CN117653650A - Use of triacetyl-3-hydroxy-phenyl adenosine in the treatment of obesity - Google Patents

Abstract

The invention discloses an application of triacetyl-3-hydroxy phenyl adenosine shown in a formula (I) in treating obesity. The triacetyl-3-hydroxy-phenyl adenosine can remarkably improve the blood lipid level of obese mice, slow down the weight increase of the obese mice, improve glucose tolerance and liver lipid accumulation, increase oxygen consumption, reduce TNF-alpha, IL-1 beta, IFN-beta and the likeSerum inflammatory factor level, has remarkable curative effect on obesity treatment and small toxic and side effects.

Description

Use of triacetyl-3-hydroxy-phenyl adenosine in the treatment of obesity

Technical field

The invention belongs to the technical field of medicines, and particularly relates to application of triacetyl-3-hydroxy phenyl adenosine and a pharmaceutical composition containing the same in treating obesity.

Background

Obesity has become one of the chronic diseases that severely affects human health, and obesity and its closely related insulin resistance significantly increase the risk of developing diabetes, non-alcoholic fatty liver, cardiovascular and cerebrovascular diseases, and neurodegenerative diseases, tumors. The excessive energy intake and sedentary lifestyle promotes visceral fat accumulation, accompanied by hypertrophy of adipocytes, death of adipocytes, or local hypoxia due to expansion of adipose tissue, significant increases in synthesis, secretion of inflammatory and chemotactic factors by adipocytes and macrophages, which signal molecules, in addition to induction of mononuclear macrophage recruitment, infiltration and inflammatory differentiation, promote recruitment and infiltration of many other immune cells including eosinophils, dendritic cells, NKT cells, adaptive T cells and B cells, resulting in chronic low grade systemic inflammation (now also referred to as metabolic inflammation). Chronic low inflammatory states are considered to be an important mechanism for complications associated with the development of obesity. While the reduction or inhibition of inflammation helps to improve insulin resistance and metabolic function.

The triacetyl-3-hydroxy phenyl adenosine (also called IMM-H007 or WS070117, which is firstly published in patent number ZL200980101131.6, bulletin number CN101874036B and bulletin day 2012.01.25) is a novel structure type compound screened from cordycepin derivatives in the medical research of China medical science college, and has the characteristics of small toxic and side effects, good pharmacokinetics and the like, and is currently in a clinical research stage. There is no report on the use of IMM-H007 in the treatment of obesity.

Disclosure of Invention

The inventor of the invention discovers that the triacetyl-3-hydroxy phenyl adenosine has remarkable effect on the aspect of treating obesity for the first time, which provides scientific basis for the clinical application of the triacetyl-3-hydroxy phenyl adenosine in treating obesity. The structural formula of the triacetyl-3-hydroxy phenyl adenosine is shown as the following formula (I):

accordingly, a first aspect of the present application relates to the use of triacetyl-3-hydroxy-phenyl adenosine, as shown in formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of obesity or obesity-related glycolipid metabolic disorders.

A second aspect of the present application relates to the use of a pharmaceutical composition comprising triacetyl-3-hydroxy-phenyl adenosine of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for the manufacture of a medicament for the treatment of obesity or obesity-related glycolipid metabolic disorders.

In the present application, examples of pharmaceutically acceptable salts of the compounds of formula (I) include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexylamine sulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2- (4-hydroxybenzyl) benzoate, hydrochloride (i.e., chloride), bromide, iodide, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, napthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate, trifluoroacetate, and the like.

In this application, unless otherwise indicated, references to triacetyl-3-hydroxy-phenyl adenosine or a pharmaceutically acceptable salt thereof by structural formula, name or code encompass solvates, hydrates, tautomers, isotopically modified compounds (e.g., deuterium modified compounds), and also include various solid forms thereof (e.g., various crystalline or amorphous forms).

In some embodiments, the obesity is obesity caused by a genetic defect.

