Application of pyrrolotriazine compound in preparation of medicine for preventing or treating obesity

Abstract

The invention discloses application of pyrrolotriazine compounds in preparation of medicines for preventing or treating obesity, and belongs to the technical field of medical chemistry. The invention provides application of pyrrolotriazine compounds or salts thereof in preparation of medicines for preventing or treating obesity in order to develop novel anti-obesity medicines which have the effects of reducing weight and have no side effects of appetite inhibition, muscle loss and the like. The compound or the salt thereof can obviously reduce the body weight of a mouse, slow down the body weight increase speed, reduce the contents of perirenal fat, epididymal fat and groin fat and reduce the fat content in the liver, has no influence on appetite, and provides a new choice for development and application of medicines for preventing and treating obesity.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to the use of a pyrrolo[1,2-a]triazine compound or a salt thereof in the preparation of a drug for preventing or treating obesity. Background Art

[0002] With the improvement of people's living standards, especially the change of lifestyle, the problems of obesity and overweight have become increasingly prominent. Obesity refers to a certain degree of obvious overweight and excessive fat layer, which is a state caused by excessive accumulation of body fat. It is not simply an increase in weight, but a state of excessive accumulation of body fat tissue. Excessive food intake or changes in body metabolism can lead to excessive accumulation of body fat, resulting in excessive weight gain and causing pathological and physiological changes or latent problems in the human body.

[0003] Obesity can lead to a variety of chronic diseases, and more than 200 diseases have been confirmed to be related to obesity. From 1975 to 2016, the global obesity rate almost tripled and has reached the scale of "pandemic". From 1990 to 2022, the obesity rate of men increased from 4.8% to 14.0%, and that of women increased from 8.8% to 18.5%. The number of obese adults globally increased from 194 million in 1990 to 878 million in 2022. By 2023, approximately 224 million children and adolescents globally will be suffering from obesity, and another 353 million people are overweight but do not meet the obesity criteria. Surveys show that 89.1% of obese people have at least one complication, including hypertension (36.9%), dyslipidemia (42.4%), diabetes (14.6%) and pre-diabetes (36.9%), fatty liver (81.8%).

[0004] Many obesity drugs have been withdrawn from the market due to various serious side effects (including but not limited to severe addiction, irreversible damage to the cardiovascular and cerebrovascular systems, central nervous system, etc.). Currently marketed GLP-1 drugs such as semaglutide present problems such as loose facial skin, sunken cheeks, an overall older appearance of the face, and sunken areas around the eyes due to suppressing appetite and muscle loss.

[0005] Therefore, there is an urgent need to develop a related drug that can lose weight without suppressing appetite and without muscle loss to meet the related needs of obese or overweight people. Summary of the Invention

[0006] To solve the current related problems of preventing or treating obesity, the present invention provides the use of a pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating obesity, and the structural formula of the pyrrolo[1,2-a]triazine compound is shown as Formula I:

[0007]

[0008] Among them, R1 is selected from H, F, Cl, Br or C 1-3 alkyl;

[0009] R2 and R3 are each independently selected from H, substituted or unsubstituted C 1-3 alkyl, wherein the substituted C 1-3 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br or I;

[0010] or R2 and R3 are joined together with the carbon atom to which they are attached to form a substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted piperidyl, wherein the substituted cyclopentyl, substituted cyclohexyl, substituted piperidyl are optionally substituted by 1, 2 or 3 R a substituted;

[0011] Each R a is independently selected from H, F, Cl, Br or C 1-3 alkyl;

[0012] R4 is selected from H, F, Cl, Br or C 1-3 alkyl;

[0013] R5 and R6 are each independently selected from H, F, Cl, Br, I or C 1-3 alkyl;

[0014] R7 is a substituted or unsubstituted pyrrolidinyl, wherein the substituted pyrrolidinyl is optionally substituted by 1, 2 or 3 R b substituted;

[0015] Each R b is independently selected from H, F, Cl, Br, I, substituted or unsubstituted C 1-3 alkyl, wherein the substituted C 1-3 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br or I;

[0016] n is 1 or 2;

[0017] The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

[0018] In some embodiments of the present invention, each of the above R a is independently selected from H, F, Cl, Br, -CH3 or -CH2CH3, and other variables are as defined in the present invention.

