenzoic acid capsules (food grade), 3 times a day, 2 capsules each time (0.5g/grain). After taking it for 3 months, other hypoglycemic drugs were completely stopped, and blood glucose levels were tested and compared. The results are shown in Table 2 (only 7 patients took it for 3 months as required).
  • This compound can quickly reduce serum ferritin and solve the problem of iron overload
  • the compound has the effects of lowering blood sugar and stabilizing blood sugar
  • the animal tests are as follows:
  • mice The inventor of this application entrusted Shanxi Medical University to do a hypoglycemic experiment on 2,4-dihydroxybenzoic acid in mice (diabetic model mice):
  • Diabetes model mice 10 db/db mice;
  • High-dose group 10 db/db mice, 125mg/kg/time.
  • Gavage 2 times a day, at 9 am and 4 pm each day.
  • the actual dosage is administered according to the actual body weight of each group of mice during the week, and adjusted once a week.
  • mice and 30 db/db diabetic mice arrived in the laboratory.
  • the preliminary examination of animal vital signs was normal, which met the requirements of the experiment.
  • the animals are kept in the SPF Laboratory Animal Center of Shanxi Medical University.
  • the experiment started after one week of adaptive feeding.
  • the basic indicators of each group of animals were determined, and the administration intervention was started on June 16.
  • the high-dose group was almost the same as the control group, or even lower than the control group, and the low-dose group was between the model group and the control group. It can be seen that as the dose of 2,4-dihydroxybenzoic acid is higher, the hypoglycemic effect is better and closer to the normal value.
  • the high-dose group first increased and then decreased, and finally was significantly lower than the control group, while the low-dose group was basically the same as the control group.
  • the high-dose group was significantly lower than the low-dose group, almost the same as the control group, and the stability was good.
  • the compound has the function of reducing serum ferritin, and there is a dose effect.
  • the compound has the effect of lowering fasting blood sugar and post-meal blood sugar, and at the same time has the effect of stabilizing glycosylated hemoglobin.
  • mice had no abnormal reaction, and there was no toxic or side effect in the dose.

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Abstract

Disclosed is an application of 2,4-dihydroxybenzoic acid or an isomer thereof in foods, health products or medicines for treating or preventing related diseases or conditions caused by iron overload. The isomer of the 2,4-dihydroxybenzoic acid is selected from 2,3-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid. The design is reasonable, and direct administration of the 2,4-dihydroxybenzoic acid and isomer thereof is employed to achieve the aim of directly reducing the "iron ions" in the non-protein complexed iron in cells, so as to quickly remove excess iron from the body to achieve the purpose of treating various related diseases (especially diabetes) caused by iron overload.

Description

2,4-二羟基苯甲酸或其同分异构体在铁过载引发相关疾病或状况中的应用Application of 2,4-dihydroxybenzoic acid or its isomers in related diseases or conditions caused by iron overload
本申请要求2019年9月23日向中国国家知识产权局提交的，专利申请号为201910899911.5，发明名称为“2,4-二羟基苯甲酸在治疗铁过载引发相关疾病的食品药品中的应用”在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。This application requires that it be filed with the State Intellectual Property Office of China on September 23, 2019. The patent application number is 201910899911.5, and the title of the invention is "The application of 2,4-dihydroxybenzoic acid in the treatment of food and drug related diseases caused by iron overload." Priority to apply first. The full text of this application is incorporated into this application by reference.
技术领域Technical field
本发明属于降铁药物领域，具体涉及2,4-二羟基苯甲酸或其同分异构体在铁过载引发相关疾病或状况中的应用。The invention belongs to the field of iron-lowering drugs, and specifically relates to the application of 2,4-dihydroxybenzoic acid or its isomers in related diseases or conditions caused by iron overload.
背景技术Background technique
越来越多的研究结果表明，一些重大疾病与细胞内铁过载相关，如：糖尿病、高血压、高血脂、肝硬化、高尿酸、痛风病、肺纤维化、类风湿性关节炎、心脏病、血管硬化、脑梗、老年性痴呆、肿瘤、乙肝病毒、肌肉萎缩、衰老、抑郁症、血液病等。有专家指出：人类60％常见疾病与铁过载相关，更有研究者预言：如果能解决细胞内铁过载问题，人类寿命可延长10～15年。More and more research results show that some major diseases are related to intracellular iron overload, such as: diabetes, hypertension, hyperlipidemia, cirrhosis, hyperuricemia, gout, pulmonary fibrosis, rheumatoid arthritis, heart disease , Vascular sclerosis, cerebral infarction, senile dementia, tumor, hepatitis B virus, muscle atrophy, aging, depression, blood disease, etc. Some experts pointed out that 60% of common human diseases are related to iron overload, and some researchers predict that if the problem of iron overload in cells can be solved, human life span can be extended by 10 to 15 years.
