TW201909902A - Use and pharmaceutical composition for metabolic disease prevention and/or treatment - Google Patents

Abstract

The present invention discloses a pharmaceutical composition including Adenosine analogues and the application thereof. As confirmed by the researches of the present invention, said pharmaceutical composition including Adenosine analogues has the activities of mediating the concentration of the blood glucose and therefore obtain the efficacy of Diabetes or metabolic disease prevention and/or treatment. Accordingly, the present invention dislcoses a novel pharmaceutical application of Adenosine analogues and provides an alternative prevention and/or treatment regime of Diabetes or metabolic disease for the field.

Description

 Pharmaceutical composition for preventing and/or treating metabolic diseases and use thereof  

The present invention relates to a pharmaceutical composition for preventing and/or treating metabolic diseases and uses thereof; more specifically, to a pharmaceutical composition comprising an adenosine analogue for preventing and/or treating diabetes and use thereof.

Diabetes (Diabetes mellitus, DMs)

Diabetes is a metabolic disease characterized by a patient's blood sugar that is higher than the standard value for a long time, and there are symptoms of polyphagia, polydipsia, polyuria, and weight loss. Other general symptoms include blurred vision, headache, muscle weakness, slow wound healing, and itchy skin. Diabetes is divided into two types, and the time course of the symptoms is different. The symptoms of type 1 diabetes appear from one week to one month, while the second type of diabetes is shown later. Regardless of the type 1 diabetes or type 2 diabetes mentioned above, there is a risk of causing many complications if left untreated. Acute complications include diabetic ketoacidemia and high osmolality and hyperglycemia non-ketoacidic coma; severe long-term complications include cardiovascular disease, stroke, chronic kidney disease, diabetic foot, and retinopathy. There are two main causes of diabetes: one is that the pancreas cannot produce enough insulin, and the other is that the cells are not sensitive to insulin. With the changes in living environment and eating habits, statistics show that the number of patients suffering from diabetes is rising rapidly. In 1997, the number of patients with diabetes worldwide was 124 million, and it was estimated that there were 422 million adults in 2014. Moreover, because diabetes is associated with long-term complications, it also causes aggravation of the financial burden of patients, which in turn leads to a decline in their quality of life.

blood sugar

Blood sugar refers to glucose in the blood. The glucose obtained after digestion enters the bloodstream through the small intestine and is transported by blood to individual cells in the body as a main source of energy for chemical reactions in various organisms. According to the molecular weight of glucose (C ₆ H ₁₂ O ₆ ) is 180 g / mol, so if one liter of blood contains 1 millimol of glucose, that is, the concentration is 1 mmol / L, the blood glucose content is about 18 mg / dL . The blood sugar concentration in the human body is strictly regulated, that is, the blood sugar is constant. The blood glucose concentration is usually maintained at 900 mg/L (5 mmol/L), while the tolerable normal range is 4-6 mmol/L, while the normal range of glucose content in circulating blood is 3.3-7 g. Blood sugar levels change, rising after eating for one to two hours, and dropping to the lowest in the morning. Unbalanced blood glucose levels, such as hyperglycemia with persistently high blood glucose levels and low hypoglycemia, can lead to a variety of diseases. Diabetes is a disease of persistent hyperglycemia caused by a variety of causes, which is the most significant disease associated with blood glucose levels. In addition to glucose, the blood actually contains a certain amount of fructose and galactose, but only the concentration level of glucose can be used as a signal for metabolic regulation (regulated by insulin and glucagon).

Regulating blood sugar drugs

Currently used to regulate blood sugar or clinical treatment of diabetes is oral medication, insulin injection, and with diet control. For patients with severe type 2 diabetes and severe obesity, recent developments in gastric bypass surgery can be used to adjust their blood glucose levels and significantly improve symptoms.

Oral hypoglycemic drugs can be divided into seven according to their physiological effects, and there are risks of different side effects:

1. Sulfonamide: The mechanism of action is to increase the amount of insulin secreted by stimulating the pancreas. This drug has a good blood sugar lowering effect. Such drugs may, for example, be Amaryl, Glibenclamide, Minidiab, Diamicron or the like. Such drugs may cause side effects such as hypoglycemia, skin rash and itching, weight gain, gastrointestinal irritation, sporadic edema or hepatitis.

