Use of nitrone compounds for the preparation of a product for preventing or treating side effects caused by drugs for the treatment of obesity

Abstract

The application of nitrone compounds in the preparation of a product for preventing or treating side effects caused by drugs for preventing or treating obesity. Animal experiments show that the use of nitrone compounds in combination with glucagon-like peptide-1 drugs not only does not affect the ability of glucagon-like peptide-1 drugs to reduce the fat mass of mice, but also can resist / attenuate the side effects of glucagon-like peptide-1 drugs; and after stopping the use of glucagon-like peptide-1 drugs, continuing to administer nitrone compounds can delay the speed of weight rebound after drug withdrawal, especially the speed of fat mass rebound. The nitrone compounds of the application can effectively prevent or treat the side effects of glucagon-like peptide-1 drugs, and have important clinical significance.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to the application of nitroketone compounds in the preparation of products for preventing or treating side effects caused by drugs for obesity. Background Technology

[0002] Obesity is a chronic, progressive, and recurrent disease caused by excessive accumulation or distribution of adipose tissue and abnormal function, resulting from both genetic and environmental factors. In obese individuals, high body weight and excessive fat cause mechanical compression and space-occupying effects on multiple organs throughout the body. At the same time, the chronic inflammatory response caused by fat deposition also leads to a series of metabolic damages, thereby increasing the risk of chronic complications. Overweight / obesity is also the sixth leading risk factor for death and disability in my country in 2019 (Pan XF, Wang L, Pan A. Epidemiology and determinants of obesity in China[J].Lancet Diabetes Endocrinol, 2021,9(6):373-392.).

[0003] Glucagon-like peptide-1 (GLP-1) drugs are a new type of weight loss drug developed in recent years. They work by suppressing appetite, slowing gastric emptying, increasing satiety, reducing calorie intake, and affecting energy metabolism to achieve weight loss. A large-scale clinical trial involving 16 countries worldwide showed that semaglutide, a glucagon-like peptide-1 drug, has a significant weight loss effect. Subjects who received weekly subcutaneous injections of 2.4 mg of semaglutide experienced an average weight loss of 15.3 kg (Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002.). Results of a randomized, controlled, double-blind phase 3 clinical trial of Tirzepatide showed that once-weekly administration of 15 mg of Tirzepatide significantly reduced body weight, with an average weight loss of 23.6 kg (Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216.).Results of the GLORY-1 phase 3 clinical trial of mazdutide showed that after 48 weeks of treatment with 6 mg of mazdutide once a week, obese subjects experienced an average weight loss of 14.84%, compared to 0.47% in the placebo group (Ji L, Jiang H, Li H, et al. 1856-LB: efficacy and safety of mazdutide in Chinese participants with overweight or obesity (GLORY-1)[J]. Diabetes, 2024,73:1856-LB.). Results from the global phase 2 clinical trial of Survodutide showed that after 46 weeks of treatment with Survodutide 4.8 mg once weekly, obese subjects achieved an average weight loss of 14.9%, compared to 2.8% in the placebo group (Le Roux CW, Steen O, Lucas KJ, et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial[J]. Lancet Diabetes Endocrinol, 2024, 12(3): 162-173.). Results from a global phase 2 clinical trial of retatrutide in overweight / obese individuals showed that treatment with retatrutide 12 mg once weekly for 48 weeks resulted in a mean weight loss of 24.2%, compared to 2.1% in the placebo group (Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide forobesity—a phase 2 trial[J]. N Engl J Med, 2023, 389(6): 514-526.).

[0004] Although glucagon-like peptide-1 (GLP-1) drugs have outstanding weight loss effects, even when used at normal doses as prescribed (not due to drug abuse), they can cause many side effects such as decreased appetite (anorexia), constipation, and thyroid C-cell tumors. Due to the large number of unacceptable side effects of GLP-1 drugs, the proportion of subjects who drop out of clinical trials is as high as 15%-25%. Retrospective analysis found that it takes about a year to achieve the maximum weight loss effect with GLP-1 drugs, but only 40% of patients can persist for a year (Gasoyan H, Pfoh ER, Schulte R, Le P, Rothberg MB. Early- and later-stage persistence with antiobesity medications: A retrospective cohort study. Obesity. 2024 Mar;32(3): 486-493.).