[0019] In some embodiments of the present invention, the above R2 and R3 are each independently selected from H, -CH3 or -CH2CH3, and other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, R2 and R3 are connected to the carbon atom to which they are attached to form R a and other variables as defined in the present invention.

[0021] In some embodiments of the present invention, R2 and R3 are connected to the carbon atom to which they are attached to form Other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, the above structural unit is selected from R1, R a Other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, the above structural unit is selected from

[0024] Other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, R1 is selected from C 1-3 alkyl, such as methyl, ethyl or propyl, and other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, R2 and R3 are connected to the carbon atom to which they are attached to form Other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, R4 is selected from C 1-3 alkyl, such as methyl, ethyl or propyl, and other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, R5 and R6 are each independently selected from H or methyl, and other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, n is 2, and other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above structural unit is R5, R6 and other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, R7 is selected from substituted by 1, 2 or 3 H, F, Cl or methyl Other variables are as defined in the present invention.

[0032] Preferably, the compound of formula I has a structure represented by any of the structural formulas of formula (I-1) to (I-4):

[0033]

[0034] wherein, R1, R4, R5, R6, R7, R a and n are as defined in the present invention.

[0035] In some embodiments of the present invention, each of the above R b is independently selected from H, F, Cl, Br, I, Other variables are as defined in the present invention.

[0036] In some embodiments of the present invention, the above R7 is selected from substituted or unsubstituted substituted or unsubstituted wherein the substituted substituted is optionally substituted by 1 or 2 R b and R b and other variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the above R7 is selected from R b and other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the above R7 is selected from Other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the above R4 is selected from H or -CH3, and other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the compound of formula I has a structure represented by any of the structural formulas of formula (I-5) to formula (I-9):

[0041]

[0042] wherein, R1, R5, R6, R a and R b are as defined in the present invention.

[0043] In some embodiments of the present invention, the above R1 is selected from H, F, Cl or Other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above R5 and R6 are each independently selected from H or Other variables are as defined in the present invention.

[0045] According to the solution of the present invention, the compound shown in Formula I is selected from the following structures:

[0046]

[0047]

[0048] In some solutions of the present invention, the inorganic acid of the above-mentioned inorganic acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid or phosphorous acid; the organic acid of the above-mentioned organic acid salt is selected from acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acids (such as arginine, etc.) or glucuronic acid.

[0049] In some preferred solutions of the present invention, the above-mentioned pharmaceutically acceptable salt is hydrochloride or p-toluenesulfonate.

[0050] In some solutions of the present invention, the dosage of the above-mentioned pyrrolo[1,2-a]triazine compound or its pharmaceutically acceptable salt is 5 - 600 mg / kg (specifically, it can be 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 50 mg / kg, 100 mg / kg, 150 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, etc.).

[0051] In some preferred solutions of the present invention, the dosage of the above-mentioned pyrrolo[1,2-a]triazine compound or its pharmaceutically acceptable salt is 5 - 20 mg / kg (specifically, it can be 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, etc.), 80 - 120 mg / kg (specifically, it can be 80 mg / kg, 90 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, etc.) or 280 - 320 mg / kg (specifically, it can be 280 mg / kg, 290 mg / kg, 300 mg / kg, 310 mg / kg, 320 mg / kg, etc.).

[0052] In some more preferred solutions of the present invention, the dosage of the above-mentioned pyrrolo[1,2-a]triazine compound or its pharmaceutically acceptable salt is 10 ± 0.1 mg / kg, 100 ± 1 mg / kg or 300 ± 3 mg / kg.