2. Biguanide: The mechanism of action is to inhibit the absorption of sugar and amino acids in the small intestine and inhibit the production of glucose in the liver. Such drugs are less likely to cause side effects of hypoglycemia or weight gain. Such drugs may, for example, be Glucophage. Such drugs may cause side effects such as lactic acidosis, gastrointestinal discomfort (such as flatulence, diarrhea, etc.), metallic taste of the tongue, and fatigue. In addition, people with high risk of mild liver function or abnormal liver function may experience severe fatigue or jaundice after taking this medicine.

3. Oxazolidines: also known as insulin sensitizers. The mechanism of action is to reduce insulin resistance. Those with a history of heart disease should be careful to use these drugs. Such drugs may, for example, be Actos (Atomic Ingot), Avandia (Vatican Ingot). Such drugs may cause side effects such as lower extremity edema, nausea, diarrhea, and occasional hepatitis. In addition, heart failure, chronic active hepatitis, or liver function-AST (GPT) is more than 2.5 times normal, and this drug is not recommended. In addition, patients with abnormal liver function or high risk of liver function may have severe fatigue or jaundice after taking this drug.

4. Meglitonin: The mechanism of action is to stimulate the pancreas to secrete insulin. The drug is characterized by rapid drug action and short duration of action. The metabolic pathway of this drug is mainly liver. Such drugs may, for example, be Novonorm (Norro) and Starlix (sugar release film ingot). Such drugs may cause side effects such as hypoglycemia, nausea, or diarrhea.

5. α-type disaccharide decomposition 脢 inhibitor: the mechanism of action is to inhibit the decomposition of carbohydrates in the intestinal tract to reduce the absorption of sugar. This medication is recommended for meals to control postprandial blood glucose levels. Such drugs may, for example, be Glucobay. Such drugs may cause flatulence or cause side effects such as increased gastrointestinal exhaust.

6. Double peptide proteolytic enzyme inhibitor: the mechanism of action is to promote the action of gut hormones. The characteristics of this drug are less likely to cause hypoglycemia, and the effect of controlling postprandial blood glucose concentration is good. Such drugs are exemplified by Januvia. Such drugs may cause side effects such as cold symptoms, headache or gastrointestinal discomfort.

7. SGLT2 inhibitor: sodium-glucose co-transporter 2, which reduces the absorption of glucose by the kidneys and helps patients directly excrete sugar from the urine. However, due to the increase in urine sugar, there is a risk of urinary tract, genital tract infection, and side effects of mild diuresis and dehydration, and those with poor kidney function are not suitable for side effects.

Adenosine compound

Adenosine compounds have been developed in the field of medicine. Studies have indicated that adenosine compounds have physiological activity in various physiological mechanisms, and can be applied to drug development for treating related diseases, and the drug containing adenosine compound is also reached. Effective therapeutic effect. Examples of physiological activities and drug treatments of adenosine compounds are listed below:

1. Treatment of Nervous System Diseases: Some adenosine compounds can be used to treat neurological diseases associated with adenosine receptor modulating agents, such as sedative hypnosis, anticonvulsant, brain protection, Parkinson's disease, and drug addiction.

2. Analgesic and antipyretic: Some adenosine compounds can bind to the α receptor, inhibit the release of neurotransmitters, and have an analgesic effect. It has been confirmed by animal experiments that some adenosine compounds can significantly reduce the body temperature of rats with normal body temperature or artificially heated rats, and can achieve the effects of cooling and antipyretic.

3. Calcium ion antagonism: Some adenosine compounds are involved in the regulation of muscle contraction, and thus may be helpful for diseases related to muscle contraction, such as arrhythmia, myocardial ischemia, angina pectoris, hypertension, thrombosis, and the like.

4. Renal protection: Some adenosine compounds have protective effects on the damage caused by renal ischemia-reperfusion in mice.

However, in the current research report, there is no report that adenosine compounds or analogs are related to the regulation of blood sugar, treatment of diabetes or metabolic related diseases, and therefore whether adenosine compounds or analogues are involved in the regulation of blood glucose constancy, and whether diabetes can be treated, Or other metabolic diseases are still unknown.