[0005] Lean body mass includes cells, body water, muscle, bones, and other organs such as the heart, liver, and kidneys. Lean body mass is crucial for a healthy body; significant reduction can lead to various health problems, including difficulty fighting infections, osteoporosis, decreased muscle strength, difficulty regulating body temperature, and even an increased risk of death. In the general population, reducing energy intake is often aimed at fat loss. An important consideration associated with such dietary conditions is the ability to maintain lean body mass or slow its loss. Because lean body mass contributes significantly to the resting metabolic rate, maintaining it helps maintain energy expenditure. Therefore, the optimal fat loss plan should promote maximum lean body mass retention.

[0006] Glucagon-like peptide-1 (GLP-1) drugs affect energy metabolism, significantly reducing both fat mass and lean mass. Furthermore, fat mass rebounds after discontinuation of the drug, while lean mass is difficult to restore. Unlike muscle loss caused by disease or age, GLP-1-induced lean mass reduction has typical characteristics: it is induced by GLP-1 drugs, and lean mass reduction occurs from the very beginning of GLP-1 drug use. In a sub-study of the SUSTAIN 8 trial of semaglutide, after 52 weeks of treatment with 0.1 mg / week of semaglutide, the average reduction in adipose tissue weight was 3.4 kg, and the reduction in lean body mass (fat-free body mass) was 2.3 kg, with the lean body mass reduction accounting for 40% of the total weight loss (McCrimmon RJ, Catarig AM, Frias JP, Lausvig NL, le Roux CW, Thielke D, Lingvay I. Effects of once-weekly semaglutide vs once-daily canagliflozin onbody composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial. Diabetologia. 2020 Mar;63(3):473-485.). In the phase II clinical trial of masutilide, the lean body mass reduction in the 6 mg masutilide group accounted for 35% of the total weight loss after 24 weeks. In a Phase III clinical trial of liraglutide, the liraglutide group experienced a 29.8% reduction in lean body mass compared to total weight loss. Lean body mass reduction caused by glucagon-like peptide-1 drugs is a unique and extremely concerning side effect. This potentially irreversible loss of lean body mass is catastrophic for patients and could even lead to significant public health problems in the future.

[0007] Weight rebound is also a serious challenge that glucagon-like peptide-1 drugs need to face. The results of the STEP 1 (Semaglutide Treatment Effect in People with obesity 1) clinical trial extension showed that after 68 weeks of treatment, the subjects in the semaglutide group lost about 17% of their weight. After 52 weeks of treatment cessation, the subjects in the semaglutide group regained 11.6% of their weight, that is, rebounded to two-thirds of the previous weight loss (Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, Lingvay I, McGowanBM, Oral TK, Rosenstock J, Wadden TA, Wharton S, Yokote K, Kushner RF; STEP 1Study Group. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-1564.). A study published in JAMA showed that subjects taking tirzepatide lost approximately 20.9% of their body weight after 36 weeks, and recovered 11.1% of their body weight 52 weeks after stopping treatment (Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY, Ahmad NN, Zhang S, Liao R, Bunck MC, Jouravskaya I, Murphy MA; SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024 Jan 2;331(1):38-48.).

[0008] Main content

[0009] In order to address the problems in the prior art, the present invention aims to provide new uses for nitroketone compounds or pharmaceutically acceptable salts thereof, particularly the use of said compounds or pharmaceutically acceptable salts thereof in the preparation of products for the prevention or treatment of side effects caused by drugs for obesity.

[0010] The nitrone compound of the present invention has the structure shown in general formula (I):

[0011]

[0012] Where R1 is hydrogen, methyl, or; ;

[0013] R2 and R3 may be the same or different, and each is independently selected from hydrogen or C1-C6 alkyl; R4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl, and R5 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.

[0014] In some specific embodiments, the C1-C6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, preferably methyl, ethyl, or propyl.

[0015] In some specific embodiments, the nitrone compound is preferably TBN or TN-2:

[0016] .

[0017] In some specific embodiments, the "pharmaceutically acceptable salt" of the nitrone compound can be a salt formed with an inorganic acid, such as salts formed with the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfonic acid, phosphoric acid, or nitric acid; or a salt formed with an organic acid, such as salts formed with the following organic acids: methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, hexanoic acid, benzoic acid, salicylic acid, cinnamic acid, cyclopentanepropionic acid, dodecyl sulfuric acid, 2-naphthalenesulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, D-gluconic acid, or aspartic acid. Other pharmaceutically acceptable salts are also within the scope of this invention.