In some embodiments, the obesity-related glycolipid metabolic disorder is an obesity-related glycolipid metabolic disorder caused by a genetic defect, more specifically an obesity and an abnormal elevation of blood lipids and blood glucose caused by a genetic defect.

In some embodiments, treating obesity or obesity-related glycolipid metabolic disorders is reducing serum total cholesterol, triglycerides, low density lipoprotein cholesterol, and glucose levels, slowing body weight gain, improving glucose tolerance, improving liver lipid accumulation, increasing oxygen consumption, reducing serum inflammatory factors TNF- α, IL-1 β, IFN- β levels in an obese patient. Preferably, the treatment of obesity is to reduce serum total cholesterol, triglycerides, low density lipoprotein cholesterol and glucose levels, slow weight gain, improve glucose tolerance, improve liver lipid accumulation, increase oxygen consumption, reduce serum inflammatory factors TNF- α, IL-1 β, IFN- β levels in obese patients. Preferably, the treatment of obesity-related glycolipid metabolic disorders is lowering serum total cholesterol, triglycerides, low density lipoprotein cholesterol and glucose levels, slowing weight gain, improving glucose tolerance in a patient suffering from obesity-related glycolipid metabolic disorders.

In some embodiments, the medicament is a tablet, capsule, pill, or injection.

In some embodiments, the drug is a sustained release formulation, a controlled release formulation, or various microparticle delivery systems.

In some embodiments, the route of administration of the drug is selected from the group consisting of oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, dermal, vaginal and rectal administration.

In some embodiments, the dosage of triacetyl-3-hydroxy-phenyl adenosine of formula (I) or a pharmaceutically acceptable salt thereof is from 0.001 to 250mg/kg body weight, preferably from 0.1 to 220mg/kg body weight, more preferably from 100 to 210mg/kg body weight, most preferably from 150 to 200mg/kg body weight. In some embodiments, the amount of triacetyl-3-hydroxy-phenyl adenosine of formula (I) or the pharmaceutically acceptable salt thereof is 100mg/kg body weight, 110mg/kg body weight, 120mg/kg body weight, 130mg/kg body weight, 140mg/kg body weight, 150mg/kg body weight, 160mg/kg body weight, 170mg/kg body weight, 180mg/kg body weight, 190mg/kg body weight, 200mg/kg body weight, or 210mg/kg body weight.

In some embodiments, the triacetyl-3-hydroxy-phenyl adenosine represented by formula (I) or a pharmaceutically acceptable salt thereof in the medicament is as an active ingredient.

A third aspect of the present application relates to a method of treating obesity or an obesity-related glycolipid metabolic disorder, comprising administering to a subject in need thereof triacetyl-3-hydroxyphenyladenosine as shown in formula (I) or a pharmaceutically acceptable salt thereof.

A fourth aspect of the present application relates to a method of treating obesity or an obesity-related glycolipid metabolic disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising triacetyl-3-hydroxy-phenyl adenosine of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the obesity is obesity caused by a genetic defect.

In some embodiments, the obesity-related glycolipid metabolic disorder is an obesity-related glycolipid metabolic disorder caused by a genetic defect, more specifically an obesity-related dyslipidemia, an abnormal elevation of blood glucose caused by a genetic defect.

In some embodiments, treating obesity or obesity-related glycolipid metabolic disorders is reducing serum total cholesterol, triglycerides, low density lipoprotein cholesterol, and glucose levels, slowing body weight gain, improving glucose tolerance, improving liver lipid accumulation, increasing oxygen consumption, reducing serum inflammatory factors TNF- α, IL-1 β, IFN- β levels in an obese patient. Preferably, the treatment of obesity is to reduce serum total cholesterol, triglycerides, low density lipoprotein cholesterol and glucose levels, slow weight gain, improve glucose tolerance, improve liver lipid accumulation, increase oxygen consumption, reduce serum inflammatory factors TNF- α, IL-1 β, IFN- β levels in obese patients. Preferably, the treatment of obesity-related glycolipid metabolic disorders is lowering serum total cholesterol, triglycerides, low density lipoprotein cholesterol and glucose levels, slowing weight gain, improving glucose tolerance in an obesity-related glycolipid metabolic disorder patient.