铁过载是一种普遍现象，这是由铁的代谢方式所决定的。铁在人体内没有明显的排出机制，而且可以反复利用，其主要是通过肠粘膜上皮细胞控制吸收来控制铁的总量。正常情况下，随着年龄的增长，细胞内的铁会越来越多。临床上绝对性缺铁非常罕见，只有在胃肠道切除、慢性出血、溶血、妊娠等情况下才会发生。一般性贫血患者同时存在铁过载，这主要是贮存铁的转换机制出了问题。血红蛋白和一些功能性酶中的铁都是二价铁，而贮存和转运的铁全是三价铁。因此，铁过载主要是针对三价铁而言。一方面三价铁过载会直接与大分子化合物反应，形成不溶性颗粒，造成铁沉积，如在肝硬化、肺纤维化、心 脏病等都是三价铁沉积造成的严重后果；另一方面三价铁过载会直接诱发自由基产生，由此引发脂质过氧化反应，严重破坏细胞功能。目前在临床上应用于治疗铁过载的药物甚少，仅有去铁胺、去铁酮和斯诺去铁片三种。然而这三种药物都不能进入到细胞内，而主要是去络合置换血清铁蛋白中的三价铁。因此，这三种药都具有用量大、时间长、副作用大的缺点，因此还不能作为治疗细胞内铁过载的一般性药物。目前临床上仅将上述药物用于治疗地中海贫血症患者因输血过多而造成的铁过载。Iron overload is a common phenomenon, which is determined by the way iron is metabolized. Iron has no obvious excretion mechanism in the human body, and it can be used repeatedly. It is mainly controlled by the absorption of intestinal mucosal epithelial cells to control the total amount of iron. Under normal circumstances, as we age, there will be more and more iron in the cells. Absolute iron deficiency is very rare in clinical practice, and it only occurs under conditions such as gastrointestinal resection, chronic bleeding, hemolysis, and pregnancy. Patients with general anemia also have iron overload, which is mainly due to a problem with the conversion mechanism of iron storage. The iron in hemoglobin and some functional enzymes is divalent iron, while the iron stored and transported is all trivalent iron. Therefore, iron overload is mainly for ferric iron. On the one hand, trivalent iron overload will directly react with macromolecular compounds to form insoluble particles and cause iron deposition. For example, in liver cirrhosis, pulmonary fibrosis, heart disease, etc., these are the serious consequences of trivalent iron deposition; on the other hand, trivalent iron Iron overload directly induces the production of free radicals, which triggers lipid peroxidation and severely damages cell functions. At present, there are very few drugs used in clinical treatment of iron overload, and there are only three kinds of drugs: deferoxamine, deferiprone and snow deferox tablets. However, these three drugs can not enter the cell, but mainly decomplex and replace the ferric iron in the serum ferritin. Therefore, these three drugs all have the disadvantages of large dosage, long time, and large side effects, so they cannot be used as general drugs for the treatment of intracellular iron overload. At present, only the above-mentioned drugs are clinically used to treat iron overload caused by excessive blood transfusion in patients with thalassemia.
糖尿病患者的胰岛素抵抗已明确知道与铁过载相关，但在临床上却无除铁药可用。由此可见，通过降铁来治疗糖尿病等相关疾病，目前在临床上还属于空白领域。Insulin resistance in diabetic patients has been clearly known to be related to iron overload, but there is no iron remover available clinically. It can be seen that the treatment of diabetes and other related diseases by lowering iron is still a blank field in clinical practice.
为什么至今在临床上还不能通过降铁而治疗相关疾病呢？实际情况是无药可用。之所以科学家们长时间没有研发出降铁药，是因为人们对铁过载的认识存在误区：自从发现了铁蛋白之后，人们更多的是将它视为体内最重要的铁的贮存形式，将“铁过载”与“铁贮存过剩”等同起来。细胞内的铁蛋白浓度目前还无法测定，但血液中的铁蛋白是各组织细胞释放的，它是各组织细胞释放铁蛋白的集合。因此，在正常情况下血清铁蛋白浓度的高低，基本可以反映体内铁的贮存情况。正是基于这样的认识，人们将“血清铁蛋白”作为衡量铁过载的主要指标，同时也将其作为降低铁过载的唯一靶点。这就带来了两个问题：一是限定了除铁的场所只能是在血液中，血液中的铁蛋白浓度降低了，细胞会自然进行再释放，由此达到降低细胞中铁蛋白浓度的目的，这就使得用药量非常大，每天输铁络合剂在6g以上，需要的时间非常长，一般需在一年以上；二是限定了药物络合铁的能力一定要比铁蛋白强，只有这样才能除去铁蛋白中的铁。这样以来，一些主要酶中的络合铁也被除去，会带来极大的副作用。正是在这种惯性思维框定下，除铁药物的研发没有大的突破。Why hasn't it been used clinically to treat related diseases by lowering iron? The reality is that no medicine is available. The reason why scientists have not developed iron-lowering drugs for a long time is because people have misunderstandings about iron overload: since the discovery of ferritin, people have regarded it as the most important form of iron storage in the body. "Iron overload" is equivalent to "iron storage excess". The concentration of ferritin in cells cannot be determined at present, but ferritin in blood is released by cells of various tissues, which is a collection of ferritin released by cells of various tissues. Therefore, under normal circumstances, the level of serum ferritin concentration can basically reflect the iron storage in the body. It is based on this understanding that people regard "serum ferritin" as the main indicator to measure iron overload and at the same time as the only target to reduce iron overload. This brings about two problems: one is that the place for iron removal can only be in the blood. When the concentration of ferritin in the blood is reduced, the cells will naturally re-release, thereby achieving the purpose of reducing the concentration of ferritin in the cells. This makes the dosage of the drug very large. The iron complexing agent is more than 6g per day, and the time required is very long, generally more than one year; the second is that the ability of the drug to complex iron must be stronger than that of ferritin, only Only in this way can the iron in ferritin be removed. In this way, the complex iron in some major enzymes has also been removed, which will bring great side effects. It is precisely within the framework of this inertial thinking that there is no major breakthrough in the research and development of iron removal drugs.
铁过载诱发相关疾病主要是自由铁离子在起主导作用。但是铁蛋白中的三价铁是没有活性的，是不会诱发自由基反应的。正常情况下人血浆铁蛋白平均 负载量仅达其容量的20％～30％，所以在血浆中游离的铁盐实际为零。铁蛋白实为一种抗氧化剂，它的存在遏制了自由铁离子的存在，因此，血清铁蛋白浓度高了，只能代表铁过载，并不会对细胞造成损伤，能对细胞造成损伤并引发疾病的只能是自由铁离子。由此看来，通过降低血清铁蛋白浓度来降低自由铁离子浓度，是绕了个大圈子，甚至是一种非常浪费的做法。The related diseases induced by iron overload are mainly free iron ions playing a leading role. However, the trivalent iron in ferritin is inactive and will not induce free radical reactions. Under normal circumstances, the average load of human plasma ferritin is only 20%-30% of its capacity, so the free iron salt in the plasma is actually zero. Ferritin is actually an antioxidant, and its presence inhibits the existence of free iron ions. Therefore, a high concentration of serum ferritin can only represent iron overload and will not cause damage to cells, but can cause damage to cells and trigger The disease can only be free iron ions. From this point of view, reducing the concentration of free iron ions by reducing the concentration of serum ferritin is a big circle, and even a very wasteful practice.