[0018] In some specific embodiments, the side effect is one or more of decreased appetite, decreased lean body mass, and constipation. In some specific embodiments, the side effect is decreased appetite (anorexia). In some specific embodiments, the side effect is decreased lean body mass. In some specific embodiments, the side effect is constipation.

[0019] This invention also provides the use of the above-mentioned nitroketone compounds or pharmaceutically acceptable salts thereof in the preparation of products for preventing or treating weight rebound or recovery after discontinuation of drugs for obesity. In some specific embodiments, the use is to delay the rate of weight rebound or recovery after drug discontinuation; preferably, the use is to delay the rate of fat weight rebound or recovery.

[0020] In some specific implementations, the product is a pharmaceutical product.

[0021] This invention also provides the use of nitroketone compounds or pharmaceutically acceptable salts thereof in combination with glucagon-like peptide-1 (GLP-1) drugs in the preparation of medicaments for treating obesity. In some specific embodiments, TBN and GLP-1 drugs are used in combination in the preparation of medicaments for treating obesity. This application involves TBN counteracting the side effects of GLP-1 drugs, such as decreased appetite, constipation, and reduced lean body mass, while simultaneously slowing down the rate of weight rebound / recovery after discontinuation of GLP-1 drugs, especially the rate of fat weight rebound / recovery.

[0022] In some specific embodiments, the obesity drug is a glucagon-like peptide-1 drug; preferably, it is a glucagon-like polypeptide drug containing the sequence glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl.

[0023] In some specific implementations, glucagon-like peptide-1 drugs are selected from dulaglutide, liraglutide, smegglutide, telpogglutide, enogglutide, mastodextide, esupragglutide, CagriSema, Cotadutide, Survodutide, HRS9531, HS-20094, BGM0504, Retatrutide, Efocipegdutide, Pemvidutide, DD01, Pemvidutide, PB-718, AZD9550, TB001, AMG133, CT-868, GMA106, VK2735, RAY1225, CT-388, HEC88473, MWN101, NN9487, DR10624, ZT002, MET097i, GSBR-1290, Petrelintide, etc.

[0024] In one embodiment, glucagon-like peptide-1 drugs are preferably dulaglutide, liraglutide, smegglutide, telpoglutide, mastodextide, inoglutide, Survodutide, Cotadutide, CagriSema, Retatrutide, HRS9531, HS-20094, or BGM0504.

[0025] In some specific embodiments, the glucagon-like peptide-1 drug is preferably smegglutide.

[0026] In some specific embodiments, the glucagon-like peptide-1 drug is preferably telpolide.

[0027] The combination of glucagon-like peptide-1 drugs and nitro ketone compounds described in this invention is based on the ability of the drugs to produce an effect in the body of the drug recipient. For example, the dosage can be selected from the commonly used clinical dosages of both drugs.

[0028] The administration method of the nitroketone compound or glucagon-like peptide-1 drug described in this invention can be selected in accordance with conventional methods in the art, and the administration method does not limit the effects produced by the combination of the present invention.

[0029] Glucagon-like peptide-1 (GLP-1) drugs suppress appetite, delay gastric emptying, increase satiety, and reduce calorie intake through the central nervous system, thereby affecting energy metabolism and achieving weight loss. Decreased appetite (anorexia) and constipation are common side effects of these drugs, and these side effects are clearly stated in the package inserts of GLP-1 drugs including smegglutide, telpoxetine, liraglutide, and dulaglutide. Decreased appetite (anorexia) is a group of diseases characterized by disordered eating behavior. Patients often experience malnutrition, metabolic disorders, and endocrine disorders. In severe cases, extreme malnutrition can lead to cachexia, organ failure, and even death. Constipation is a clinical symptom closely related to anorectal diseases, characterized by difficulty in defecation and / or reduced frequency of defecation, with hard, dry stools, severely impacting the patient's quality of life.

[0030] Based on extensive animal experiments investigating the efficacy of nitrone compounds, this invention reveals that DIO mice administered glucagon-like peptide-1 (GLP-1) drugs exhibit a significant decrease in water and food intake, and simultaneously develop constipation from the first day of administration. This invention is the first to demonstrate that the combination of nitrone compounds and GLP-1 drugs can improve water and food intake (increasing water and food consumption) and defecation patterns (improving stool color, volume, and consistency) in DIO mice, thereby alleviating side effects such as decreased appetite and constipation.

