Composition for preventing, ameliorating or treating metabolic diseases comprising lappaconitine derivative as active ingredient

Abstract

The present invention relates to a composition for preventing or treating metabolic diseases, comprising a novel lappaconitine derivative or an acceptable salt thereof as an active ingredient. The composition comprising a lappaconitine derivative, according to the present invention, effectively suppresses body weight gain without significantly affecting food intake, and exhibits a dual effect of reducing body fat and, at the same time, preventing a reduction in muscle mass and bone weight. In addition, the composition improves blood glucose and cholesterol levels, and thus can be used as a pharmaceutical composition for the prevention and treatment of metabolic diseases, including high-fat diet-induced obesity and menopausal obesity, and osteosarcopenic obesity syndrome.

Description

A composition for the prevention, improvement, or treatment of metabolic diseases comprising a rapaconitine derivative as an active ingredient

[0001] The present invention relates to a pharmaceutical composition for treating metabolic diseases, a health functional food composition, and a food composition comprising a rapaconitine derivative as an active ingredient.

[0002] Obesity refers to a condition in which adipose tissue is excessively accumulated in the body, and it can generally be caused by a long-term imbalance between energy intake and expenditure. Obesity is known to increase the risk of developing various metabolic diseases, such as type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease.

[0003] In particular, postmenopausal women are prone to increased body fat due to factors such as decreased estrogen, increased age, reduced basal metabolic rate, and decreased muscle mass, and changes in body fat distribution, such as abdominal fat accumulation, may occur. These changes may be accompanied by a decrease in muscle and bone tissue along with metabolic abnormalities, and as a result, can progress to complex pathological conditions such as osteosarcopenic obesity.

[0004] In addition, it is known that obesity induced by a high-fat diet can be accompanied not only by weight gain but also by metabolic abnormalities such as elevated blood sugar, lipid metabolism abnormalities, and insulin resistance.

[0005] Meanwhile, conventional obesity treatments induce weight loss through mechanisms such as appetite suppression, inhibition of fat absorption, or hormone regulation; however, they have limitations, including central nervous system-related side effects, gastrointestinal adverse reactions, or safety concerns regarding long-term administration. In particular, while recently used GLP-1 receptor agonist obesity treatments demonstrate excellent weight loss effects, issues regarding muscle mass or bone health have often occurred during the weight loss process.

[0006] Therefore, there is a need to develop a composition with a new mechanism capable of inhibiting fat accumulation while simultaneously inhibiting the reduction of muscle mass and bone tissue.

[0007] Accordingly, the inventors conducted research to solve the above-mentioned problem and identified a composition useful for inhibiting fat accumulation as well as protecting muscle and bone tissues, and based on this, completed the present invention.

[0008] The technical problem to be solved by the present invention is to provide a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a rapaconitine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] Another technical objective of the present invention is to provide a health functional food composition for the prevention or improvement of metabolic diseases comprising a rapaconitine derivative as an active ingredient.

[0010] Another technical objective of the present invention is to provide a food composition for the prevention or improvement of metabolic diseases comprising a rapaconitine derivative as an active ingredient.

[0011] Another technical objective of the present invention is to provide a method for preventing or treating metabolic diseases, comprising the step of administering a rapaconitine derivative or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0012] Another technical objective of the present invention is to provide a lapaconitine derivative or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of metabolic diseases.

[0013]

[0014] As one embodiment for achieving the above technical problem, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a lapaconitine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] [Chemical Formula 1]

[0016]

[0017] In Formula 1, R1 and R2 may each be independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxyalkyl, dihydroxyalkyl, aryl, arylalkyl, aminoalkyl, alkylaminoalkyl, acylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, allyl and / or heterocyclic groups. Specifically, the rapaconitine derivative of Formula 1 may be a compound represented by Formula 2.