In some embodiments, the pharmaceutical compositions are tablets, capsules, pills, and injections.

In some embodiments, the pharmaceutical composition is a sustained release formulation, a controlled release formulation, or various microparticle delivery systems.

In some embodiments, the route of administration is selected from the group consisting of oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, dermal, vaginal and rectal.

In some embodiments, the dosage of triacetyl-3-hydroxy-phenyl adenosine of formula (I) or a pharmaceutically acceptable salt thereof is from 0.001 to 250mg/kg body weight, preferably from 0.1 to 220mg/kg body weight, more preferably from 100 to 210mg/kg body weight, most preferably from 150 to 200mg/kg body weight. In some embodiments, the amount of triacetyl-3-hydroxy-phenyl adenosine of formula (I) or the pharmaceutically acceptable salt thereof is 100mg/kg body weight, 110mg/kg body weight, 120mg/kg body weight, 130mg/kg body weight, 140mg/kg body weight, 150mg/kg body weight, 160mg/kg body weight, 170mg/kg body weight, 180mg/kg body weight, 190mg/kg body weight, 200mg/kg body weight, or 210mg/kg body weight.

A fifth aspect of the present application relates to the use of triacetyl-3-hydroxy-phenyl adenosine as shown in formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a weight loss medicament.

A sixth aspect of the present application relates to the use of a pharmaceutical composition comprising triacetyl-3-hydroxy-phenyl adenosine of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for the manufacture of a medicament for reducing weight.

In some embodiments, the pharmaceutical composition or medicament may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be made by combining the triacetyl-3-hydroxy-phenyl adenosine or pharmaceutically acceptable salts thereof of the invention with one or more pharmaceutically acceptable solid or liquid carriers or excipients and/or other adjuvants. The content of the triacetyl-3-hydroxy-phenyl adenosine or the pharmaceutically acceptable salt thereof of the present invention in the pharmaceutical composition or the medicament thereof is usually 0.1 to 99% by weight.

The triacetyl-3-hydroxy-phenyl adenosine of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or medicament containing the same may be administered in unit dosage form by enteral or parenteral administration, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal administration, and the like.

The triacetyl-3-hydroxy-phenyl adenosine or pharmaceutically acceptable salt thereof of the invention or a pharmaceutical composition or administration form of a drug containing the same may be a liquid form, a solid form or a semisolid form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like. The preferred dosage forms of the pharmaceutical composition are selected from the group consisting of tablets, capsules, pills, and injections.

The triacetyl-3-hydroxy-phenyl adenosine or pharmaceutically acceptable salts thereof or pharmaceutical compositions or medicaments containing the same can be prepared into common preparations, and also into sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.

For the purpose of tableting the compound or composition or medicament of the present invention, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be one or more selected from starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be selected from one or more of water, ethanol, isopropanol and the like; the binder can be one or more selected from starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be one or more selected from dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be selected from one or more of talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may further be formulated as coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or as bi-and multi-layered tablets.

In order to make the administration unit into a capsule, the compound of the present invention may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, glidants and the like used to prepare tablets of the compounds of the invention may also be used to prepare capsules of the compounds of the invention.

For preparing the compound or composition of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or glidant can be selected from one or more of poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the PH regulator can be one or more selected from phosphate, acetate, hydrochloric acid, sodium hydroxide and the like; the osmotic pressure regulator can be selected from one or more of sodium chloride, mannitol, glucose, phosphate and acetate. Mannitol, glucose and the like can be added as propping agents for preparing freeze-dried powder injection.

In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.

For the purposes of administration, the compounds or compositions or medicaments of the present invention may be administered by any known method of administration to enhance therapeutic effects.