[0031] Glucagon-like peptide-1 (GLP-1) drugs affect energy metabolism, significantly reducing both fat mass and lean body mass, resulting in substantial weight loss upon discontinuation. This invention is the first to discover that combining nitroketone compounds with GLP-1 drugs not only does not affect the ability of GLP-1 drugs to reduce fat mass in mice, but also counteracts / weakens the side effect of GLP-1 drugs reducing lean body mass. Furthermore, continued administration of nitroketone compounds after discontinuation of GLP-1 drugs can slow down the rate of weight rebound (recovery) after drug withdrawal, especially the rate of fat mass rebound (recovery).

[0032] In summary, the nitroketone compounds of this invention can effectively prevent or treat the side effects of glucagon-like peptide-1 drugs and can slow down the rate of weight rebound (recovery) after drug withdrawal, which has significant clinical implications. Attached Figure Description

[0033] Figure 1 This is the experimental design flowchart for Example 1;

[0034] Figure 2 Example 1 shows the effects of combined administration of TBN and smegglutinin on the weight loss of DIO mice and on the body weight, fat weight, lean body weight, and body free water of mice after 4 weeks of administration.

[0035] Figure 3 This is the effect of TBN during the extended period of Example 1 on weight rebound after discontinuation of semaglutide;

[0036] Figure 4 Example 2: Effects of combined administration of TBN and smegglutinin for 4 weeks on body weight and fat mass in DIO mice;

[0037] Figure 5 Example 3: Effect of combined administration of TBN and telpolide for 4 weeks on DIO's drinking water and diet;

[0038] Figure 6 Example 3: Effects of combined administration of TBN and telpolide for 4 weeks on body weight, fat mass, lean body mass, and body free water in DIO mice;

[0039] Figure 7 Example 4 shows the effect of combined administration of TBN and telpolide for 1 week on feces in DIO mice. Detailed Implementation

[0040] The present invention will now be described in detail through specific embodiments. It should be noted that these embodiments are for further illustration only and should not be construed as limiting the scope of protection of the present invention. All glucagon-like peptide-1 drugs used in the embodiments of the present invention are commercially available products. Unless otherwise specified, all parts mentioned in the present invention are parts by weight, and all percentages are mass percentages.

[0041] Example 1: TBN for the prevention or treatment of side effects of semaglutide (Sema)

[0042] The experimental procedure is as follows Figure 1 As shown.

[0043] Phase 1 of the experiment: Obese male C57BL / 6J mice (DIO mice) induced by a high-fat diet were used. Mice were fed a high-fat diet starting at 5 weeks of age, with an average weight exceeding 45 grams at the start of the experiment. The animals were randomly assigned to two groups: a semaglutide monotherapy group (Sema 10 nmol / kg) and a semaglutide plus TBN combination therapy group (Sema 10 nmol / kg + TBN 30 mg / kg). TBN was administered twice daily by gavage at a dose of 30 mg / kg, while semaglutide was administered once daily by subcutaneous injection at a dose of 10 nmol / kg, for 4 consecutive weeks.

[0044] Phase II of the experiment: Starting from day 29, mice in the semagraft treatment group were further divided into a saline group and a TBN group. Mice in the saline group received semagraft treatment for 28 days, then discontinued treatment during the extension period (days 29-49) without receiving any other treatment; these were the mice that did not receive TBN throughout the experiment. Mice in the TBN group received semagraft treatment for 28 days, then discontinued semagraft treatment during the extension period (days 29-49), but received TBN treatment (30 mg / kg twice daily by gavage).

[0045] Similarly, starting from day 29, mice in the semaglutide and TBN combination treatment group were further subdivided into saline and TBN groups. Mice in the saline group received 28 days of combination treatment, and during the extension period (days 29-49), all treatment was discontinued, and they were given an equal volume of saline. Mice in the TBN group received 28 days of combination treatment, and during the extension period (days 29-49), semaglutide treatment was discontinued, but TBN treatment continued at the same dose; these were the mice that received TBN throughout the experiment. Mouse weight was measured weekly, and fat mass, lean mass, and fluid mass were measured using MRI on days 28 and 49. Data were analyzed using unpaired t-tests. Data are expressed as mean ± SEM, where n is the number of animals. **P < 0.001 compared to the semaglutide group. Abbreviation: Semaglutide (Sema), high-fat diet-induced obesity (DIO).

