Application of N-{4-[(4-cycloalkyl-1-piperazinyl) sulfonyl] phenyl} amide in preparation of medicine for treating obesity and related diseases thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to application of N-{4-[(4-cycloalkyl-1-piperazinyl) sulfonyl] phenyl} amide with a structure shown in a formula 1 in preparation of medicines for treating obesity and related diseases thereof, and in the formula 0 #, R1 is a C4-C10 saturated carbocyclic ring; and R2 is alkyl with 1 to 4 carbon atoms. The accidental research shows that the compound with the structure shown in the formula 1 and the derivative thereof can accidentally realize synergy based on the molecular structure and the combined synergy of the three-dimensional structure formed by the molecular structure, can effectively promote fat metabolism, has the effects of reducing blood sugar and losing weight, increasing the energy consumption of an organism and the like, and can be used for treating obesity and related diseases thereof.

Description

Technical field:

[0001] The present application belongs to the field of pharmaceutical technology, and specifically relates to the field of treatment of obesity-related diseases. Background technology:

[0002] In recent decades, overweight / obesity has become an epidemic disease that seriously threatens human health worldwide and has become a common problem on a global scale.

[0003] Obesity greatly increases the incidence of metabolic diseases (such as fatty liver and hyperlipidemia), cardiovascular and cerebrovascular diseases (such as hypertension, myocardial infarction and shock), bone and joint diseases (such as femoral osteoarthritis), Alzheimer's disease, depression, and even certain tumors (such as breast, pancreatic and liver tumors). In addition, obesity may also reduce the quality of life, weaken work creativity, lead to unemployment and other problems, and significantly increase the global health burden. Therefore, it is imperative to solve the problem of obesity.

[0004] At present, the methods for treating obesity mainly include exercise, drug intervention, health care therapy and surgical intervention. Among these methods, drug therapy has attracted much attention due to its high compliance and reliable efficacy, and the development of weight loss drugs has gradually become an important direction of global drug research and development. At present, peptide weight loss drugs on the market, such as human glucagon-like peptide-1 (GLP-1) analogs, have achieved great success in weight loss applications. These drugs lower blood sugar by enhancing insulin secretion and inhibiting glucagon secretion, while delaying gastric emptying and intestinal motility, prolonging satiety, and affecting the hypothalamus to control appetite, thereby reducing food intake. However, although this type of drug has specific market potential, there are some problems. For example, a study recently published in the Journal of the American Medical Association (JAMA) showed that GLP-1 weight loss drugs may increase the risk of patients suffering from "rare but serious" gastrointestinal diseases such as gastroparesis. In addition, although protein therapeutic proteins have high activity and specificity, they have limitations such as short half-life, poor stability, low solubility, and poor immunogenicity, and cannot prolong their therapeutic activity. Therefore, exploring small molecule compounds against obesity is of great significance for the effective treatment of obesity and related diseases. Summary of the invention

[0005] In order to solve the deficiencies in the prior art, the present invention provides an application of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide in the preparation of a drug for treating obesity and related diseases.

[0006] The second object of the present invention is to provide drugs and preparations for treating obesity and related diseases comprising the active molecules.

[0007] A use of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide in the preparation of a drug for treating obesity and related diseases, wherein the N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide is a compound having a structure of formula 1 and a pharmaceutically acceptable derivative thereof;

[0008]

[0009] In formula 1, R1 is C4~C 10 Saturated carbon ring;

[0010] The R2 is a C1-C4 alkyl group.

[0011] The present invention unexpectedly studies that the compound having the structure of formula 1 and its derivatives can unexpectedly achieve synergy based on the combined synergy of their molecular structure and the three-dimensional structure they form, can effectively promote fat metabolism, have the functions of reducing blood sugar and losing weight, increase the body's energy consumption, and can be used for the treatment of obesity and its related diseases. In addition, the compound of formula 1 described in the present invention has the characteristics of safety and non-toxicity.

[0012] In the present invention, the C4 to C 10 The saturated carbocyclic ring is a saturated monocyclic, spirocyclic or bridged ring having 4 to 10 carbon atoms; preferably, it is a monocyclic cycloalkyl group, such as cyclopentane, cyclohexane, cycloheptane and the like.

[0013] In the present invention, R2 is methyl or ethyl.

[0014] In the present invention, the N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide is a compound having a structure of formula 1-A;

[0015]

[0016] In the present invention, the pharmaceutically acceptable derivative is at least one of a pharmaceutically acceptable salt, crystal, cocrystal, and solvate of the compound of formula 1.