[0053] In some solutions of the present invention, the administration method of the above-mentioned pyrrolo[1,2-a]triazine compound or its pharmaceutically acceptable salt is oral administration.

[0054] In some embodiments of the present invention, the dosing frequency of the pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof is once a day, twice a day, three times a day, once a week, twice a week or three times a week.

[0055] In some embodiments of the present invention, when obesity presents with obesity-related non-alcoholic fatty liver disease, the dosing amount of the pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof is 5 - 600 mg / kg (specifically, it can be 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 50 mg / kg, 100 mg / kg, 150 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, etc.).

[0056] In some preferred embodiments of the present invention, when obesity presents with obesity-related non-alcoholic fatty liver disease, the dosing amount of the pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof is 5 - 20 mg / kg (specifically, it can be 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, etc.), 80 - 120 mg / kg (specifically, it can be 80 mg / kg, 90 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, etc.) or 280 - 320 mg / kg (specifically, it can be 280 mg / kg, 290 mg / kg, 300 mg / kg, 310 mg / kg, 320 mg / kg, etc.).

[0057] In some more preferred embodiments of the present invention, when obesity presents with obesity-related non-alcoholic fatty liver disease, the dosing amount of the pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof is 10 ± 0.1 mg / kg or 300 ± 3 mg / kg.

[0058] In some embodiments of the present invention, when obesity presents with obesity-related kidney disease, the dosing amount of the pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof is 5 - 600 mg / kg (specifically, it can be 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 50 mg / kg, 100 mg / kg, 150 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, etc.).

[0059] In some preferred embodiments of the present invention, when obesity presents with obesity-related nephropathy, the dosage of the pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof is 5-20 mg / kg (specifically, it can be 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, etc.), 25-35 mg / kg (specifically, it can be 25 mg / kg, 30 mg / kg, 35 mg / kg, etc.), 80-120 mg / kg (specifically, it can be 80 mg / kg, 90 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, etc.), 280-320 mg / kg (specifically, it can be 280 mg / kg, 290 mg / kg, 300 mg / kg, 310 mg / kg, 320 mg / kg, etc.) or 580-600 mg / kg (specifically, it can be 580 mg / kg, 590 mg / kg, 600 mg / kg, etc.).

[0060] In some more preferred embodiments of the present invention, when obesity presents with obesity-related nephropathy, the dosage of the pyrrolo[1,2-a]triazine compound or a pharmaceutically acceptable salt thereof is 10±0.1 mg / kg, 100±1 mg / kg or 300±3 mg / kg.

[0061] The present invention investigated the weight loss efficacy of the drug dosage on mice through an obesity model induced by a simple high-fat diet (DIO, Diet Induced Obesity) in C57BL / 6J mice. Therefore, the dosage given above in the present invention is also generalized based on mice. However, those skilled in the art know that the dosages for different species can be converted through body surface area. Therefore, when actually applied to other species such as humans, the dosage range will change accordingly. Based on the dosage given above in the present invention, those skilled in the art can obtain the corresponding dosages for other species such as humans according to the corresponding relationship between the body surface area and the dosage known in the art. For example, when the above dosage is 5-600 mg / kg, the dosage converted to the human dose according to the body surface area is approximately 0.45-53.53 mg / kg; another example is that when the above dosage is 10±0.1 mg / kg, the dosage converted to the human dose according to the body surface area is approximately 0.893±0.00893 mg / kg; and so on.