It is an object of the present invention to provide a method for treating and preventing a metabolic disease such as diabetes, which in turn regulates blood glucose concentration within a normal range.

Another object of the present invention is to develop a medical use of adenosine analogs and thereby enhance its pharmaceutical application value.

In order to achieve the aforementioned object, the present invention provides a use of a compound of the following formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for controlling metabolic diseases; Wherein R1 and R2 are independently hydrogen, an alkyl group having 1 to 4 carbon atoms or an alcohol group; and R3 is hydrogen, an alkylol group having 1 to 4 carbon atoms or an alkylthiol group having 1 to 4 carbon atoms.

Preferably, R ₁ and R ₂ of the compound of formula (I) are hydrogen and R ₃ is an alkanol group having 1 to 4 carbon atoms.

Preferably, the compound of formula (I) is N6-(2-hydroxyethyl)-adenosine (HEA) of formula (II);

Preferably, the pharmaceutical composition comprises an effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.

Preferably, the effective amount is from 45 to 100 mg / 60 kg body weight / day.

Preferably, the pharmaceutically acceptable carrier is water, alcohol, glycerol, dimethyl hydrazine, carboxymethyl cellulose, vegetable oil, organic ester, organic acid, aqueous salt solution, aqueous electrolyte solution, or a combination thereof.

Preferably, the pharmaceutical composition further comprises an additive which is an excipient, a preservative, a diluent, a filler, a binder, a disintegrant, an absorption enhancer, a sweetener, or a combination thereof.

Preferably, the pharmaceutical composition is a tablet, capsule, granule, powder, solution, syrup, suspension emulsion or injection.

Preferably, the pharmaceutical composition is administered by oral, sublingual, mucosal absorption, topical application, injection or spray inhalation.

Preferably, the metabolic disease refers to the prevention and treatment of diabetes.

Preferably, the metabolic disease refers to the regulation of blood sugar.

In order to achieve the aforementioned object, the present invention further provides a pharmaceutical composition for controlling metabolic diseases, which comprises the following compound of the formula (I) or a pharmaceutically acceptable salt thereof; Wherein R1 and R2 are independently hydrogen, an alkyl group having 1 to 4 carbon atoms or an alcohol group; and R3 is hydrogen, an alkylol group having 1 to 4 carbon atoms or an alkylthiol group having 1 to 4 carbon atoms.

Preferably, R ₁ and R ₂ of the compound of formula (I) are hydrogen and R ₃ is an alkanol group having 1 to 4 carbon atoms.

Preferably, the compound of formula (I) is N6-(2-hydroxyethyl)-adenosine (HEA) of formula (II);

Preferably, the pharmaceutical composition comprises an effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.

Preferably, the effective amount is from 45 to 100 mg / 60 kg body weight / day.

Preferably, the pharmaceutically acceptable carrier is water, alcohol, glycerol, dimethyl hydrazine, carboxymethyl cellulose, vegetable oil, organic ester, organic acid, aqueous salt solution, aqueous electrolyte solution, or a combination thereof.

Preferably, the pharmaceutical composition further comprises an additive which is an excipient, a preservative, a diluent, a filler, a binder, a disintegrant, an absorption enhancer, a sweetener, or a combination thereof.

Preferably, the pharmaceutical composition is a tablet, capsule, granule, powder, solution, syrup, suspension emulsion or injection.

Preferably, the pharmaceutical composition is administered by oral, sublingual, mucosal absorption, topical application, injection or spray inhalation.

Preferably, the anti-lethal disease refers to the prevention and treatment of diabetes.

Preferably, the metabolic disease refers to the regulation of blood sugar.

In summary, the present invention provides a use of an adenosine analog comprising the formula (I) for the preparation of a pharmaceutical composition for controlling a metabolic disease such as diabetes, and an adenosine analog comprising the formula (I). Pharmaceutical composition. The present invention successfully develops novel medical applications of adenosine analogs of the formula (I) and demonstrates that the compound has an effect of regulating blood sugar, and provides an alternative for the treatment of preventing and/or treating metabolic diseases and diabetes.

The first panel shows the effect of oral intake of 14 days of HEA on glucose tolerance in normal male C57BL/JNarl mice. The three experimental groups were control group, experimental group 1 and experimental group 2, respectively. Time to measure blood glucose concentration: 30, 60, and 120 minutes after feeding, and the vertical axis is the increase in blood glucose concentration measured at that time.