[0018] [Chemical Formula 2]

[0019]

[0020] The metabolic disease described in the above composition may be obesity, diabetes, hyperlipidemia, dyslipidemia, metabolic syndrome, insulin resistance syndrome, non-alcoholic fatty liver disease, sarcopenic obesity, hypertension, atherosclerosis, hypertriglyceridemia, senile obesity, hereditary obesity, or fatty liver, and the obesity may be menopausal obesity, high-fat diet-induced obesity, abdominal obesity, visceral obesity, childhood obesity, senile obesity, hereditary obesity, or osteosarcoma-muscleopenia-obesity syndrome.

[0021] A composition comprising Chemical Formula 1 or Chemical Formula 2 as an active ingredient can prevent or treat osteosarcopenic obesity syndrome, which is accompanied by one or more diseases selected from the group consisting of obesity, sarcopenia, osteopenia, and osteoporosis, by simultaneously inducing inhibition of fat accumulation in the body, inhibition of bone tissue reduction, and increase in muscle mass.

[0022] As another embodiment for achieving the above technical problem, the present invention provides a health functional food composition for the prevention or improvement of metabolic diseases comprising a rapaconitine derivative represented by Formula 1 as an active ingredient. Specifically, the rapaconitine derivative of Formula 1 may be a compound represented by Formula 2.

[0023] A composition comprising Chemical Formula 1 or Chemical Formula 2 as an active ingredient can prevent or improve osteosarcopenic obesity syndrome, which is accompanied by one or more diseases selected from the group consisting of obesity, sarcopenia, osteopenia, and osteoporosis, by simultaneously inducing inhibition of body fat accumulation, inhibition of bone tissue reduction, and increase in muscle mass.

[0024] As another embodiment for achieving the above technical problem, the present invention provides a food composition for the prevention or improvement of metabolic diseases comprising a lapaconitine derivative represented by Formula 1 as an active ingredient. Specifically, the lapaconitine derivative of Formula 1 may be a compound represented by Formula 2.

[0025] As another embodiment for achieving the above technical problem, the present invention provides a method for preventing or treating a metabolic disease, comprising the step of administering a lapaconitine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof. Specifically, the lapaconitine derivative of Formula 1 may be a compound represented by Formula 2.

[0026] The above individual may be a menopausal woman at risk of reduced muscle mass or reduced bone density, or a patient with osteosarcopenic obesity.

[0027] In another embodiment for achieving the above technical problem, the present invention provides a lapaconitine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of metabolic diseases. Specifically, the lapaconitine derivative of Formula 1 may be a compound represented by Formula 2.

[0028] The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases, a health functional food composition for the prevention or improvement of metabolic diseases, and a food composition for the prevention or improvement of metabolic diseases, wherein the composition has the effect of inhibiting the accumulation of body fat and simultaneously inhibiting the reduction of muscle mass and bone tissue.

[0029] Figure 1 is a graph showing the weekly changes in body weight following the administration of QG30-OB in a high-fat diet (HFD)-induced obese mouse model.

[0030] Figure 2 is a graph comparing final body weight following the administration of QG30-OB in a high-fat diet (HFD)-induced obese mouse model.

[0031] Figure 3 is a graph showing the daily dietary intake following the administration of QG30-OB in a high-fat diet (HFD)-induced obese mouse model.

[0032] Figure 4 is a graph comparing the gain of body weight following the administration of QG30-OB in a high-fat diet (HFD)-induced obese mouse model.

[0033] Figure 5 is a graph showing the weekly changes in body weight following the administration of QG30-OB in an ovarian-resection (OVX)-induced menopausal obese mouse model.

[0034] Figure 6 is a graph showing the dietary intake following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model.

[0035] Figure 7 is a graph showing the Food Efficiency Ratio (FER) following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model.

[0036] Figure 8 is a graph showing the change in visceral fat weight following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model.

[0037] Figure 9 is a graph showing the change in femoral bone weight following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model. The Y-axis represents femoral bone weight (mg) relative to body weight (g), which means femoral bone weight (mg / g) per 1 g of body weight.