细胞内的自由铁离子是怎样存在的呢？先分析一下血液中的转铁蛋白是怎样把铁交付给细胞中的铁蛋白的：转铁蛋白中的铁同样是没有活性的，转铁蛋白首先与细胞膜受体结合，形成凹陷，然后使局部pH值降低至6，这时释放出三价铁离子，自身又回到血液中。释放出的三价铁离子并不是直接与铁蛋白相结合，而是先与细胞质中的柠檬酸、ATP、ADP、CTP、磷脂等结合，这些低分子量的“非蛋白络合铁”具有自由铁的性质，能够催化Haber Weiss反应，被称为流动性的生物自由铁。这部分铁对细胞的生长、发育、代谢起着至关重要的作用。同时，这部分铁与疾病的关系也最为密切，或者说是造成细胞功能下降的主要原因。通过除铁而治疗疾病，主要是去除这部分铁。在类风湿关节炎滑膜液中已经鉴别出有这种络合铁的存在，这可能是该疾病难以治愈的主要原因。How do free iron ions in cells exist? Let’s first analyze how the transferrin in the blood delivers iron to the ferritin in the cell: the iron in the transferrin is also inactive. The transferrin first binds to the cell membrane receptor to form a depression, and then makes the local The pH value drops to 6, at this time, ferric ions are released and return to the blood by itself. The released trivalent iron ions are not directly combined with ferritin, but first combined with citric acid, ATP, ADP, CTP, phospholipids, etc. in the cytoplasm. These low molecular weight "non-protein complexed iron" have free iron The nature of it, which can catalyze the Haber Weiss reaction, is called fluid biological free iron. This part of iron plays a vital role in cell growth, development and metabolism. At the same time, this part of iron is also most closely related to diseases, or it is the main reason for the decline of cell function. The treatment of diseases by removing iron is mainly to remove this part of iron. The presence of this complexed iron has been identified in the synovial fluid of rheumatoid arthritis, which may be the main reason why the disease is difficult to cure.
非蛋白络合铁还有一个非常重要的作用，它能与铁调节蛋白络合，使其激活和构象发生改变，最终诱导铁蛋白和转铁蛋白基因表达，反过来铁蛋白又可以进一步争夺非蛋白络合铁中的三价铁，使其浓度进一步降低。因此，在铁蛋白与非蛋白络合铁之间存在着一种平衡，正是这种平衡在维持着细胞的正常功能。通过降低血清铁蛋白浓度，最终也能达到降低非蛋白络合铁的目的，但这种方法远没有进入细胞直接络合这部分铁来的更快、更容易。阿司匹林能够特异性诱导铁蛋白基因的表达，有时间和剂量效应，因此阿司匹林具有去除非蛋白络合铁的作用，可用于心脑血管等疾病的治疗。但它除铁的方法是间接的，是促进自由铁与调节蛋白结合，因而它的作用非常有限，只适用于自由铁较高的老年人。随着年龄的增长，细胞质中不溶性大分子化合物越来越多，非蛋白 络合铁的流动性越来越差，为了保证抗氧化性的铁蛋白不断产生，就需要更高浓度的非蛋白络合铁来刺激。因此，越是老化的细胞，非蛋白络合铁的浓度就越高，这是不以人们的意志为转移的，也是衰老的本质。Non-protein complexed iron also has a very important role. It can complex with iron regulatory protein to make its activation and conformation change, and finally induce the expression of ferritin and transferrin genes. In turn, ferritin can further compete for non-ferritin. The protein complexes the trivalent iron in the iron to further reduce its concentration. Therefore, there is a balance between ferritin and non-protein complexed iron, and it is this balance that maintains the normal function of cells. By reducing the concentration of serum ferritin, the goal of reducing non-protein complexed iron can eventually be achieved, but this method is far faster and easier than entering the cell to directly complex this part of iron. Aspirin can specifically induce the expression of ferritin gene and has time and dose effects. Therefore, aspirin has the effect of removing non-protein complexed iron and can be used for the treatment of cardiovascular and cerebrovascular diseases. But its iron removal method is indirect, it promotes the binding of free iron to regulatory proteins, so its effect is very limited, and it is only suitable for the elderly with high free iron. With the increase of age, there are more and more insoluble macromolecular compounds in the cytoplasm, and the fluidity of non-protein complexed iron is getting worse and worse. In order to ensure the continuous production of antioxidant ferritin, a higher concentration of non-protein complex is required Combine iron to stimulate. Therefore, the more aging cells are, the higher the concentration of non-protein complexed iron, which is not based on people's will, but is also the essence of aging.
曾经有人提出，要想治疗由于铁过载而导致的一些重大疾病，去铁胺是难以胜任的，所要寻找的化合物必须满足两个条件：一是能进入细胞内，二是络合铁的能力比较弱。这里所说的络合铁的能力弱，只是一个笼统的概念，主要考虑的是副作用的问题。但是，络合能力的大小，正是降铁成功与否的关键。It has been suggested that in order to treat some major diseases caused by iron overload, deferoxamine is incompetent. The compound to be sought must meet two conditions: one is to enter the cell, and the other is the ability to complex iron. weak. The weak ability to complex iron mentioned here is just a general concept, and the main consideration is the problem of side effects. However, the size of the complexing ability is the key to the success of iron reduction.
发明内容Summary of the invention
为改善上述技术问题，本发明提供2,4-二羟基苯甲酸或其同分异构体在治疗或预防铁过载相关的疾病或状况的食品、保健品或药品中的应用。In order to improve the above technical problems, the present invention provides the application of 2,4-dihydroxybenzoic acid or its isomers in foods, health products or medicines for treating or preventing diseases or conditions related to iron overload.
本发明还提供2,4-二羟基苯甲酸或其同分异构体在制备用于治疗或预防铁过载相关的疾病或状况的食品、保健品或药品中应用。The present invention also provides the application of 2,4-dihydroxybenzoic acid or its isomers in the preparation of foods, health products or medicines for treating or preventing diseases or conditions related to iron overload.