[0046] Results of the first phase of the experiment: During the 4-week treatment period, the weight loss of mice in both groups was as follows: Figure 2 As shown in Figure A, the weight measured on day 28 is as follows. Figure 2 As shown in B, the fat weight is as follows: Figure 2 As shown in C, lean body mass is as follows Figure 2 As shown in D, the body's free water... Figure 2 As shown in E, the mouse body weight, fat weight, lean body weight, and body free water values ​​tested on day 28 are as follows: Figure 2 As shown in F.

[0047] The results showed that compared with semaglutide alone, Sema + TBN treatment resulted in a 9.1% increase in body weight, but also an overall increase in lean body mass of 9.3%. Furthermore, compared with semaglutide alone, the fat mass remained essentially unchanged with Sema + TBN treatment, indicating that Sema + TBN therapy effectively prevented semaglutide-induced lean body mass loss without compromising the fat reduction effect of semaglutide.

[0048] Phase II results: Continued TBN treatment after discontinuation of semaglutide delayed weight regain.

[0049] Four weeks after administration of semaglutide, half of the DIO mice discontinued the drug, while the other half continued administration of TBN for three weeks. The effect on the degree of weight loss was as follows: Figure 3 As shown in A, the specific values ​​for the weight loss are as follows: Figure 3As shown in B. After 4 weeks of combined administration of TBN and smegglutinin, half of the DIO mice discontinued the drug, while the other half continued administration of TBN for 3 weeks. The effect on the degree of weight loss in the other half of the DIO mice is shown in Figure B. Figure 3 As shown in C, the specific values ​​for the weight loss are as follows: Figure 3 As shown in D. The experimental results showed that all groups experienced varying degrees of weight rebound after drug withdrawal. Among them, the weight rebound of mice that received extended TBN administration after semaglutide withdrawal was significantly less than that of mice that did not receive TBN.

[0050] Table 1 below shows the body weight, fat mass, lean mass, and body free water of mice that were not given TBN throughout the experiment (0-49 days) and mice that were given TBN throughout the experiment.

[0051] Table 1. Weight, fat mass, and lean mass measured on day 49.

[0052]

[0053] Table 1 clearly shows that mice that did not receive TBN throughout the experiment experienced a significantly greater weight rebound during the extended phase than mice that received TBN throughout the experiment. Furthermore, after discontinuation of Sema, lean body mass did not increase with overall body weight; the weight gain was primarily fat. Mice that did not receive TBN experienced an 83.52% rebound in fat weight, while mice that received TBN throughout the experiment experienced only a 68.65% rebound, significantly lower than the mice that did not receive TBN. This indicates that TBN can prevent weight rebound after discontinuation of glucagon-like peptide-1 (GLP-1) drugs for weight loss, especially fat rebound.

[0054] Example 2: TBN does not affect the weight loss and fat mass reduction effects of smegglutinin.

[0055] Obese male C57BL / 6J mice (DIO mice) induced by a high-fat diet were used. Mice were fed a high-fat diet starting at 5 weeks of age, with an average weight exceeding 45 grams at the start of the experiment. The animals were randomly assigned to three groups: a saline control group (DIO), a semaglutide-only treatment group (Sema), and a semaglutide-TBN combination treatment group (Sema + TBN). TBN was administered twice daily by gavage at a dose of 30 mg / kg, while semaglutide was administered once daily by subcutaneous injection at a dose of 30 nmol / kg for 4 weeks.

[0056] The experimental results showed that after 4 weeks, the body weight of DIO mice increased by 1% compared to baseline (before drug administration). The body weight change rates relative to baseline in the Sema-only group and the combined drug group (Sema + TBN) were -27% and -25%, respectively. Figure 4As shown in Figure A. After 4 weeks of experimentation, the fat mass of DIO mice decreased by 1% from baseline. The fat mass change rates relative to baseline in the Sema-only group and the combined drug group (Sema + TBN) were -57.8% and -58%, respectively. The experimental results are as follows. Figure 4 As shown in B. The above results demonstrate that TBN does not affect the effects of smegglutinin on weight loss and fat mass reduction.