[0038] Figure 10 is a graph showing the change in muscle weight following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model. The Y-axis represents muscle weight (mg) relative to body weight (g), which means muscle weight (mg / g) per 1 g of body weight.

[0039] Figure 11 is a graph showing serum glucose concentrations following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model. The values ​​indicated inside each bar represent the average serum glucose concentration (mg / dl) measured in the corresponding group.

[0040] Figure 12 is a graph showing serum total cholesterol (T-CHO) concentrations following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model. The Y-axis represents serum total cholesterol concentration (mg / dL), and the values ​​inside each bar represent the average total cholesterol concentration measured in the corresponding group.

[0041] Figure 13 is a graph showing the change in relative weight of major organs (liver and spleen) following the administration of QG30-OB in an ovariectomized (OVX) menopausal obese mouse model. The Y-axis represents the relative ratio of organ weight to the vehicle control (% of vehicle control), where 100 is set as the reference value for the organ weight of the vehicle control. The substance labeled 'QG' refers to the compound listed as 'QG30-OB'.

[0042]

[0043] The meanings of the symbols commonly used in the drawings and experimental examples of this specification are as follows.

[0044] CTL (Control): CTL stands for Control, referring to a control group that has not been administered the drug.

[0045] QG30-OB: Rapaconitine derivative compound according to one embodiment of the present invention

[0046] Sham: Normal control group without ovarian removal (gastric surgery group)

[0047] Vehicle (or Control): A control group that was not administered drugs after disease induction (excipient-administered group)

[0048] OVX: Menopausal-induced obesity model via ovarian resection (Ovariectomized)

[0049] HFD: High-Fat Diet Feeding Obesity Model

[0050] PTH: Parathyroid hormone (positive control drug)

[0051] mpk: mg / kg (drug dosage per animal body weight)

[0052] FER: Food Efficiency Ratio

[0053] T-CHO: Total Cholesterol

[0054] bw: Body weight

[0055] Statistical Analysis: All experimental data were expressed as mean ± standard error (SEM), and statistical significance between groups was verified using Student's t-test or ANOVA. (*p < 0.05, **p < 0.01 vs. Vehicle or OVX control group)

[0056] Expressions such as “comprising,” “comprising,” “having,” etc. as described in this specification should be understood as open-ended terms implying the possibility of including other embodiments in a manner similar to “comprising,” unless otherwise stated in the phrase or sentence containing such expressions.

[0057] Meanwhile, regarding technical and scientific terms used in this specification, unless otherwise defined, they have the meanings commonly understood by those skilled in the art to which this invention pertains. These terms are defined in consideration of their functions within the invention and may vary depending on the intent or convention of the user or operator. Therefore, the definitions of these terms should be based on the content throughout this specification, and descriptions of known functions and configurations that could unnecessarily obscure the essence of the invention are omitted in the following description.

[0058] The language used in the specification and claims of this application shall not be interpreted as being limited to ordinary or dictionary meanings, but rather, based on the principle that the inventor may appropriately define the concepts of terms to best describe his invention, it shall be interpreted in a meaning and concept consistent with the technical spirit of the invention. Accordingly, the configurations of the embodiments described in this specification are merely one preferred embodiment of the invention and do not represent all of the technical spirit of the invention; therefore, it should be understood that various equivalents and modifications capable of replacing them may exist at the time of filing this application.

[0059]

[0060] The present invention will be described in more detail below.

[0061] The present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a lapaconitine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0062] [Chemical Formula 1]

[0063]

[0064] In Formula 1, R1 and R2 can each be independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxyalkyl, dihydroxyalkyl, aryl, arylalkyl, aminoalkyl, alkylaminoalkyl, acylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, allyl and / or heterocyclic groups.