本发明还提供一种治疗或预防铁过载相关的疾病或状况的方法，包括向有需要的患者施用2,4-二羟基苯甲酸或其同分异构体。The present invention also provides a method for treating or preventing diseases or conditions related to iron overload, which comprises administering 2,4-dihydroxybenzoic acid or an isomer thereof to a patient in need.
根据本发明的实施方案，所述患者优选哺乳动物，更优选人，例如成年人或未成年人。According to an embodiment of the present invention, the patient is preferably a mammal, more preferably a human, such as an adult or a minor.
根据本发明的实施方案，对于成年人患者，每天可施用2,4-二羟基苯甲酸和/或其同分异构体的总剂量可以为0.5～3g，例如每天可分为三次服用。对于未成年人，可基于体重酌减对其施用的剂量。According to an embodiment of the present invention, for an adult patient, the total dose of 2,4-dihydroxybenzoic acid and/or its isomers can be 0.5-3 g per day, for example, it can be divided into three doses per day. For minors, the dose administered to them can be reduced based on their body weight.
根据本发明的实施方案，所述疾病或状况包括选自下列中的一种或多种：糖尿病、高血压、高血脂、肝硬化、肺纤维化、高尿酸、痛风、类风湿性关节炎、心脏疾病、血管硬化、脑梗、老年性痴呆、肿瘤、乙肝病毒、抑郁症、衰老、血液病等。According to an embodiment of the present invention, the disease or condition includes one or more selected from the group consisting of diabetes, hypertension, hyperlipidemia, liver cirrhosis, pulmonary fibrosis, hyperuric acid, gout, rheumatoid arthritis, Heart disease, vascular sclerosis, cerebral infarction, senile dementia, tumor, hepatitis B virus, depression, aging, blood disease, etc.
本发明还提供一种食品、保健品或药物的组合物，包含选自2,4-二羟基苯甲酸或其同分异构体中的至少一种，其中所述组合物可用于治疗或预防选自如下疾病或状况中的一种或多种：糖尿病、高血压、高血脂、肝硬化、肺纤维化、 高尿酸、痛风、类风湿性关节炎、心脏疾病、血管硬化、脑梗、老年性痴呆、肿瘤、乙肝病毒、抑郁症、衰老、血液病等。The present invention also provides a food, health care product or pharmaceutical composition comprising at least one selected from 2,4-dihydroxybenzoic acid or its isomers, wherein the composition can be used for treatment or prevention One or more of the following diseases or conditions: diabetes, hypertension, hyperlipidemia, liver cirrhosis, pulmonary fibrosis, hyperuric acid, gout, rheumatoid arthritis, heart disease, vascular sclerosis, cerebral infarction, old age Dementia, tumors, hepatitis B virus, depression, aging, blood diseases, etc.
根据本发明的实施方案，所述疾病或状况可以为与铁过载相关的上述疾病或状况，例如由铁过载引发的上述相关疾病或状况。According to an embodiment of the present invention, the disease or condition may be the above-mentioned disease or condition related to iron overload, for example, the above-mentioned related disease or condition caused by iron overload.
根据本发明的实施方案，所述组合物可以为制剂形式，例如选自口服剂、注射剂或其他剂型中的一种。According to an embodiment of the present invention, the composition may be in the form of a preparation, for example, one selected from oral agents, injections or other dosage forms.
根据本发明优选的实施方案，所述疾病或状况为糖尿病。According to a preferred embodiment of the present invention, the disease or condition is diabetes.
根据本发明的实施方案，所述2,4-二羟基苯甲酸的同分异构体优选为2,4-二羟基苯甲酸的位置异构体，例如选自2,3-二羟基苯甲酸，2,5-二羟基苯甲酸，3,4-二羟基苯甲酸，3,5-二羟基苯甲酸。According to an embodiment of the present invention, the isomer of 2,4-dihydroxybenzoic acid is preferably a positional isomer of 2,4-dihydroxybenzoic acid, for example selected from 2,3-dihydroxybenzoic acid , 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid.
根据本发明的实施方案，所述2,4-二羟基苯甲酸、其同分异构体或其组合物用于降低细胞内的非蛋白络合铁中的三价铁。According to an embodiment of the present invention, the 2,4-dihydroxybenzoic acid, its isomers or a combination thereof are used to reduce the ferric iron in the non-protein complexed iron in the cell.
根据本发明的实施方案，所述2,4-二羟基苯甲酸、其同分异构体或其组合物用于降低细胞内的自由铁。According to an embodiment of the present invention, the 2,4-dihydroxybenzoic acid, its isomers or a combination thereof are used to reduce free iron in cells.
根据本发明的实施方案，所述2,4-二羟基苯甲酸、其同分异构体或其组合物用于降低血清铁蛋白的浓度。According to an embodiment of the present invention, the 2,4-dihydroxybenzoic acid, its isomers or a combination thereof are used to reduce the concentration of serum ferritin.
根据本发明的实施方案，2,4-二羟基苯甲酸及其同分异构体的主要功能是降低细胞内非蛋白络合铁。目前还不能直接测定细胞内的非蛋白络合铁，但是它与血清铁蛋白存在线性关系，可以用血清铁蛋白的高低来间接表示。因此，在无感染、无炎症、无酗酒的情况下，通过测定血清铁蛋白值，可以准确判断细胞内非蛋白络合铁的变化。那么，通过降低细胞内非蛋白络合铁，则降低了血清铁蛋白的浓度，可以治疗细胞内非蛋白络合铁过载而形成的选自下列的一种或多种疾病或状况：糖尿病、高血压、高血脂、肝硬化、肺纤维化、高尿酸、痛风、类风湿性关节炎、心脏疾病、血管硬化、脑梗、老年性痴呆、肿瘤、乙肝病毒、抑郁症、衰老、血液病等。According to an embodiment of the present invention, the main function of 2,4-dihydroxybenzoic acid and its isomers is to reduce intracellular non-protein complexed iron. At present, it is not possible to directly measure the non-protein complexed iron in cells, but it has a linear relationship with serum ferritin, which can be expressed indirectly by the level of serum ferritin. Therefore, in the absence of infection, inflammation, and alcohol abuse, by measuring the serum ferritin value, the changes in the intracellular non-protein complexed iron can be accurately determined. Then, by reducing the intracellular non-protein complexed iron, the serum ferritin concentration is reduced, which can treat one or more of the following diseases or conditions formed by the intracellular non-protein complexed iron overload: diabetes, high Blood pressure, hyperlipidemia, liver cirrhosis, pulmonary fibrosis, hyperuric acid, gout, rheumatoid arthritis, heart disease, vascular sclerosis, cerebral infarction, senile dementia, tumor, hepatitis B virus, depression, aging, blood disease, etc.