[0062] Advantages of the present invention:

[0063] The present invention provides the use of pyrrolo[1,2 - a]triazine compounds or their salts in the preparation of drugs for preventing and / or treating obesity. Animal experiments show that pyrrolo[1,2 - a]triazine compounds or their salts can significantly reduce the body weight of mice, slow down the body weight growth rate, reduce the content of perirenal fat, epididymal fat and inguinal fat, and reduce the fat content in the liver, and have no effect on appetite; the present invention further studies the effect of the dosage of pyrrolo[1,2 - a]triazine compounds or their salts on the body weight of mice, the effect of different dosages on the fat weight of different parts, and different parts show different weight - loss effects. The application of the present invention can provide a new drug source for the prevention or treatment of obesity, and has potential significant economic and social benefits. The preparation prepared from pyrrolo[1,2 - a]triazine compounds or their salts has the prospect of being used as a drug for treating obesity, and is expected to become a new drug for efficiently preventing and treating obesity without affecting appetite, and has a broad industrialization prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 Figure showing the body shape and liver appearance of mice 43 days after drug administration.

[0065] Figure 2 Figure showing the body weight growth curve and change rate of mice; among them, A is the growth curve and B is the body weight change rate.

[0066] Figure 3 Figure showing the comparison of the body weight of mice before the experiment and 41 days after drug administration.

[0067] Figure 4 Figure showing the food intake of mice during drug administration.

[0068] Figure 5 Figure showing the liver weight of mice 43 days after drug administration.

[0069] Figure 6 Figure showing the inguinal fat weight of mice 43 days after drug administration.

[0070] Figure 7 Figure showing the epididymal fat weight of mice 43 days after drug administration.

[0071] Figure 8 Figure showing the perirenal fat weight of mice 43 days after drug administration.

[0072] Figure 9 Figure showing the soleus muscle index of mice 43 days after drug administration. DETAILED DESCRIPTION OF THE INVENTION

[0073] The present invention will be further described in detail below through examples, but the protection scope of the present invention is not limited to the scope of the examples described herein.

[0074] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

[0075] The structural formula of the tosylate of Compound 12 (hereinafter referred to as tosylate) is shown below and is synthesized by existing processes (such as CN202380024770.7).

[0076]

[0077] Example 1: Pharmacodynamic study on weight loss of the tosylate of Compound 12 in an obesity model induced by a simple high-fat diet (DIO, Diet Induced Obesity) in C57BL / 6J mice

[0078] Model establishment: DIO mice of C57BL / 6J were purchased from Jiangsu Jicui Yakang Biotechnology Co., Ltd. The animals were housed in an SPF-level barrier system, following the international standard temperature, humidity, and light control system. The animals were housed individually in cages. The 60 kcal% high-fat diet was purchased from Research Diets. The mice had free access to food, and secondary reverse osmosis water was provided for them to drink freely. C57BL / 6J mice were fed a 60 kcal% high-fat diet starting from 6 weeks of age. After 14 weeks of feeding, they were 20 weeks old, and their body weight at 20 weeks was 45.35 ± 2.77 g. After a one-week adaptation period, they entered the experiment, and the high-fat diet was continuously fed during the adaptation period and the experiment period.

[0079] Experimental grouping and dosing cycle: The mice after the adaptation period were grouped. After grouping, the body weight of each group of mice was about 46.03 - 46.57 g, and there was no significant difference in the average body weight of each group of mice. They were respectively Group-1 10 mg / kg (n = 9), Group-2 30 mg / kg (n = 9), Group-3 100 mg / kg (n = 9), Group-4 300 mg / kg (n = 9), Group-5 600 mg / kg (n = 9); Group-6 saline (n = 3).

[0080] Table 1 Experimental grouping and dosing cycle

[0081] Grouping Quantity Model Information Test Article Dosing Dose (mg / kg) Dosing Period Group-1 9 DIO p-Toluenesulfonate 10 6 weeks Group-2 9 DIO p-Toluenesulfonate 30 6 weeks Group-3 9 DIO p-Toluenesulfonate 100 6 weeks Group-4 9 DIO p-Toluenesulfonate 300 6 weeks Group-5 9 DIO p-Toluenesulfonate 600 6 weeks Group-6 3 DIO Blank Vehicle NA 6 weeks

[0082] The dosing method for Group-1 to Group-6 was gavage, and the dosing frequency was once a day.