[0065] Rapaconitine derivatives represented by Chemical Formula 1 may be used alone or in the form of a mixture of two or more, and may exist in the form of pharmaceutically acceptable salts.

[0066] The above "pharmaceuticalally acceptable salt" may include alkali metal salts or alkaline earth metal salts (calcium salts, etc.) such as ammonium salts, lithium, sodium, potassium, magnesium, and calcium salts, methylamine, ethylamine, propylamine, isopropylamine, butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidein, pyridine, quinoline, isoquinoline, benzathine, N-methyl-D-glucarmine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and hydravamin, salts with organic bases formed with arginine, lysine, etc.

[0067] As a preferred embodiment of the present invention, a lapaconitine derivative represented by Formula 1 may include a compound represented by Formula 2. 'QG30-OB' used in the following examples may refer to a lapaconitine derivative represented by Formula 2.

[0068] [Chemical Formula 2]

[0069]

[0070] A composition comprising a rapaconitine derivative of the present invention or a pharmaceutically acceptable salt thereof may act on energy metabolism regulatory pathways in the body to inhibit fat accumulation and exhibit effects of preventing loss of muscle and bone tissue. Specifically, the composition may exhibit effects of inhibiting weight gain and reducing body fat by regulating metabolic pathways that increase energy consumption while inhibiting adipogenesis or reducing fat accumulation. More specifically, the composition may act in a manner that inhibits fat synthesis and promotes fat oxidation by regulating energy homeostasis-related signaling pathways such as the AMP-activated protein kinase (AMPK) pathway.

[0071] In addition, a composition comprising a rapaconitine derivative of the present invention or a pharmaceutically acceptable salt thereof can exhibit a protective effect on muscle and bone tissue in addition to weight loss, rather than weight loss caused by simple appetite suppression, and thereby can inhibit the decrease in muscle mass and bone tissue that typically accompanies the weight loss process.

[0072] Accordingly, a composition comprising a rapaconitine derivative of the present invention or a pharmaceutically acceptable salt thereof can be usefully applied to the prevention or treatment of various metabolic diseases, including menopausal obesity and musculoskeletal obesity syndrome, through a multi-target metabolic regulatory mechanism that simultaneously regulates adipose tissue, muscle tissue, and bone tissue.

[0073]

[0074] In the present invention, the compound of Formula 1 can be prepared through reaction schemes 1 to 3. Specifically, the compound of Formula 1 can be prepared through the steps of: (a) reacting rapaconitine with an oxidizing agent; and (b) reacting the product of (a) with an organic solvent in the presence of a base.

[0075] According to one embodiment of the present invention, the rapaconitine of (a) may be rapaconitine hydrogen bromide, in which case step (a) may further include a process of removing hydrogen bromide before reacting the rapaconitine with an oxidizing agent. For example, the process of removing hydrogen bromide from rapaconitine hydrogen bromide may be carried out using dichloromethane in the presence of a base as shown in Reaction Scheme 1 below.

[0076]

[0077] [Reaction Equation 1]

[0078]

[0079] Subsequently, the above rapaconitine reacts with an oxidizing agent as shown in Reaction Scheme 2 and is oxidized to produce a rapaconitine derivative (LAD). The oxidizing agent may be selected from the group consisting of phenyl iodine diacetate (PhI(OAc)2) dissolved in dimethylformamide (DMF), lead(II) acetate (Pb(CH3CO2)2), lead(IV) acetate (Pb(CH3CO2)4), ozone, and HIO4.

[0080]

[0081] [Reaction Equation 2]

[0082]

[0083] In the present invention, the synthesized rapaconitine derivative (LAD) can react with an organic solvent in the presence of a base to produce a compound of QG30-OB (Chemical Formula 2). The base may be selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and potassium hydroxide, and the organic solvent may be an aliphatic alcohol or an alkoxy alcohol.