The amount of the compound or composition or medicament of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, suitable daily dosages of the compounds of the present invention will range from 0.001 to 250mg/kg body weight, preferably from 0.1 to 220mg/kg body weight, more preferably from 100 to 210mg/kg body weight, and most preferably from 150 to 200mg/kg body weight, for example 100mg/kg body weight, 110mg/kg body weight, 120mg/kg body weight, 130mg/kg body weight, 140mg/kg body weight, 150mg/kg body weight, 160mg/kg body weight, 170mg/kg body weight, 180mg/kg body weight, 190mg/kg body weight, 200mg/kg body weight or 210mg/kg body weight. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.

Advantageous technical effects

The invention provides a novel therapeutic drug, namely triacetyl-3-hydroxy phenyl adenosine, for treating chronic diseases with complex pathogenesis and poor therapeutic effect, such as obesity or obesity-related glycolipid metabolic disorder, and has the advantages of remarkable curative effect, small toxic and side effects and safe use in the aspect of treating obesity or obesity-related glycolipid metabolic disorder.

Drawings

In order that the invention may be more readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings, in which,

FIG. 1 shows the changes in blood lipid and blood glucose levels in mice; wherein a shows the results at four weeks of administration and B shows the results at eight weeks of administration.

FIG. 2 shows oil red O staining and HE staining patterns of mouse liver lipid accumulation; wherein a illustrates O staining results and B illustrates HE staining results.

Figure 3 shows the change in mouse body weight; wherein a shows the weight change of mice, B shows the weight gain of mice, and C shows the average food intake of mice.

FIG. 4 shows the change in glucose tolerance in mice; wherein a shows the change in blood glucose levels in mice and B shows the AUC of glucose in mice.

Fig. 5 shows the change in oxygen consumption and energy expenditure of mice; wherein a illustrates oxygen intake of mice, B illustrates carbon dioxide discharge of mice, and C illustrates energy expenditure of mice.

FIG. 6 shows serum inflammatory factor levels in mice; wherein A, B, C and D show the levels of serum inflammatory factors IL-1α, TNF- α, IL-1β, IFN- β, respectively.

Detailed Description

It will be appreciated that the different applications of the disclosed products and methods may be adapted to the specific needs in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

Examples

The following examples serve to further illustrate the invention but are not meant to be limiting in any way.

Example 1:

1. experimental materials

1. Reagent(s)

Rogowski activity type glucometer; ROCHE ACCU-CHEK Active test paper; kit for detecting serum inflammatory factors of mice, LEGENDplex ^TM Mouse Information Panel (13-plex) 740446; zhongsheng Bei control gallbladder-securing deviceAlcohol determination kit (CHDD-PAP method); a medium north-control triglyceride assay kit (GPO-PAP method); a medium north-control low-density lipoprotein cholesterol determination kit (direct method-surfactant removal method); a north-control glucose determination kit (glucose oxidase method).

2. Instrument for measuring and controlling the intensity of light

Multipurpose low temperature high speed centrifuges from eppendorf, germany; paraffin microtomes from lycra, germany; frozen microtomes from lycra, germany; en Vision multifunctional microplate reader, from Perkinelmer Inc., USA; BD fasmedy flow cytometer from Bi Di (BD); LE1305 respiratory metabolic analysis System from Panlab company.

3. Animal treatment

14C 57BL/6 mice with the age of 8 weeks, male and SPF grade; 27 obese mice of day-8 ob/ob, male, SPF grade, purchased from Beijing vitamin Shang Li Tu technology Co., ltd., license number: SCXK (jing) 2016-0009.

2. Experimental method

1. Grouping and feeding animals

Animal feeding is carried out in animal experiment centers of pharmaceutical institute of Chinese medical science, and the feeding conditions are as follows: and (3) shielding the environment, wherein the temperature is 22+/-2 ℃, the humidity is 50% -60%, and food and water are obtained randomly according to 12/12h day and night rules.

After 1 week of adaptive feeding, C57BL/6 mice were set as Control group (Control), and ob/ob obesity model mice were randomly divided into three groups: (1) a Model group (Model); (2) Experimental group 1 (Metformin (Metformin)): a dose of 250mg/kg body weight of metformin is administered by intragastric administration once a day; (3) Experimental group 2 (IMM-H007): IMM-H007 was administered at a dose of 200mg/kg body weight by intragastric administration once daily. All mice were fed normal feed.