[0083] The body weight and food intake of the mice were collected every 2 days. On Day 43, the mice were weighed. The experimental animals were anesthetized with 3 - 5% isoflurane gas, the abdominal cavity was opened, and white adipose tissue, including epididymal, perirenal, and inguinal fat, was collected. The soleus muscle was collected and weighed to calculate the organ index.

[0084] Results: Figure 1Appearance of the body shape and liver of mice 43 days after drug administration. It can be seen from Figure 1 that in the 10 mg / kg group, the body shape of the animals became smaller compared with that of the vehicle group. The surface color of the liver was dark red, with a ruddy color, smooth surface, thinner edges, clear contours, and soft and elastic texture. In the 30 mg / kg group, there was no significant difference in the volume change of the animals' body shape compared with that of the vehicle group. The surface color of the liver was light red, slightly pale, smooth surface, clear contours, soft texture, and reduced elasticity. Compared with the vehicle group, in the 100 mg / kg group, the body shape decreased, the liver was light yellow, the surface was smooth, the texture was slightly hard, and the elasticity decreased. Compared with the vehicle group, in the 300 mg / kg group, the body shape decreased, the liver was light yellow, the surface was smooth, the texture was slightly hard, and the elasticity decreased. There was no significant difference in the body shape of the animals in the 600 mg / kg group compared with that of the vehicle group. The surface color was a mixture of dark red and light yellow, the surface was smooth, the texture was slightly hard, and the elasticity decreased.

[0085] Figure 2 Body weight growth curve and change rate (average value) of mice, where Figure 2 A is the growth curve, Figure 2 B is the body weight change rate. It can be seen from Figure 2 that the body weight was measured once every 2 days. The results showed that the body weight of the animals in the vehicle group continued to increase after the adaptation period, and the body weight growth rates of all drug-administered groups were lower than that of the vehicle group. Among them, the body weights of the animals in the 10 mg / kg and 300 mg / kg groups were significantly lower than that of the vehicle group on Day 9 (p < 0.05). Starting from Day 15, the body weights and body weight growth rates of the experimental animals in the 10 mg / kg, 100 mg / kg, and 300 mg / kg groups were extremely significantly lower than those of the animals in the vehicle group (p < 0.01). After Day 35, there was no significant difference in the body weight of the animals in the 10 mg / kg group compared with that of the vehicle group (p > 0.05), but the body weight growth rate was still significantly lower than that of the vehicle group (p < 0.01). The body weights and body weight growth rates of the 100 mg / kg and 300 mg / kg groups continued to be extremely significantly lower than those of the vehicle group (p < 0.01) until the end point. The body weights and body weight growth rates of the 30 mg / kg and 600 mg / kg groups were lower than those of the vehicle control group since Day 15, but there was no significant difference.

[0086] Figure 3 Comparison chart of body weight of mice before the experiment and 41 days after drug administration (average value). It can be seen from Figure 3It can be seen that compared with Day0, the body weight of mice in the solvent group increased significantly (p<0.05) on Day41, the body weight of mice in the 10mg / kg group decreased significantly (p<0.05), the body weight of mice in the 100mg / kg group decreased significantly (p<0.05), and the body weight of mice in the 300mg / kg group decreased extremely significantly (p<0.01). After 41 days of drug administration, the body weights of mice in the 30mg / kg and 600mg / kg groups showed no obvious changes compared with the pre-experiment body weights, and there was no significant increase similar to that in the solvent group.

[0087] Figure 4 It is the food intake graph (average value) of mice during drug administration. The feeding results of animals once every 2 days showed that there were no significant differences in food intake after the animals adapted to the drug administration period (p>0.05).