[0084] The above aliphatic alcohols refer to alcohols represented by the general formula CH3(CH2)nOH (where n is 0 or a positive integer), and the alkoxy alcohols refer to alcohols represented by the general formula CH3(CH2)nO(CH2)nCH3 (where n is independently 0 or a positive integer). For example, the above aliphatic alcohols may specifically be methanol, ethanol, n-propanol, isopropanol, n-butanol, etc., and the alkoxy alcohols may be methoxymethanol, methoxyethanol, ethoxyethanol, etc.

[0085] For example, the above rapaconitine derivative (LAD) can react with ethanol in the presence of sodium hydroxide as shown in Reaction Scheme 3 below to produce the compound of Formula 2 (QG30-OB).

[0086]

[0087] [Reaction Equation 3]

[0088]

[0089] QG30-OB can bind to target protein X and activate PKA (Protein Kinase A). Activated PKA induces phosphorylation of CREB (cAMP Response Element-Binding protein), and simultaneously, QG30-OB can promote phosphorylation of ERK1 / 2 (Extracellular signal-Regulated Kinase 1 / 2). Meanwhile, phosphorylated CREB and ERK1 / 2 move into the nucleus and increase the activity of transcription factors, including RUNX2 (Runt-related transcription factor 2). On the other hand, as a counterbalance to the activation of the above signaling pathway, the activity of adipocyte differentiation-related transcription factors, such as PPARγ (Peroxisome Proliferator-Activated Receptor gamma), can be inhibited.

[0090] Through the above mechanism, QG30-OB can exhibit an effect of preventing or treating obesity by inhibiting the differentiation of mesenchymal stem cells into adipocytes.

[0091] In addition, activation of the transcription factor RUNX2 actively promotes the differentiation of osteoblasts and muscle metabolism, thereby inhibiting the decrease in bone and muscle mass caused by aging and menopause, while simultaneously inhibiting PPARγ activity can selectively block only the differentiation and accumulation into adipocytes. Through this, the side effects of 'muscle and bone loss,' which are fatal limitations of conventional GLP-1 receptor agonist drugs, can be fundamentally overcome, and furthermore, therapeutic efficacy for 'osteosarcopenic obesity' can be demonstrated.

[0092] In the present invention, the term “metabolic disease” may refer to a disease caused by abnormalities in energy metabolism, glucose metabolism, and lipid metabolism within the body. Specifically, the metabolic disease may include obesity, diabetes, hyperlipidemia, dyslipidemia, metabolic syndrome, insulin resistance syndrome, non-alcoholic fatty liver disease, sarcopenic obesity, hypertension, atherosclerosis, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, senile obesity, hereditary obesity, or fatty liver.

[0093] The above-mentioned diabetes may include type 1 or type 2 diabetes and may include all forms of glucose metabolism abnormalities associated with increased insulin resistance or abnormal insulin secretion. In addition, the above-mentioned hyperlipidemia and dyslipidemia may include lipid metabolism abnormalities such as an increase in blood total cholesterol, low-density lipoprotein (LDL), and triglycerides, or a decrease in high-density lipoprotein (HDL). Furthermore, the above-mentioned fatty liver may include non-alcoholic fatty liver disease (NAFLD) and may include various liver metabolic abnormalities resulting from increased fat accumulation in liver tissue. Specifically, the above-mentioned obesity may include menopausal obesity, high-fat diet-induced obesity, abdominal obesity, visceral obesity, childhood obesity, senile obesity, hereditary obesity, or musculopenia-obesity syndrome.

[0094] In addition, the above pharmaceutical composition may be characterized by preventing or treating osteosarcopenic obesity syndrome (OSO) accompanied by one or more diseases selected from the group consisting of obesity, sarcopenia, osteopenia, and osteoporosis, by simultaneously inducing inhibition of body fat accumulation, inhibition of bone tissue reduction, and increase in muscle mass. Specifically, the above pharmaceutical composition may be characterized by preventing or treating osteosarcopenic obesity syndrome (OSO) in which obesity, sarcopenia, and osteopenia appear in combination, or in which obesity, sarcopenia, and osteoporosis appear in combination.