[0017] In the present invention, the obesity-related diseases are complications caused by obesity, for example, metabolic diseases (such as fatty liver, hyperlipidemia), cardiovascular and cerebrovascular diseases (such as hypertension, myocardial infarction and shock), bone and joint diseases (such as femoral osteoarthritis), Alzheimer's disease, depression, and even certain tumors (such as breast, pancreatic and liver tumors) caused by obesity.

[0018] The present invention also provides a drug for treating obesity and related diseases, which comprises a pharmaceutically effective amount of the N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide.

[0019] The drug for treating obesity and its related diseases of the present invention further comprises pharmaceutically acceptable excipients, such as stabilizers, preservatives, excipients, cosolvents, flavoring agents, fillers, binders, disintegrants, solvents and other pharmaceutically acceptable ingredients for formulation requirements.

[0020] The drug for treating obesity and its related diseases of the present invention is also allowed to contain other active ingredients for treating obesity and its related diseases.

[0021] The medicine for treating obesity and its related diseases of the present invention also has a pharmaceutically acceptable dosage form.

[0022] In the present invention, the drug for treating obesity and its related diseases can be in oral or injectable form.

[0023] The oral preparations may be tablets, granules, oral solution preparations, capsules, etc. The injections may be intramuscular injections, intravenous injections, subcutaneous injections, etc.

[0024] Beneficial Effects

[0025] The present invention develops an application of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide in the preparation of a drug for treating obesity and related diseases. In addition, the drug of the present invention is safe and effective. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Formula 1-A reduces obesity and improves metabolic phenotype as a result.

[0027] Figure 2 This is to compare the results of formula A in reducing obesity and improving metabolic phenotype. DETAILED DESCRIPTION

[0028] Example 1: Formula 1-A increases fat thermogenesis and reduces obesity and insulin resistance caused by high-fat diet

[0029] C57Bl / 6 mice purchased from Jackson Lab were housed in a specific pathogen-free animal facility at a temperature of (23±1)°C, a relative humidity of 50-60%, and a light / dark cycle of 12 h. Mice had free access to food and water and were fed either normal chow or a high-fat diet (60% fat; Research Diets, New Brunswick, NJ) ad libitum. All animal studies were performed in accordance with protocols approved by the Animal Care and Use Committee of Central South University and in compliance with all relevant ethical regulations for animal testing and research.

[0030] In order to determine the function of the molecule of formula 1-A in the regulation of energy homeostasis, we introduced this organic molecule into high-fat-fed obese C57Bl / 6 mice by injection or gavage. First, we dissolved the molecule of formula 1-A in DMSO and prepared a 100 mg / ml stock solution. Then, we further diluted formula 1-A with saline to prepare a working solution with a concentration of 500 μg / mL or 50 μg / mL. Each mouse was injected with a corresponding volume of the working solution of the molecule of formula 1-A according to its body weight to ensure that the final concentration of formula 1-A in the mouse was 0.5 mg / kg or 5 mg / kg, respectively. The control group used the same volume of DMSO and added it to saline. The concentration of the working solution used in the gavage experiment was also the same as that of the injection. The control group was injected or gavaged with an equal amount of the dissolved solution of the molecule of formula 1-A. The effects of the molecule of formula 1-A on glucose tolerance and insulin sensitivity in mice were determined by glucose tolerance test (GTT) and insulin tolerance test (ITT). C56Bl / 6 mice and their 8-week-old littermates were fed ND or 60% HFD (Research Diets Inc; USA) for 12 weeks. For GTT, mice were fasted overnight and treated by intraperitoneal injection of glucose (2 g / kg). For ITT, mice were fasted for 6 hours and then injected with insulin (0.75 U / kg) intraperitoneally. Blood glucose levels were monitored using an ACCU-CHEK active blood glucose meter (Roche).

[0031] The effect of Formula 1-A molecules on mouse gene expression was detected by real-time quantitative PCR (qPCR). Mouse tissues were snap-frozen in liquid nitrogen and stored at -80°C until use. Total RNA was extracted using TRIzol reagent (Life Technologies, Carlsbad, USA) according to the manufacturer's instructions. mRNA was reverse transcribed and amplified using a 7900HT real-time PCR system (Applied Biosystem, USA). Changes in mouse protein expression were determined by immunoblotting.

[0032] The weight of mice was monitored weekly. The body fat composition of mice was determined using Minispec body fat composition analyzer LF50 (Bruker, Germany). The food intake and feces production of mice raised alone were measured every day for 4 consecutive days. The feces were dried and ground into fine powder, and then tested with an oxygen bomb calorimeter (IKA, Germany) according to the manufacturer's instructions. The heat excretion was calculated by multiplying the feces produced by the calorie content per gram of feces.