The second panel shows the effect of oral intake of 14 days of HEA on glucose tolerance in normal male C57BL/JNarl mice. The three experimental groups were control group, experimental group 1 and experimental group 2, respectively. The area under the curve for the increase in blood glucose concentration measured for 120 minutes.

As used herein, "prevention" refers to the protection of a body from the onset of a disease, discomfort, or harmful condition. As used herein, "treatment" refers to the process of eliminating, terminating, or reducing a disease, discomfort, or deleterious condition in a body.

As used herein, "regulating blood glucose" refers to the regulation of blood glucose concentration, which means that the blood glucose concentration is adjusted to a normal range, including increasing or decreasing blood glucose concentration. The regulation of blood glucose concentration is played by different mechanisms, and the effect of regulating blood glucose concentration is not limited in this particular way.

One aspect of the present invention is directed to a pharmaceutical use of an adenosine analog for use in the preparation of a pharmaceutical composition for the prevention of a metabolic disease such as diabetes. Another aspect of the invention relates to a pharmaceutical composition comprising an adenosine analog and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of metabolic diseases.

In a preferred embodiment, the adenosine analog is a compound of formula (I) or a pharmaceutically acceptable salt thereof as shown below: Wherein R1 and R2 are independently hydrogen, an alkyl group having 1 to 4 carbon atoms or an alcohol group; and R3 is hydrogen, an alkylol group having 1 to 4 carbon atoms or an alkylthiol group having 1 to 4 carbon atoms.

In a preferred embodiment, R ₁ and R ₂ of the compound of formula (I) are hydrogen and R ₃ is an alkano group having 1 to 4 carbon atoms.

In a preferred embodiment, the compound of the formula (I) is N6-(2-hydroxyethyl)-adenosine (HEA) of the following formula (II);

The N6-(2-hydroxyethyl)adenosine (HEA) of the formula (II) can be obtained by a commercial method, or can be prepared by a conventional method, and the HEA is not limited to a specific one without affecting the medical effect. The way of obtaining or preparing.

By "effective amount" of a pharmaceutical composition as used herein is meant an amount sufficient to produce the aforementioned prophylactic and/or therapeutic effects. Based on the in vitro cell culture experiment, the aforementioned effective amount is defined as "μg/ml" based on the total volume of the cell culture fluid used in each culture. Based on animal model experiments, the aforementioned effective amount was defined as "g/60 kg body weight/day". In addition, the effective amount of data obtained by in vitro cell culture experiments can be converted to a reasonable effective amount for animal use by the following formula:

◆Generally (Reagan-Shaw et al., 2008), 1 "μg/ml" unit (based on an effective amount in vitro cell culture experiments) can be equivalent to 1 "mg/kg body weight / day" units (based on mice) The effective amount obtained by the model experiment). Further, based on the magnification of the known metabolic rate between the mouse and the human, the effective dose of the human can be further determined.

◆ Therefore, if an effective amount is 500 μg/ml based on the in vitro cell culture experiment, the effective amount used in the mouse can be calculated as 500 mg/kg body weight/day (i.e., 0.5 g/kg body weight/day). Further, the effective rate for human use is converted in accordance with the magnification of the metabolic rate of the aforementioned mouse and human.

According to the examples described in the following paragraphs, an effective amount of 10 to 20 mg/kg body weight/day is determined based on a mouse in vivo test, and a reasonable effective dose for human use should be 45 to 100 mg/60 kg body weight/day.

In a preferred embodiment, the effective amount of the invention is from 45 to 100 mg / 60 kg body weight / day, preferably from 48.7 to 97.6 mg / 60 kg body weight / day.

In a preferred embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. The carrier may be water, alcohol, glycerol, dimethyl hydrazine, carboxymethyl cellulose, vegetable oil, organic ester, organic acid, aqueous salt solution, aqueous electrolyte solution or combinations thereof, preferably water. The selection or combination of the carrier species is not limited to the above-described species, and may be additionally combined with carriers of other different components without affecting the drug effect of the adenosine analog.