[0088] On Day43, dissections were performed, and the liver, inguinal fat, epididymal fat, perirenal fat, and soleus muscle were collected and weighed respectively. The results showed that:

[0089] (1) Figure 5 It is the liver weight graph (average value) of mice 43 days after drug administration; from Figure 5 it can be seen that in terms of the liver weight index, compared with the solvent group, all drug administration groups showed a decrease;

[0090] (2) Figure 6 It is the inguinal fat weight graph (average value) of mice 43 days after drug administration; from Figure 6 it can be seen that in terms of the inguinal fat weight index, all drug administration groups showed a decrease. Among them, the inguinal fat weights of animals in the 100mg / kg and 300mg / kg groups were extremely significantly lower than those in the solvent group (p<0.001), significantly lower than those in the 600mg / kg group (p<0.05), and extremely significantly lower than those in the 10mg / kg and 30mg / kg (p<0.01) groups of animals;

[0091] (3) Figure 7 It is the epididymal fat weight graph (average value) of mice 43 days after drug administration; from Figure 7 it can be seen that in terms of the epididymal fat weight index, compared with the solvent group, except for the 10mg / kg group, all drug administration groups showed varying degrees of decrease. Among them, the animals in the 100mg / kg group were significantly lower than the solvent group, and the animals in the 10mg / kg and 600mg / kg groups (p<0.05);

[0092] (4) Figure 8 It is the perirenal fat weight graph (average value) of mice 43 days after drug administration; from Figure 8 it can be seen that in terms of the perirenal fat weight index, compared with the solvent group, all drug administration groups showed a significant decrease;

[0093] (5) Figure 9Gastrocnemius muscle index graph (mean value) after 43 days of drug administration to mice; by Figure 9 It can be seen that in terms of the gastrocnemius muscle index, compared with the mice in the vehicle group, the animals in the 10 mg / kg group, 100 mg / kg group, 300 mg / kg group and 600 mg / kg group were all significantly increased (p < 0.05).

[0094] From the above, it can be seen that the tosylate of compound 12 can effectively reduce the body weight of DIO mice, slow down the body weight growth rate, reduce the perirenal fat, epididymal fat and inguinal fat content, and reduce the fat content in the liver, without affecting the appetite. Among them, the 10 mg / kg dose has a good effect in the early and middle stages of weight control, and there is a slight rebound in the later stage. The 100 mg / kg and 300 mg / kg doses have the best effect, with an early onset and a long duration of maintenance. The 100 mg / kg and 300 mg / kg doses have good efficacy in reducing inguinal fat. In reducing epididymal fat, the 100 mg / kg dose has a better effect. In reducing perirenal fat, the 10 mg / kg, 100 mg / kg and 300 mg / kg doses have a better effect.

Claims

1. Use of a pyrrolo[1,2 - a]triazine compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating obesity, characterized in that: The structural formula of the pyrrolo[1,2 - a]triazine compound is shown in Formula I: wherein, R1 is selected from H, F, Cl, Br, or C 1-3 alkyl; R2 and R3 are each independently selected from H, substituted or unsubstituted C 1-3 alkyl, wherein the substituted C 1-3 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br or I; or R2 and R3 are joined to the carbon atom to which they are attached to form a substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted piperidinyl, wherein the substituted cyclopentyl, substituted cyclohexyl, substituted piperidinyl are optionally substituted by 1, 2 or 3 R a substituted; Each R a is independently selected from H, F, Cl, Br or C 1-3 alkyl group; R4 is selected from H, F, Cl, Br or C 1-3 alkyl; R5 and R6 are each independently selected from H, F, Cl, Br, I or C 1-3 alkyl; R7 is a substituted or unsubstituted pyrrolidinyl, wherein the substituted pyrrolidinyl is optionally substituted by 1, 2 or 3 R b substituted; Each R b is independently selected from H, F, Cl, Br, I, substituted or unsubstituted C 1-3 alkyl, wherein the substituted C 1-3 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br or I; n is 1 or 2; The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