[0033] Thermogenesis in mice was measured by oxygen consumption and indirect calorimetry using a laboratory animal monitoring system (metabolic cages; CLAMS, Columbus Instruments, USA). Mice were fed ad libitum and housed in CLAMS and maintained under subthermoneutral (22°C) or thermoneutral (30°C) conditions for 3 days. For each experimental condition, metabolic variables were adjusted for differences in body composition by ANCOVA in the R programming language and a custom package for indirect calorimetry (CalR).

[0034] We injected formula 1-A into C57Bl / 6 mice intraperitoneally. Figure 1 . Formula 1-A can promote thermogenesis and reduce obesity. (A) Body weight changes of HFD-fed C57BL6 mice after treatment with Formula 1-A. Improvements in mouse and tissue body weight (B), glucose tolerance (C) and insulin sensitivity (D) after Formula 1-A treatment. (E) Metabolic cage assay showed that Formula 1-A treatment increased thermogenesis (E) and oxygen consumption (F). (G) Western blot analysis of UCP1 in BAT. (H) Formula 1-A treatment stimulated the expression of UCP1 in primary adipocytes. Oral administration of Formula 1-A reduced mouse body weight (I) and thermogenesis (J).

[0035] Our results showed that formula 1-A infusion significantly protected mice from high-fat feeding-induced weight gain ( Figure 1 A), while also improving glucose tolerance ( Figure 1 B) and insulin sensitivity ( Figure 1 C). Consistent with these results, metabolic cage analysis showed that injection of formula 1-A significantly increased heat production and oxygen consumption in mice ( Figure 1 D, E). After oral administration of 500 μg / mL ( Figure 1 GH) or 50 μg / mL ( Figure 1 IJ) In obese mice of formula 1-A, thermogenesis was also found to be enhanced (Figure). These findings together indicate that formula 1-A has an anti-obesity effect and may also affect energy consumption by promoting BAT thermogenesis and affecting the expression of thermogenic genes in adipocytes.

[0036] Comparative Example 1

[0037] Compared with Example 1, the only difference is that the comparative Replace the formula 1-A for comparative study, the experimental method is the same as Example 1. The results are shown in Figure 2 :

[0038] pass Figure 2 It can be seen that the formula 1-A described in the present invention can achieve a weight loss effect in a shorter time, and not only that, its weight loss effect is better.

Claims

1. Use of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide in the preparation of a drug for treating obesity and related diseases, characterized in that: The N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide is a compound having a structure of Formula 1 and a pharmaceutically acceptable derivative thereof; In formula 1, R1 is C4~C 10 Saturated carbon ring; The R2 is a C1-C4 alkyl group.

2. Use of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide according to claim 1 in the preparation of a drug for treating obesity and related diseases, characterized in that: The C4~C 10 The saturated carbocyclic ring is a saturated monocyclic ring, spirocyclic ring or bridged ring having 4 to 10 carbon atoms.

3. Use of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide according to claim 1 in the preparation of a drug for treating obesity and related diseases, characterized in that: The R2 is methyl or ethyl.

4. Use of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide according to claim 1 in the preparation of a drug for treating obesity and related diseases, characterized in that: The N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide is a compound having a structure of formula 1-A; 5. Use of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide according to any one of claims 1 to 4 in the preparation of a drug for treating obesity and related diseases, characterized in that: The pharmaceutically acceptable derivative is at least one of a pharmaceutically acceptable salt, crystal, cocrystal, and solvate of the compound of formula 1.

6. Use of N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide according to any one of claims 1 to 5 in the preparation of a drug for treating obesity and related diseases, characterized in that: The obesity-related diseases are complications caused by obesity.

7. A drug for treating obesity and its related diseases, characterized in that: A pharmaceutically effective amount of the N-{4-[(4-cycloalkyl-1-piperazinyl)sulfonyl]phenyl}amide described in any one of claims 1 to 6.

8. The drug for treating obesity and its related diseases according to claim 7, characterized in that: It is also permitted to contain other active ingredients for the treatment of obesity and its related diseases.

9. The drug for treating obesity and its related diseases according to claim 7 or 8, characterized in that: Also contains pharmaceutically acceptable excipients.

10. The drug for treating obesity and related diseases according to claim 7 or 8, characterized in that: It has a pharmaceutically acceptable dosage form, preferably an oral or injectable dosage form.

Images