[0057] Example 3: Prevention or treatment of side effects of TBN with Tirzepatide (Tirze)

[0058] Obese male C57BL / 6J mice (DIO mice) were induced to be obese using a high-fat diet. Mice were fed a high-fat diet starting at 5 weeks of age, with an average weight exceeding 45 grams at the start of the experiment. The experimental animals were randomly divided into three groups: a model group (DIO), a Tirzepatide 10 nmol / kg group (Tirze), and a combination therapy group (Tirzepatide 10 nmol / kg + TBN 30 mg / kg) (TBN+Tirze). TBN was administered twice daily by gavage at a dose of 30 mg / kg; Tirzepatide was administered once daily by subcutaneous injection at a dose of 10 nmol / kg. Administration continued for 4 weeks, and weekly body weight and total food and water intake were recorded. The rate of change in cumulative food intake in the Tirzepatide-only group and the combination therapy group (TBN+Tirze) relative to the DIO model group is shown in the figure below. Figure 5 As shown in Figure A, the rate of change of cumulative drinking water volume is as follows: Figure 5 As shown in B, the average total water and food intake per mouse over 4 weeks of drug administration is as follows: Figure 5 As shown in Figure C. The experimental results show that the water intake and food consumption of the TBN+Tirze group were significantly higher than those of the Tirze group, indicating that TBN effectively improved the decreased appetite (anorexia) in Tirze mice. Fat mass, lean mass, and fluid mass of the mice were measured using a magnetic resonance imaging (MRI) biopsy. Four weeks after administration, the rate of change in body weight between the Tirzepatide monotherapy group and the combined administration group (TBN+Tirze) relative to the model group is shown in Figure C. Figure 6 As shown in Figure A, the weight loss in both groups exceeded 30%. The rate of change in fat weight relative to the model group in the Tirzepatide monotherapy group and the combination therapy group (TBN + Tirze) is shown in Figure A. Figure 6 As shown in B, the decrease in fat weight exceeded 60% in both groups; the rate of change in lean body mass relative to the model group was as follows: Figure 6As shown in Figure C, the lean body mass decreased by 10.82% in the Tirzepatide monotherapy group, while the lean body mass decreased by 2.64% in the combination therapy group (TBN + Tirze), indicating that TBN effectively protected against the lean body mass reduction induced by tirzepatide; the changes in free water content in the body of mice in the Tirzepatide monotherapy group and the combination therapy group (TBN + Tirze) relative to the model group are shown in Figure C. Figure 6 As shown in D, TBN effectively reduced Tirzepatide-induced loss of free water in the body; specific values ​​for body weight, fat mass, lean body mass, and free water mass, as well as differences between groups, are shown in Figure D. Figure 6 As shown in E.

[0059] Example 4: TBN improves constipation caused by Tirzepatide (Tirze).

[0060] Obese male C57BL / 6J mice (DIO mice) were induced to be obese using a high-fat diet. Mice were fed a high-fat diet starting at 5 weeks of age, with an average weight exceeding 45 grams at the start of the experiment. The experimental animals were randomly divided into four groups: a model group (DIO), a TBN 30 mg / kg group (TBN), a Tirzepatide 10 nmol / kg group (Tirze), and a combination therapy group (Tirzepatide 10 nmol / kg + TBN 30 mg / kg) (TBN+Tirze). TBN was administered twice daily by gavage at a dose of 30 mg / kg; Tirzepatide was administered once daily by subcutaneous injection at a dose of 10 nmol / kg. The mice were administered the medication for one week, and their fecal samples were recorded. Fecal samples from days 1 and 7 are shown below. Figure 7 As shown, the results indicated that the Tirze group mice had smaller, darker, and harder feces, indicating constipation symptoms. The TBN+Tirze group mice showed significant improvements in fecal volume, color, and softness, suggesting that TBN improved the constipation induced by thiopeptide.

[0061] Based on the above experimental findings, TN-2 can also effectively prevent or treat the side effects of glucagon-like peptide-1 drugs.

Claims

1. The use of a nitroketone compound or a pharmaceutically acceptable salt thereof in the preparation of a product for the prevention or treatment of side effects caused by drugs for obesity; said nitroketone compound having the structure shown in general formula (I): ； in: R1 is hydrogen, methyl, or; ; R2 and R3 may be the same or different, each independently selected from hydrogen or C1-C6 alkyl groups; R4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; R5 is sec-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; the C1-C6 alkyl groups are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; preferably, the nitrone compound is selected from TBN or TN-2. 。 2. The application as described in claim 1, characterized in that: The obesity drug is a glucagon-like peptide-1 drug, preferably a glucagon-like polypeptide drug containing the sequence glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl.