2. The use according to claim 1, wherein: Said R a is independently selected from H, F, Cl, Br, -CH3 or -CH2CH3; Preferably, each of R2 and R3 independently selected from H, -CH3 or -CH2CH3; Preferably, R2 and R3 are connected to the carbon atom to which they are attached to form Preferably, R2 and R3 are connected together with the carbon atom to which they are attached to form Preferably, the selected from Preferably, the selected from Preferably, the compound of Formula I has a structure shown in any one of the structural formulas (I - 1) to (I - 4): wherein, R1, R4, R5, R6, R7, R a and n are as defined above or in claim 1; Preferably, each R b is independently selected from H, F, Cl, Br, I, Preferably, the R7 is selected from substituted or unsubstituted substituted or unsubstituted wherein the substituted substituted is optionally substituted by 1 or 2 R b ; Preferably, the R7 is selected from Preferably, the R7 is selected from Preferably, R4 is selected from H or -CH3; Preferably, the compound of Formula I has a structure shown in any one of the structural formulas (I - 5) to (I - 9): wherein, R1, R5, R6, R a and R b are as defined above or in claim 1; Preferably, R1 is selected from H, F, Cl or Preferably, each of R5 and R6 is independently selected from H or Preferably, R1 is selected from C 1-3 alkyl; Preferably, R2 and R3 are linked together with the carbon atom to which they are attached to form Preferably, R4 is selected from C 1-3 alkyl; Preferably, n is 2; Preferably, is Preferably, R7 is substituted by 1, 2 or 3 H, F, Cl or methyl Preferably, the compound shown in Formula I is selected from the following structures:

3. The use according to claim 1, characterized in that: The inorganic acid of the inorganic acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid or phosphorous acid; the organic acid of the organic acid salt is selected from acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p - toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or glucuronic acid; preferably, the pharmaceutically acceptable salt is hydrochloride or p - toluenesulfonate.

4. The use according to claim 1, wherein: The dosage of the pyrrolo[1,2 - a]triazine compound or its pharmaceutically acceptable salt is 5 - 600 mg / kg.

5. The use according to claim 4, wherein: The dosage of the pyrrolo[1,2 - a]triazine compound or its pharmaceutically acceptable salt is 5 - 20 mg / kg, 80 - 120 mg / kg or 280 - 320 mg / kg.

6. The use according to claim 5, characterized in that: The dosage of the pyrrolo[1,2 - a]triazine compound or its pharmaceutically acceptable salt is 10 ± 0.1 mg / kg, 100 ± 1 mg / kg or 300 ± 3 mg / kg.

7. Use according to claim 1, characterized in that: The administration method of the pyrrolo[1,2 - a]triazine compound or its pharmaceutically acceptable salt is oral administration.

8. The use according to claim 1, characterized in that: The administration frequency of the pyrrolo[1,2 - a]triazine compound or its pharmaceutically acceptable salt is once a day, twice a day, three times a day, once a week, twice a week or three times a week.

9. The use according to any one of claims 1 to 8, characterized in that: When obesity shows obesity - related non - alcoholic fatty liver disease, the dosage of the pyrrolo[1,2 - a]triazine compound or its pharmaceutically acceptable salt is 5 - 600 mg / kg; preferably 5 - 20 mg / kg, 80 - 120 mg / kg or 280 - 320 mg / kg; more preferably 10 ± 0.1 mg / kg or 300 ± 3 mg / kg.

10. The use according to any one of claims 1 to 8, characterized in that: When obesity shows obesity - related kidney disease, the dosage of the pyrrolo[1,2 - a]triazine compound or its pharmaceutically acceptable salt is 5 - 600 mg / kg; preferably 5 - 20 mg / kg, 25 - 35 mg / kg, 80 - 120 mg / kg, 280 - 320 mg / kg or 580 - 600 mg / kg; more preferably 10 ± 0.1 mg / kg, 100 ± 1 mg / kg or 300 ± 3 mg / kg.

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