所述2,4-二羟基苯甲酸及其同分异构体原料来源于食品添加剂、香料及医 药原料，安全无毒副作用。The raw materials of the 2,4-dihydroxybenzoic acid and its isomers are derived from food additives, spices and medical raw materials, and are safe and non-toxic and side effects.
发明人经过深入研究，将除铁的条件细化为三个条件，即不但能进入细胞内，而且其络合铁的能力要比“铁蛋白”小，同时络合铁的能力又要比细胞内“非蛋白络合铁”大。只有符合这三个条件，才能达到快速、精准、副作用小的除铁目的。治疗铁过载本质上是进入细胞内降低“非蛋白络合铁”中的三价铁，进而达到降低“细胞内自由铁”的目的。After in-depth research, the inventors refined the conditions for removing iron into three conditions, that is, not only can it enter the cell, but its ability to complex iron is smaller than that of "ferritin", and at the same time, its ability to complex iron is better than that of cells. The inner "non-protein complexed iron" is large. Only by meeting these three conditions can the goal of iron removal be achieved quickly, accurately and with little side effects. Treatment of iron overload is essentially to enter the cell to reduce the trivalent iron in the "non-protein complexed iron", and then achieve the purpose of reducing the "intracellular free iron".
基于上述研究，发明人发现了完全符合以上“三个条件”的化合物：2,4-二羟基苯甲酸及其同分异构体。其中：1.Gross CE实验证实该化合物及其同分异构体能进入细胞内。2.在柠檬酸络合铁的溶液中加入2,4-二羟基苯甲酸及其同分异构体，能使柠檬酸游离出来，表明2,4-二羟基苯甲酸及其同分异构体络合铁的能力比细胞内非蛋白络合铁强。3.络合铁的2,4-二羟基苯甲酸及其同分异构体在稀碱溶液中，并没有氢氧化铁析出，表明被络合的铁基本失去活性。它络合铁的能力远没有铁蛋白强。4.服用2,4-二羟基苯甲酸及其同分异构体的小鼠，可在尿液中检出络合铁的2,4-二羟基苯甲酸及其同分异构体，表明络合铁可以从尿液中排出。并且，此类化合物为铁试剂，无毒、无副作用，在美国、欧洲都列为食品添加剂或香料。Based on the above research, the inventors discovered compounds that fully meet the above "three conditions": 2,4-dihydroxybenzoic acid and its isomers. Among them: 1. Gross CE experiment confirmed that the compound and its isomers can enter the cell. 2. Adding 2,4-dihydroxybenzoic acid and its isomers to the solution of iron complexed with citric acid can free citric acid, indicating that 2,4-dihydroxybenzoic acid and its isomers The body's ability to complex iron is stronger than that of intracellular non-protein complexing iron. 3. The iron-complexed 2,4-dihydroxybenzoic acid and its isomers did not precipitate out of iron hydroxide in the dilute alkali solution, indicating that the complexed iron basically lost its activity. Its ability to complex iron is far less powerful than ferritin. 4. Mice taking 2,4-dihydroxybenzoic acid and its isomers can detect iron-complexed 2,4-dihydroxybenzoic acid and its isomers in urine, indicating Complexed iron can be excreted in urine. In addition, these compounds are iron reagents, which are non-toxic and have no side effects. They are listed as food additives or spices in the United States and Europe.
本发明设计合理，采用直接服用2,4-二羟基苯甲酸及同分异构体来达到直接降低细胞内非蛋白络合铁中“自由铁”的目的，进而快速除去身体内多余的铁，从而达到治疗或预防铁过载相关的疾病或状况(尤其为糖尿病)的目的。The invention has a reasonable design, and directly takes 2,4-dihydroxybenzoic acid and its isomers to achieve the purpose of directly reducing the "free iron" in the non-protein complexed iron in the cell, thereby quickly removing the excess iron in the body. So as to achieve the purpose of treating or preventing iron overload-related diseases or conditions (especially diabetes).
附图说明Description of the drawings
图1表示小鼠实验中，空腹血糖值(mmol/L)对照示意图。Figure 1 shows a schematic diagram of the control of fasting blood glucose (mmol/L) in a mouse experiment.
图2表示小鼠实验中，血清铁蛋白值(ng/mL)对照示意图。Figure 2 shows a schematic diagram of the control of serum ferritin value (ng/mL) in a mouse experiment.
图3表示小鼠实验中，HBA1C[糖化血红蛋白值(mg/DL)]对照示意图。Figure 3 shows a schematic diagram of the control of HBA1C [glycated hemoglobin value (mg/DL)] in a mouse experiment.
具体实施方式detailed description
下面对本发明的具体实施方案(在治疗糖尿病中的临床应用)进行详细说 明。The specific embodiments of the present invention (clinical application in the treatment of diabetes) are described in detail below.
铁过载与糖尿病之间的关系，目前研究的较为清楚。主要结论有两点：1、铁过载会导致胰岛素抵抗；2、铁过载会使胰岛β细胞功能下降，使胰岛素分泌减少。The relationship between iron overload and diabetes is relatively clear at present. There are two main conclusions: 1. Iron overload will cause insulin resistance; 2. Iron overload will reduce the function of pancreatic β-cells and reduce insulin secretion.