In a preferred embodiment, the pharmaceutical composition further comprises an additive. The additive may be an excipient, a preservative, a diluent, a filler, a binder, a disintegrant, an absorption enhancer, a sweetener, an emulsifier, a thickener, a lubricant, a grease or a non-greasy base, An interface active agent, suspending agent, gelling agent, adjuvant, antioxidant, stabilizer, colorant, perfume or a combination thereof. The excipient can be selected from the group consisting of sodium citrate, calcium carbonate, calcium phosphate, or a combination thereof. The preservative extends the shelf life of the pharmaceutical composition, such as benzyl alcohol, parabens. The diluent can be selected from the group consisting of water, ethanol, propylene glycol, glycerin, or a combination thereof. The filler may be selected from the group consisting of lactose, nougat, high molecular weight ethylene glycol or a combination thereof. The binder may be selected from the group consisting of sucrose, gelatin, gum arabic or combinations thereof. The disintegrant may be selected from the group consisting of potato starch, tapioca starch, citrate or a combination thereof. The absorption enhancer can be selected from the group consisting of dimethyl hydrazine (DMSO), laurel, propylene glycol, glycerin, polyethylene glycol, or a combination thereof. The sweetener may be selected from the group consisting of Acesulfame K, aspartame, saccharin, sucralose, neotame or a combination thereof. In addition to the additives listed above, other additives may be selected according to requirements without affecting the medical effects of adenosine analogs.

The pharmaceutical composition of the present invention can be used for the treatment of animals or humans, and can be made into any drug form without affecting the effect of adenosine analogs for treating diabetes, and can be administered by any route. Animal or human.

In a preferred embodiment, the pharmaceutical composition comprising the adenosine analog can be administered orally, sublingually, by mucosal absorption, by topical application, by injection or by spray, or preferably orally. For the route of administration of the injection, there are subcutaneous injections, intravenous injections or intraperitoneal injections.

In a preferred embodiment, depending on the different routes of administration of the pharmaceutical composition described above, the pharmaceutical form of the applicable pharmaceutical composition can be combined. For the oral administration route, a pharmaceutical form which can be used is, for example, a tablet, a capsule, a granule, a powder, a solution, a syrup, a suspension or an emulsion, preferably a capsule. The pharmaceutical composition may be in the form of a drug for injection, and may further comprise one or more pH adjusting agents, isotonizing agents or stabilizers, and the like, specifically, for example, sodium hydrogen sulfate or dihydrogen sulfuric acid. Sodium, sodium dihydrogen phosphate, sodium hydrogen phosphate or sodium chloride. Further, an isotonic solution, water for injection, physiological saline or a salt buffer may be further contained, and specific examples thereof include a solvent such as a phosphate buffer or a citrate buffer. According to the requirements of the injection route, the above-mentioned suitable ones are added to prepare, for example, an intravenous infusion solution, an emulsion intravenous infusion solution, a dry powder injection, a suspension injection, or a dry powder suspension injection.

The following examples are presented to further illustrate the advantages of the invention, but are not intended to limit the scope of the invention.

Example 1: The effect of adenosine analogues on blood glucose regulation by OGTT assay

Experimental principle:

Six-week-old male C57BL/6JMarl mice were used for oral glucose tolerance test to evaluate the effect of adenosine analogs or their pharmaceutically acceptable salts on blood glucose regulation. The purpose of this experiment was to test the feeding of HEA for 14 consecutive days, and whether there was an effect on oral glucose tolerance performance in normal, eight-week-old male C57BL/6JNarl mice. Thereby, the activity of the adenosine analog or a pharmaceutically acceptable salt thereof for regulating blood sugar is evaluated.

Experimental animals:

This test used C57BL/6JNarl mice. This strain of mice is commonly used for studies of obesity, hyperglycemia, hyperinsulinemia, and type 2 diabetes (NIDDM). The mice of this line are characterized by a constitution that is more likely to cause obesity on a high-calorie diet.

The feeding process is after the animals are stationed, and they are grouped in a random manner, and they are kept in a box. Feeding materials were collected from Aspen and Shredded Aspen Shavings by NEPCO (Warrensburg, NY, USA), sterilized and replaced twice a week. The way to eat and drink, and to drink. The regulation of the feeding environment was carried out in accordance with a conventional experimental animal feeding management method. The ambient temperature of the animal breeding room was set at 23 ± 2 ° C, the relative humidity was 50 ± 10%, and the light cycle was 12 hours.