3. The application as described in claim 1, characterized in that: The glucagon peptide drugs containing the glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl sequence are selected from dulaglutide, liraglutide, smegglutide, telpogglutide, enogglutide, mastodextide, esopagglutide, CagriSema, Cotadutide, Survodutide, HRS9531, HS-20094, BGM0504, Retatrutide, Efocipegdutide, Pemvidutide, DD01, Pemvidutide, PB-718, AZD9550, and TB001. AMG133, CT-868, GMA106, VK2735, RAY1225, CT-388, HEC88473, MWN101, NN9487, DR10624, ZT002, MET097i, GSBR-1290 or Petrelintide; preferably glutathione, liraglutide, smegglutide, telperidine, mastolide, inoglutide, Survodutide, Cotadutide, CagriSema, Retatrutide, HRS9531, HS-20094 or BGM0504; more preferably smegglutide or telperidine.

4. The application as described in any one of claims 1-3, characterized in that, The side effects are one or more of the following: decreased appetite, reduced lean body mass, and constipation.

5. The application as described in any one of claims 1-3, characterized in that, The side effect mentioned is decreased appetite.

6. The application as described in any one of claims 1-3, characterized in that, The side effect mentioned is a decrease in lean body mass.

7. The application as described in any one of claims 1-3, characterized in that, The side effect mentioned is constipation.

8. The use of a nitrone compound or a pharmaceutically acceptable salt thereof in the preparation of a product for the prevention or treatment of weight rebound or recovery after discontinuation of a drug for the prevention or treatment of obesity; said nitrone compound having the structure shown in general formula (I): ； in: R1 is hydrogen, methyl, or; ; R2 and R3 may be the same or different, and each is independently selected from hydrogen or C1-C6 alkyl; R4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; R5 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl. Preferably, the nitrone compound is selected from TBN or TN-2: 。 9. The application as described in claim 8, characterized in that, The application is to delay the rate of weight rebound or recovery after discontinuation of medication; preferably, the application is to delay the rate of fat weight rebound or recovery.

10. The application as described in claim 8 or 9, characterized in that, The obesity drug is a glucagon-like peptide-1 drug, preferably a glucagon-like polypeptide drug containing the sequence glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl.

11. The application as described in claim 10, characterized in that: The glucagon-like peptide drugs containing the glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl sequence are selected from dulaglutide, liraglutide, smegglutide, telpogglutide, enogglutide, mastodextide, esopagglutide, CagriSema, Cotadutide, Survodutide, HRS9531, HS-20094, BGM0504, Retatrutide, Efocipegdutide, Pemvidutide, DD01, Pemvidutide, PB-718, AZD9550, and TB001. AMG133, CT-868, GMA106, VK2735, RAY1225, CT-388, HEC88473, MWN101, NN9487, DR10624, ZT002, MET097i, GSBR-1290 or Petrelintide; preferably glutathione, liraglutide, smegglutide, telperidine, mastolide, inoglutide, Survodutide, Cotadutide, CagriSema, Retatrutide, HRS9531, HS-20094 or BGM0504; more preferably smegglutide or telperidine.

12. The use of a nitroketone compound or a pharmaceutically acceptable salt thereof in combination with a glucagon-like peptide-1 drug in the preparation of a medicament for treating obesity; said nitroketone compound having the structure shown in general formula (I): ； in: R1 is hydrogen, methyl, or; ; R2 and R3 may be the same or different, and each is independently selected from hydrogen or C1-C6 alkyl; R4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; R5 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl. Preferably, the nitrone compound is selected from TBN or TN-2: 。 13. The application as described in claim 12, characterized in that, The glucagon-like peptide-1 drugs are glucagon-like polypeptide drugs containing the sequence glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl; preferably dulaglutide, liraglutide, smegglutide, telpogglutide, enogglutide, mastodextide, esupragglutide, CagriSema, Cotadutide, Survodutide, HRS9531, HS-20094, BGM0504, Retatrutide, Efocipegdutide, Pemvidutide, DD01, Pemvidutide, PB-718, and AZD9550. The preferred formulations are: TB001, AMG133, CT-868, GMA106, VK2735, RAY1225, CT-388, HEC88473, MWN101, NN9487, DR10624, ZT002, MET097i, GSBR-1290, or Petrelintide; more preferably, glutathione, liraglutide, smegglutide, telperidine, mastolide, inoglutide, Survodutide, Cotadutide, CagriSema, Retatrutide, HRS9531, HS-20094, or BGM0504; further preferably, smegglutide or telperidine.

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