Mice were dosed continuously for 8 weeks. Body weight and food intake were measured weekly. At 4 weeks of administration, about 50. Mu.L of blood was taken from the canthus vein, and the blood lipid change was examined to determine the experimental node.

2. Observation index and measurement method

2.1 serum Biochemical index

Animals were fasted for 12 hours, 0.5ml of blood was collected from the inner canthus vein, left for 30min, centrifuged for 10min at 2000g, and the supernatant was aspirated as much as possible, and serum total cholesterol (Total cholesterol, TC), triglyceride (TG) Low-density lipoprotein cholesterol (Low-density lipoprotein cholesterol, LDL-c) and Glucose (Glucose) levels were measured as per the medium north blood lipid control kit instructions.

The experiment was fasted overnight before the end point, 3% sodium pentobarbital was intraperitoneally injected for anesthesia, the abdominal cavity was exposed, and the liver was rapidly isolated after the abdominal aorta was bled. Leaving one leaf of liver, cutting a piece of 1X 1cm at the fixed part ³ After the pellet, the pellet was put into 10% neutral formalin fixed solution and stored at 4 ℃.

2.2 pathological staining of liver tissue

2.2.1 preparation of Paraffin sections

Washing the liver fixed with paraformaldehyde fixing solution with tap water, dehydrating according to the following steps, wherein 70% ethanol is used overnight, 80% ethanol is used overnight, 90% ethanol is used for 30min,95% ethanol is used for 60min,100% ethanol is used for 60min, and normal tissues can be properly dehydrated for a long time. After tissue dehydration, supersafety is used for transparency, supersafety is used for 60min, and the liver of a normal control group can properly prolong the transparency time. Wax dipping at 65 ℃, paraffin I for 50min, paraffin II for 50min, paraffin III for 50min, embedding, slicing with thickness of 7um, spreading at 45 ℃ and baking at 50 ℃ overnight.

2.2.2 oil Red O staining

Freezing sections are fixed in neutral formalin solution for 10min, washing with tap water for 2min, rinsing with 60% isopropanol for 5 seconds, dyeing with 0.5% oil red O working solution in a shading dyeing box for 10min,60% isopropanol for several seconds, washing with tap water gently, counterstaining with hematoxylin for 1min, washing with tap water gently, sealing with glycerinum gel, and observing under a lens.

2.2.3 HE staining

Paraffin sections were dehydrated in the following steps, superampane I5min, superampane II5min, superampane III5min,100% ethanol I3min,100% ethanol II3min,95% ethanol I3min,95% ethanol II3min,80% ethanol 3min, and tap water rinse 1min. Hematoxylin is dyed for 5min, 1min is washed by tap water, 1% hydrochloric acid and ethanol are differentiated for a few seconds, tap water is washed for returning blue, 80% ethanol is put into the blue for a few seconds, eosin is dyed for 10 seconds, 80% ethanol and 95% ethanol are used for color mixing, dehydration is carried out, namely, 95% ethanol, 100% ethanol I, 100% ethanol II, super-safety I, super-safety II and super-safety III are respectively carried out for 2min, and ultra-clean high-grade sealing sheets are glued and sealed, and are observed under a lens.

2.2.4 glucose tolerance

After 6 weeks of administration, mice were fasted without water for 16h and basal blood glucose was measured by blood collection from the tail tip. Then, a 20% glucose solution (prepared with physiological saline) was administered by gavage at a dose of 2g/kg body weight, and blood was collected from the tail tips 30min, 60min, 90min, and 120min after glucose loading, respectively, and the glucose concentration in the blood was measured by a blood glucose meter (Roche).

2.2.5 oxygen consumption and energy detection

After the ob/ob mice were given metformin and IMM-H007 treatment for eight weeks, the mice were placed in a metabolic detection system for 16H in advance, and respiratory entropy, gas changes (oxygen (VO 2), carbon dioxide (VCO 2), water vapor), and feeding, water intake, exercise, energy consumption (EE), etc. of the mice were measured simultaneously.