The 30, 6-week-old, male C57BL/6JNarl mice used in this trial were purchased from the Experimental Animal Center of the National Experimental Research Institute.

Experimental sample:

The HEA used in this test was purchased from Youhe Trading Company.

experimental method:

The Oral Glucose Tolerance Test (OGTT) is a method for examining blood glucose regulation by observing changes in blood glucose levels through oral glucose to detect whether blood glucose regulation is normal.

Under normal circumstances, almost all of the oral glucose will be absorbed by the intestines, causing the blood sugar concentration to rise rapidly. For a rapidly rising blood glucose concentration, if the blood sugar regulation mechanism works normally, insulin is secreted to promote the utilization of glucose in the blood by the tissue. Accordingly, the time course of the change in blood glucose concentration is roughly divided into two periods. After the first period of oral glucose, the blood glucose concentration peaks at about 30 to 60 minutes, but the peak value generally does not exceed 200 mg/Dl. In the second stage, the blood glucose concentration drops after reaching the peak, and decreases to a normal level of blood glucose concentration in about 2 hours.

However, in the case of diabetes, the peak of blood glucose concentration after oral administration of glucose exceeds 200 mg/dL due to the low function of the glucose tolerance of the subject. In addition, there is a delay in the peak of blood glucose concentration, and it is not possible to return to the normal blood glucose level.

In this experiment, 30 mice in each group were divided into three groups, and the three groups were the control group, the experimental group 1 and the experimental group 2. First, the feeding was continued for 14 consecutive days. The control group was only fed with water, and the experimental group 1 and the experimental group 2 were fed with HEA at a dose of 10 and 20 mg/kg mouse, respectively, and the volume of each feeding was 10 mL/kg/day.

After 14 days of feeding, the OGTT was tested. After fasting for 16 hours in each group of C57BL/6JNarl mice, blood samples were taken from the tail end, and fasted (0) was detected with a blood glucose tester (Gluccosure II, Apex Bio Inc., Taiwan) with a blood glucose test piece (glucose oxidase method). Minutes) blood sugar level. Next, each group of mice was given a glucose solution (2 g/kg) in a tube feeding manner. At 30, 60, and 120 minutes after tube feeding, each group of mice was tested for blood glucose concentration in the same manner as described above.

Statistical analysis method:

The results of the experiment were expressed by Mean ± SEM, and the experimental group 1 and the experimental group 2 were compared with the control group by Student's st-test.

Experimental results:

The blood glucose delta values of the experimental results are shown in Table 1, and are drawn as the first graph. According to the 120-minute blood glucose rise curve in the first graph, the area under the statistical curve (iAUC 120 min) is plotted as the second graph.

Evaluation of results:

According to Table 1, the blood glucose values of the control group, the experimental group 1 and the experimental group 2 before the glucose solution was fed (0 minutes) were measured, and the blood glucose increments measured at 30 minutes were 253.4 ± 12.4, 210.2, respectively. ±22.2 and 209.2±15.5, the blood glucose increment values measured at 60 minutes were 156.2±10.5, 114.7±8.8, and 125.1±10.6, respectively. The blood glucose increment values measured at 120 minutes were 66.3±4.9, 61.5.±6.0, and 58.1 ± 6.0. The blood glucose increment value measured in the experimental group 1 for 60 minutes was statistically significantly lower than the blood glucose increment value of the control group. In the experimental group 2, the blood glucose increment values measured at 30 and 60 minutes were statistically significantly lower than the blood glucose increment values of the control group. It can also be clearly seen from the first graph that the curves of the blood glucose increment values of the experimental group 1 and the experimental group 2 are significantly lower than those of the control group.

Similarly, according to Table 1, the area under the 120-minute blood glucose rise curve of the control group, the experimental group 1 and the experimental group 2 (abbreviated as iAUC for 120 minutes) were 16730±824, 13315±1053, and 13647±944, respectively. The area under the 120-minute blood glucose rise curve of the experimental group 1 and the experimental group 2 was statistically significantly smaller than that of the control group, and the result was also apparent from the second figure.