胰岛素抵抗的本质至今尚未阐明，因此，消除胰岛素抵抗在临床上只是一种理念。胰岛素起到降糖作用的机理如下：首先它与细胞膜受体相结合，然后在葡萄糖耐量因子的作用下，将葡萄糖从细胞外转送到细胞内，这是胰岛素的核心功能。在这一过程中，葡萄糖耐量因子发挥着至关重要的作用，而该物质的活性中心是三价的铬离子。已经证明糖尿病患者血液中三价铬离子总是减少的，人们采用多种办法进行补铬，但是在临床上收效甚微。原来三价铬离子与三价铁离子在血液中用的是同一种转运蛋白，即转铁蛋白，正常情况下，转铁蛋白的饱和度不超过35％，当铁过载时转铁蛋白饱和度升高，甚至超过50％，这样三价铬离子的转运就遇到困难，因而影响到葡萄糖耐量子的活性，这时即便是胰岛素结构正常，甚至产生的量较多，也不能正常发挥作用。如果不解决铁过载问题，补再多的三价铬也无济于事，因为运转困难会影响到铬离子的吸收，这是造成胰岛素抵抗的本质原因。The nature of insulin resistance has not yet been elucidated. Therefore, eliminating insulin resistance is only a clinical concept. The mechanism of insulin's hypoglycemic effect is as follows: First, it binds to cell membrane receptors, and then transfers glucose from outside the cell to the cell under the action of glucose tolerance factors, which is the core function of insulin. In this process, the glucose tolerance factor plays a vital role, and the active center of the substance is the trivalent chromium ion. It has been proved that trivalent chromium ions in the blood of diabetic patients are always reduced, and people use a variety of methods to supplement chromium, but they have little clinical effect. The original trivalent chromium ions and trivalent iron ions use the same transport protein in the blood, that is, transferrin. Under normal circumstances, the saturation of transferrin does not exceed 35%. When the iron is overloaded, the saturation of transferrin is Increase, or even exceed 50%, so that the transport of trivalent chromium ions will encounter difficulties, which will affect the quantum tolerance activity of glucose. At this time, even if the insulin structure is normal, or even the amount produced is large, it cannot function normally. If the iron overload problem is not solved, no more trivalent chromium will help, because difficulty in operation will affect the absorption of chromium ions, which is the essential cause of insulin resistance.
铁过载引起的氧应激反应会严重损害胰岛功能，使产生的胰岛素量减少。如果时间较长，II型糖尿病会自发转化成I型糖尿病。所以，除铁有望成为解决糖尿病问题的主要方法。除此之外，只能是控制、延缓，伴随着终生用药，而且副作用较大。The oxygen stress response caused by iron overload can severely damage the function of the islets and reduce the amount of insulin produced. If it takes a long time, type II diabetes will spontaneously transform into type I diabetes. Therefore, iron removal is expected to become the main method to solve the problem of diabetes. In addition, it can only be controlled and delayed, accompanied by lifelong medication, and the side effects are relatively large.
实施例1Example 1
临床试验如下：The clinical trials are as follows:
本申请发明人首先选择了多名注射胰岛素，但血糖值仍居高不下的糖尿病患者，然后检测血清铁蛋白值，从中选择了10名血清铁蛋白超标的患者。通过服用2,4-二羟基苯甲酸胶囊(食品级)，一天3次，每次2粒(0.5g/粒)。三个月后，对血清铁蛋白、糖化血红蛋白及血糖值作对照检测(见表1)。The inventor of the present application first selected a number of diabetic patients whose blood glucose level was still high after insulin injection, and then tested the serum ferritin value, and selected 10 patients whose serum ferritin exceeded the standard. By taking 2,4-Dihydroxybenzoic acid capsules (food grade), 3 times a day, 2 capsules each time (0.5g/capsule). Three months later, the serum ferritin, glycosylated hemoglobin and blood glucose levels were tested for comparison (see Table 1).
血清铁蛋白男性正常值为：15～130ng/ml；女性正常值为：15～80ng/ml。The normal value of serum ferritin for men is 15 to 130 ng/ml; the normal value for women is 15 to 80 ng/ml.
表1 服用前后血清铁蛋白、糖化血红蛋白及血糖值浓度高低对比Table 1 Contrast of serum ferritin, glycosylated hemoglobin, and blood glucose levels before and after taking
Figure PCTCN2020116613-appb-000001
Figure PCTCN2020116613-appb-000001
由表1可以看出，对于5名男性来说，血清铁蛋白浓度在服用后，有四名恢复到了正常值，另一名也下降了45.3％；血糖值在“空腹”和“饭后”两个指标服用后也是明显下降；糖化血红蛋白在服用后也是明显下降至正常水平。对于5名女性来说，血清铁蛋白浓度在服用后，有三名恢复到了正常值，另两名中，其中一名也下降了56.9％，几乎至正常水平，另一名则下降了48.5％；血糖值在“空腹”和“饭后”两个指标服用后也是明显下降；糖化血红蛋白在服用后也是明显下降至正常水平。It can be seen from Table 1 that for the five men, the serum ferritin concentration returned to normal after taking four men, and the other fell by 45.3%. The blood glucose levels were "fasting" and "after meals". The two indicators also dropped significantly after taking; glycosylated hemoglobin also dropped to normal levels after taking it. For 5 women, after taking the serum ferritin concentration, three returned to normal values, among the other two, one also dropped by 56.9%, almost to the normal level, and the other dropped by 48.5%; The blood glucose level also dropped significantly after taking the two indicators of "fasting" and "after meals"; the glycosylated hemoglobin also dropped to a normal level after taking it.
本申请发明人又选择了10名病史不足两年，没有并发症征兆，病情较轻的糖尿病患者，通过服用2,4-二羟基苯甲酸胶囊(食品级)，一天3次，每次2粒(0.5g/粒)。服用3个月后，完全停服其它降糖药，对血糖值进行了检测对比。结果见表2(只有7名患者按要求服用3个月)。The inventor of the present application selected 10 diabetic patients with a medical history of less than two years, no signs of complications, and milder illnesses, by taking 2,4-dihydroxybenzoic acid capsules (food grade), 3 times a day, 2 capsules each time (0.5g/grain). After taking it for 3 months, other hypoglycemic drugs were completely stopped, and blood glucose levels were tested and compared. The results are shown in Table 2 (only 7 patients took it for 3 months as required).