2.2.6 serum inflammatory factor detection

Eight weeks after administration, the inner canthus was collected with a 12-hour empty stomach, the blood was allowed to stand at room temperature for 30min or more, and then centrifuged at 2000/x g for 10min at 4℃to collect serum. Serum is packaged and stored at-80 ℃ for standby.

According to the instruction of the kit, the serum inflammatory factor level is detected by adopting a flow cytometry method, and the serum inflammatory factor level reflects the inflammatory level in the mouse body.

2.3 statistical analysis

All data are expressed as mean ± SE. The inventors compared between two sets of data using the two-tailed Student's t-test, and compared and calculated more than two sets of data using the one-way ANOVA and Tukey's post-hoc test. The comparison of differences between the non-normal distribution data sets was tested using Kruskal-Wallis sum-rank test and Wilcoxon rank-sum test; and comparing and analyzing the images.

3. Experimental results

3.1 Effects of IMM-H007 on blood lipid and blood glucose levels in mice

The results of the blood lipid and blood glucose levels in mice are shown in figure 1. The results showed that the mice in the model group had significantly elevated serum TC, LDL-C and glucose when dosed for four weeks (panel A) compared to the control group; compared with the model group, TC, TG, LDL-C and glucose were significantly reduced after IMM-H007 treatment.

Eight weeks of dosing (panel B), mice in the model group had significantly elevated serum TC, LDL-C and glucose compared to the control group; compared to the model group, TC, TG, LDL-C and glucose were significantly reduced after metformin or IMM-H007 treatment.

3.2 IMM-H007 improved liver lipid accumulation in obese mice

The results of the oil red O staining and the HE staining are shown in fig. 2, and the results of the oil red O staining (A diagram) show that the liver cells of the animals in the control group are arranged in a radial shape around the central vein as the center, and the intracellular neutral fat content is low; a large amount of fat is deposited in liver cells of the animal in the model group, and cavitation occurs; fat deposition was also seen in hepatocytes of animals in the metformin group and in the IMM-H007 group, but was significantly reduced compared to the model group.

HE staining (panel B) results show that the liver cells of the control group animals are radially arranged around the central vein as the center, and collagen fibers are regularly distributed on the central vein and other vascular walls; cavitation of animal liver cells of the model group occurs, collagen fibers appear among the liver cells, and the distribution is irregular; cavitation appears in liver cells of the metformin group animals, collagen fibers appear among the liver cells, and irregular distribution appears. The IMM-H007 hepatic cells are radially arranged around the central vein, and collagen fibers are regularly distributed in the boundary region of the central vein and hepatic lobular.

3.3 IMM-H007 slowed weight gain in obese mice

The results of the change in body weight of the mice are shown in FIG. 3. As can be seen from the graph (a graph) of the Body weight of mice as a function of the number of weeks, the Body weights of mice in the model group, metformin and IMM-H007 group all increased slowly over time and the trend was consistent as compared with the control group. As can be seen from the graph (B graph) of Body weight gain as a function of week number, the mice in the model group significantly increased in weight compared to the control group; mice gain reduced body weight after metformin or IMM-H007 treatment compared to the model group. As can be seen from the average food intake (Average food intake) graph (C) of the mice, the food intake of the mice in the model group, the metformin and the IMM-H007 group did not differ significantly.

3.4 IMM-H007 improving glucose tolerance in obese mice

The results of glucose tolerance in mice are shown in FIG. 4. As can be seen from the graph of Blood glucose (a) levels in mice over time, the IMM-H007 group showed significantly lower Blood glucose levels compared to the model group. As can be seen from the graph (B) of the glucose AUC (area under the curve, area under the drug time curve) for mice, the model group mice had reduced glucose tolerance compared to the control group mice; compared with the model group, the oral glucose tolerance of mice is obviously improved after the metformin or IMM-H007 treatment is given.