Accordingly, from the experimental results in Table 1, the first figure and the second figure, HEA can significantly reduce the increase in blood glucose after the mice are fed with glucose, and HEA is active for blood glucose regulation. This result also indicates that adenosine analogs having a similar structure to HEA are useful for regulating blood sugar, and the use of adenylate for the prevention or/and treatment-related medical use of human diabetic patients has been developed. Another novel treatment option is also offered for other metabolic diseases.

Claims (22)

Use of a compound of the following formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for preventing and/or treating metabolic diseases; Wherein R ₁ and R _{2 are} independently hydrogen, an alkyl group having 1 to 4 carbon atoms or an alcohol group; and R ₃ is hydrogen, an alkylol group having 1 to 4 carbon atoms or an alkylthiol group having 1 to 4 carbon atoms. The use according to claim 1, wherein R ₁ and R ₂ of the compound of the formula (I) are hydrogen and R ₃ is an alkano group having 1 to 4 carbon atoms. The use according to claim 1, wherein the compound of the formula (I) is N6-(2-hydroxyethyl)-adenosine (HEA) of the formula (II);  The use of any one of claims 1 to 3, wherein the pharmaceutical composition comprises an effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.    The use of claim 4, wherein the effective amount is 45 to 100 mg / 60 kg body weight / day.    The use according to claim 4, wherein the pharmaceutically acceptable carrier is water, alcohol, glycerin, dimethyl hydrazine, carboxymethyl cellulose, vegetable oil, organic ester, organic acid, saline solution, aqueous electrolyte solution, or Its combination.    The use according to claim 4, wherein the pharmaceutical composition further comprises an additive, which is an excipient, a preservative, a diluent, a filler, a binder, a disintegrant, an absorption enhancer, a sweetener, or a combination thereof. .    The use according to claim 4, wherein the pharmaceutical composition is a tablet, a capsule, a granule, a powder, a solution, a syrup, a suspension emulsion or an injection.    The use according to claim 4, wherein the pharmaceutical composition is administered orally, sublingually, by mucous membrane absorption, by external application, by injection or by spray.    The use of claim 4, wherein the metabolic disease is diabetes.    The use according to claim 4, wherein the metabolic disease is a regulation of blood sugar.   A pharmaceutical composition for preventing and/or treating a metabolic disease, which comprises a compound of the following formula (I) or a pharmaceutically acceptable salt thereof; Wherein R ₁ and R _{2 are} independently hydrogen, an alkyl group having 1 to 4 carbon atoms or an alcohol group; and R ₃ is hydrogen, an alkylol group having 1 to 4 carbon atoms or an alkylthiol group having 1 to 4 carbon atoms. The pharmaceutical composition according to claim 12, wherein R ₁ and R ₂ of the compound of the formula (I) are hydrogen and R ₃ is an alkano group having 1 to 4 carbon atoms. The pharmaceutical composition according to claim 12, wherein the compound of the formula (I) is N6-(2-hydroxyethyl)-adenosine (HEA) of the formula (II);  The pharmaceutical composition according to any one of claims 12 to 14, which comprises an effective amount of the compound of the formula (I) and a pharmaceutically acceptable carrier.    The pharmaceutical composition according to claim 15, wherein the effective amount is 45 to 100 mg / 60 kg body weight / day.    The pharmaceutical composition according to claim 15, wherein the pharmaceutically acceptable carrier is water, alcohol, glycerin, dimethyl hydrazine, carboxymethyl cellulose, vegetable oil, organic ester, organic acid, saline solution, aqueous electrolyte solution. Or a combination thereof.    The pharmaceutical composition according to claim 15, which further comprises an additive which is an excipient, a preservative, a diluent, a filler, a binder, a disintegrant, an absorption enhancer, a sweetener or a combination thereof.    The pharmaceutical composition according to claim 15, which is a tablet, a capsule, a granule, a powder, a solution, a syrup, a suspension emulsion or an injection.    The pharmaceutical composition according to claim 15 which is administered orally, sublingually, by mucous membrane absorption, by external application, by injection or by spray inhalation.    The pharmaceutical composition according to claim 15, wherein the metabolic disease is diabetes.    The pharmaceutical composition according to claim 15, wherein the metabolic disease means regulating blood sugar.