表2 服用前后血糖高低变化对比(单位：mmol/l)Table 2 Comparison of blood glucose levels before and after taking (unit: mmol/l)
Figure PCTCN2020116613-appb-000002
Figure PCTCN2020116613-appb-000002
由表2可以看出，7名患者中至少有5名患者在服用3个月后血糖值在“空腹”和“饭后”两个指标是明显下降；另两名患者也有下降，但效果不是很显著。It can be seen from Table 2 that at least 5 of the 7 patients had a significant decrease in blood glucose levels in the two indicators of "fasting" and "after meals" after taking 3 months; the other two patients also had a decrease, but the effect was not It's remarkable.
对此，临床实验得出如下结论：In this regard, clinical trials have reached the following conclusions:
(1)、该化合物能够快速降低血清铁蛋白，解决铁过载问题；(1) This compound can quickly reduce serum ferritin and solve the problem of iron overload;
(2)、该化合物具有降糖、稳定血糖的作用；(2) The compound has the effects of lowering blood sugar and stabilizing blood sugar;
(3)、该化合物在实验剂量中没有发现任何不良反应。(3) No adverse reactions were found in the experimental dose of the compound.
实施例2Example 2
动物试验如下：The animal tests are as follows:
本申请发明人委托山西医科大学对2,4-二羟基苯甲酸做了小鼠(糖尿病模型鼠)降糖实验：The inventor of this application entrusted Shanxi Medical University to do a hypoglycemic experiment on 2,4-dihydroxybenzoic acid in mice (diabetic model mice):
1、实验分组：1. Experiment grouping:
1.1、WT对照组：C57小鼠8只；1.1. WT control group: 8 C57 mice;
1.2、糖尿病模型鼠：db/db小鼠10只；1.2. Diabetes model mice: 10 db/db mice;
1.3、低剂量组：db/db小鼠10只，62.5mg/kg/次；1.3. Low-dose group: 10 db/db mice, 62.5mg/kg/time;
1.4、高剂量组：db/db小鼠10只，125mg/kg/次。1.4. High-dose group: 10 db/db mice, 125mg/kg/time.
2、给药方式2. Method of administration
灌胃，2次/日，每日上午9点，下午4点各一次。Gavage, 2 times a day, at 9 am and 4 pm each day.
实际给药量根据每组小鼠当周实际体重给药，每周调整一次。The actual dosage is administered according to the actual body weight of each group of mice during the week, and adjusted once a week.
5月29日C57小鼠8只，db/db糖尿病小鼠30只抵达实验室，初步检测动物生命体征一切正常，符合实验要求。动物饲养于山西医科大学SPF级实验动物中心。适应性饲养一周后开始实验。测定各组动物基础指标，于6月16日开始给药干预。On May 29, 8 C57 mice and 30 db/db diabetic mice arrived in the laboratory. The preliminary examination of animal vital signs was normal, which met the requirements of the experiment. The animals are kept in the SPF Laboratory Animal Center of Shanxi Medical University. The experiment started after one week of adaptive feeding. The basic indicators of each group of animals were determined, and the administration intervention was started on June 16.
3、实验结果3. Experimental results
以每只小鼠各测定指标给药前初始值为参考基数进行统计。The initial value of each measured index of each mouse before administration was used as the reference base for statistics.
如图1所示，空腹血糖浓度中，高剂量组几乎与对照组持平，甚至低于对照组，低剂量组间于模型组和对照组之间。可见，随着2,4-二羟基苯甲酸的剂量越高，降糖效果越好，越接近于正常值。As shown in Figure 1, in the fasting blood glucose concentration, the high-dose group was almost the same as the control group, or even lower than the control group, and the low-dose group was between the model group and the control group. It can be seen that as the dose of 2,4-dihydroxybenzoic acid is higher, the hypoglycemic effect is better and closer to the normal value.
如图2所示，血清铁蛋白浓度中，高剂量组则是先升高后降低，并且最终明显低于对照组，低剂量组则基本与对照组持平。As shown in Figure 2, in the serum ferritin concentration, the high-dose group first increased and then decreased, and finally was significantly lower than the control group, while the low-dose group was basically the same as the control group.
如图3所示，糖化血红蛋白浓度中，高剂量组明显低于低剂量组，几乎与对照组持平，而且稳定性好。As shown in Figure 3, in the glycosylated hemoglobin concentration, the high-dose group was significantly lower than the low-dose group, almost the same as the control group, and the stability was good.
4、结论4 Conclusion
(1)该化合物具有降低血清铁蛋白的功能，存在剂量效应。(1) The compound has the function of reducing serum ferritin, and there is a dose effect.
(2)该化合物具有降低空腹血糖和饭后血糖的作用，同时具有稳定糖化血红蛋白的作用。(2) The compound has the effect of lowering fasting blood sugar and post-meal blood sugar, and at the same time has the effect of stabilizing glycosylated hemoglobin.
(3)该化合物在实验过程中，小鼠无异常反应，剂量内无毒副作用。(3) During the experiment of the compound, the mice had no abnormal reaction, and there was no toxic or side effect in the dose.
最后应说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照本发明实施例进行了详细说明，本领域的普通技术人员应当理解，对本发明的技术方案进行修改或者等同替换，都不脱离本发明的技术方案的精神和范围，其均应涵盖本发明的权利要求保护范围中。Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although detailed descriptions have been made with reference to the embodiments of the present invention, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or modified. Equivalent replacements do not depart from the spirit and scope of the technical solution of the present invention, and they should all be covered by the protection scope of the claims of the present invention.

Claims (10)

  1. 治疗或预防铁过载相关的疾病或状况的方法，包括向有需要的患者施用2,4-二羟基苯甲酸或其同分异构体。A method of treating or preventing diseases or conditions related to iron overload includes administering 2,4-dihydroxybenzoic acid or its isomers to patients in need.
  2. 2,4-二羟基苯甲酸或其同分异构体在制备用于治疗或预防铁过载相关的相关疾病或状况的食品、保健品或药品中应用。2,4-Dihydroxybenzoic acid or its isomers are used in the preparation of foods, health products or medicines for treating or preventing related diseases or conditions related to iron overload.