3.5 IMM-H007 increased oxygen consumption in obese mice, with a trend toward increased energy expenditure in obese mice.

The results of oxygen consumption and energy expenditure in mice are shown in fig. 5. As can be seen from the time-dependent graph (a), the time-dependent graph (B) and the time-dependent graph (C) of the oxygen intake (VO 2), the carbon dioxide discharge (VCO 2) and the energy consumption (EE) of the mice, the trend of oxygen consumption and energy consumption of the mice in the model group was significantly reduced compared to the control group, and the oxygen consumption and energy consumption of the mice were significantly increased and the energy consumption of the mice was increased after the metformin or IMM-H007 treatment, regardless of the light or dark conditions.

3.6 IMM-H007 reduces serum inflammatory factor levels in obese mice

After eight weeks of IMM-H007 treatment, ob/ob mice were tested for serum inflammatory factor levels using flow cytometry and the results are shown in FIG. 6. The results show that administration of IMM-H007 treatment significantly reduced serum concentrations of IL-1α (panel A), TNF- α (panel B), IL-1β (panel C), IFN- β (panel D) serum inflammatory factors (Serum concentration), and thus reduced levels of these serum inflammatory factors.

In conclusion, the triacetyl-3-hydroxy phenyl adenosine (IMM-H007) can improve the obesity-related glycolipid metabolic disorder, obviously reduce the serum TC, TG, LDL-C and blood sugar level of obese mice, slow down the weight increase of the obese mice, improve the glucose tolerance and liver lipid accumulation, increase the oxygen consumption and reduce the serum inflammatory factors such as TNF-alpha, IL-1 beta, IFN-beta and the like. The above results suggest that IMM-H007 may be useful for the treatment of obesity.

Claims (10)

1. The application of triacetyl-3-hydroxy phenyl adenosine shown as the formula (I) or pharmaceutically acceptable salt thereof in preparing medicaments for treating obesity or obesity-related glycolipid metabolic disorders,

2. the use according to claim 1, wherein the obesity is obesity caused by a gene defect; the obesity-related glycolipid metabolic disorder is an obesity-related glycolipid metabolic disorder caused by a gene defect.

3. The use according to claim 1 or 2, wherein the treatment of obesity or obesity-related glycolipid metabolism disorder is reduction of serum total cholesterol, triglycerides, low density lipoprotein cholesterol and glucose levels, slowing of weight gain, improving glucose tolerance, improving liver lipid accumulation, increasing oxygen consumption, or reducing serum inflammatory factors TNF- α, IL-1 β, IFN- β levels in obese patients.

4. Use of a pharmaceutical composition comprising triacetyl-3-hydroxy-phenyl adenosine of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient,

5. the use according to claim 4, wherein the obesity is obesity caused by a gene defect and the obesity-related glycolipid metabolism disorder is obesity-related glycolipid metabolism disorder caused by a gene defect.

6. The use according to claim 4 or 5, wherein the treatment of obesity or obesity-related glycolipid metabolism disorder is lowering serum total cholesterol, triglycerides, low density lipoprotein cholesterol and glucose levels, slowing weight gain, improving glucose tolerance, improving liver lipid accumulation, increasing oxygen consumption, or lowering serum inflammatory factors TNF- α, IL-1 β, IFN- β levels in obese patients.

7. The use according to any one of claims 1 to 6, wherein the medicament is in the form of tablets, capsules, pills and injections.

8. The use according to any one of claims 1 to 6, wherein the medicament is a sustained release formulation, a controlled release formulation or a variety of particulate delivery systems.

9. The use according to any one of claims 1 to 6, wherein the route of administration of the medicament is selected from the group consisting of oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, cutaneous, vaginal and rectal administration.

10. The use according to any one of claims 1 to 6, wherein the dosage of triacetyl-3-hydroxy-phenyl adenosine of formula (i) or a pharmaceutically acceptable salt thereof is 0.001-250mg/kg body weight, preferably 0.1-220mg/kg body weight, more preferably 100-210mg/kg body weight, most preferably 150-200mg/kg body weight.