  3. 根据权利要求1所述的方法或权利要求2所述的应用，其中2,4-二羟基苯甲酸的同分异构体为2,4-二羟基苯甲酸的位置异构体，例如选自2,3-二羟基苯甲酸，2,5-二羟基苯甲酸，3,4-二羟基苯甲酸，3,5-二羟基苯甲酸。The method according to claim 1 or the application according to claim 2, wherein the isomers of 2,4-dihydroxybenzoic acid are positional isomers of 2,4-dihydroxybenzoic acid, for example selected from 2,3-Dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid.
  4. 根据权利要求1所述的方法或权利要求2或3所述的应用，其中所述疾病或状况包括选自下列中的一种或多种：糖尿病、高血压、高血脂、肝硬化、肺纤维化、高尿酸、痛风、类风湿性关节炎、心脏疾病、血管硬化、脑梗、老年性痴呆、肿瘤、乙肝病毒、抑郁症、衰老、血液病等；The method of claim 1 or the use of claim 2 or 3, wherein the disease or condition comprises one or more selected from the group consisting of diabetes, hypertension, hyperlipidemia, liver cirrhosis, lung fiber Hyperuricemia, high uric acid, gout, rheumatoid arthritis, heart disease, vascular sclerosis, cerebral infarction, senile dementia, tumor, hepatitis B virus, depression, aging, blood diseases, etc.;
    优选地，所述2,4-二羟基苯甲酸或其同分异构体用于降低细胞内的非蛋白络合铁中的三价铁；Preferably, the 2,4-dihydroxybenzoic acid or an isomer thereof is used to reduce the trivalent iron in the non-protein complexed iron in the cell;
    优选地，所述2,4-二羟基苯甲酸或其同分异构体用于降低细胞内的自由铁；Preferably, the 2,4-dihydroxybenzoic acid or an isomer thereof is used to reduce free iron in cells;
    优选地，所述2,4-二羟基苯甲酸或其同分异构体用于降低血清铁蛋白的浓度。Preferably, the 2,4-dihydroxybenzoic acid or an isomer thereof is used to reduce the concentration of serum ferritin.
  5. 根据权利要求1所述的方法，其中所述患者优选哺乳动物，更优选人，例如成年人或未成年人。The method according to claim 1, wherein the patient is preferably a mammal, more preferably a human, such as an adult or a minor.
  6. 根据权利要求5所述的方法，其中对于成年人患者，每天施用2,4-二羟基苯甲酸和/或其同分异构体的总剂量可以为0.5～3g，例如每天可分为三次服用；对于未成年人，可基于体重酌减对其施用的剂量。The method according to claim 5, wherein for an adult patient, the total dose of 2,4-dihydroxybenzoic acid and/or its isomers administered daily can be 0.5-3 g, for example, it can be divided into three doses per day ; For minors, the dose administered to them can be reduced based on their body weight.
  7. 一种食品、保健品或药物的组合物，包含选自2,4-二羟基苯甲酸或其同分异构体中的至少一种，其中所述组合物可用于治疗或预防选自如下疾病或状况中的一种或多种：糖尿病、高血压、高血脂、肝硬化、肺纤维化、高尿酸、 痛风、类风湿性关节炎、心脏疾病、血管硬化、脑梗、老年性痴呆、肿瘤、乙肝病毒、抑郁症、衰老、血液病等；A food, health care product or pharmaceutical composition comprising at least one selected from 2,4-dihydroxybenzoic acid or its isomers, wherein the composition can be used to treat or prevent diseases selected from the following Or one or more of the conditions: diabetes, hypertension, hyperlipidemia, liver cirrhosis, pulmonary fibrosis, hyperuric acid, gout, rheumatoid arthritis, heart disease, vascular sclerosis, cerebral infarction, senile dementia, tumor , Hepatitis B virus, depression, aging, blood diseases, etc.;
    优选地，所述组合物用于降低细胞内的非蛋白络合铁中的三价铁；Preferably, the composition is used to reduce trivalent iron in non-protein complexed iron in cells;
    优选地，所述组合物用于降低细胞内的自由铁；Preferably, the composition is used to reduce free iron in cells;
    优选地，所述组合物用于降低血清铁蛋白的浓度。Preferably, the composition is used to reduce the concentration of serum ferritin.
  8. 根据权利要求7所述的组合物，其中：The composition of claim 7, wherein:
    所述2,4-二羟基苯甲酸或其同分异构体用于降低细胞内的非蛋白络合铁中的三价铁；The 2,4-dihydroxybenzoic acid or its isomer is used to reduce the trivalent iron in the non-protein complexed iron in the cell;
    优选地，所述2,4-二羟基苯甲酸或其同分异构体用于降低细胞内的自由铁；Preferably, the 2,4-dihydroxybenzoic acid or an isomer thereof is used to reduce free iron in cells;
    优选地，所述2,4-二羟基苯甲酸或其同分异构体用于降低血清铁蛋白的浓度。Preferably, the 2,4-dihydroxybenzoic acid or an isomer thereof is used to reduce the concentration of serum ferritin.
  9. 根据权利要求7或8所述的组合物，其中2,4-二羟基苯甲酸的同分异构体为2,4-二羟基苯甲酸的位置异构体，例如选自2,3-二羟基苯甲酸，2,5-二羟基苯甲酸，3,4-二羟基苯甲酸，3,5-二羟基苯甲酸。The composition according to claim 7 or 8, wherein the isomer of 2,4-dihydroxybenzoic acid is a positional isomer of 2,4-dihydroxybenzoic acid, for example selected from 2,3-dihydroxybenzoic acid. Hydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid.
  10. 根据权利要求7-9任一项所述的组合物，其中所述组合物为制剂形式，例如选自口服剂、注射剂或其他剂型中的一种。The composition according to any one of claims 7-9, wherein the composition is in the form of a preparation, for example, one selected from an oral agent, an injection, or other dosage forms.
PCT/CN2020/116613 2019-09-23 2020-09-21 Application of 2,4-dihydroxybenzoic acid or isomer thereof in related diseases or conditions caused by iron overload WO2021057680A1 (en)

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