[0095] The above-mentioned osteosarcopenic obesity syndrome may refer to a pathological condition that goes beyond a simple increase in body fat and involves a combination of decreased bone density, increased fat accumulation in the bone marrow, decreased muscle mass, muscle strength, and muscle function, as well as an increase in body fat or fat redistribution. This condition can be understood as a complex metabolic disease state in which the homeostasis of bone tissue, muscle tissue, and adipose tissue is simultaneously impaired. The above-mentioned pharmaceutical composition may have preventive or therapeutic efficacy against osteosarcopenic obesity syndrome (OSO), which is a complex metabolic disease state.

[0096] Furthermore, the pharmaceutical composition of the present invention can exhibit a multi-target effect that comprehensively controls complex metabolic diseases by normalizing energy metabolism in the body to downregulate glucose concentration (improvement of diabetes) and suppressing total cholesterol (T-CHO) levels (improvement of dyslipidemia). In particular, according to one embodiment of the present invention, a composition comprising a rapaconitine derivative of the present invention or a pharmaceutically acceptable salt thereof can inhibit PPARγ activity and reduce glucose and total cholesterol (T-CHO) levels in the body to a significant degree, thereby blocking excessive lipid accumulation in liver tissue to directly contribute to the improvement of fatty liver, and can enable the fundamental treatment of diabetes by improving insulin sensitivity. Through this, it can be seen that a composition comprising a rapaconitine derivative of the present invention or a pharmaceutically acceptable salt thereof can exert therapeutic efficacy not only for the prevention and / or treatment of simple obesity but also across metabolic syndrome.

[0097] In particular, the above pharmaceutical composition may have excellent efficacy in the prevention or treatment of metabolic diseases in menopausal women that may be accompanied by abnormal bone metabolism, reduced muscle synthesis, and increased fat accumulation due to estrogen deficiency. In menopausal women, hormonal changes can lead to a simultaneous decrease in bone mass, a decrease in muscle mass, and an increase in body fat, making it highly likely to progress to osmotic obesity syndrome.

[0098] Meanwhile, while conventional obesity treatments, such as some drugs including GLP-1 receptor agonists, may exhibit excellent weight loss effects, a decrease in body fat mass, deterioration of bone health, or a decrease in muscle mass may occur during the weight loss process. In contrast, the above pharmaceutical composition inhibits fat accumulation while simultaneously acting on mechanisms related to bone formation and mechanisms related to muscle tissue maintenance or differentiation, thereby exhibiting useful efficacy in inhibiting or mitigating the reduction of bone and muscle tissue that may accompany the weight control process.

[0099] Specifically, the pharmaceutical composition of the present invention inhibits hypertrophy and fat accumulation of adipocytes, while regulating the activation of osteoblasts or bone formation-related pathways and acting on differentiation mechanisms related to the maintenance of muscle stem cells or muscle tissue. Accordingly, the pharmaceutical composition of the present invention can exhibit effective efficacy in the prevention or treatment of osteosarcoma-obesity syndrome (OSO) through the complex regulation of adipose tissue, bone tissue, and muscle tissue.

[0100] That is, the pharmaceutical composition of the present invention can be applied to the prevention or treatment of menopausal obesity caused by hormonal imbalance due to estrogen deficiency and the accompanying osteosarcopenic obesity (OSO).

[0101]

[0102] QG30-OB, the active ingredient of the pharmaceutical composition of the present invention, can inhibit or improve bone mass loss or the decline of bone-related indicators through the regulation of PKA / CREB and ERK1 / 2 pathways and mechanisms related to RUNX2 activity, and can also contribute to alleviating muscle tissue atrophy. In addition, QG30-OB can inhibit adipocyte differentiation and abdominal fat tissue accumulation by inhibiting PPARγ activity.

[0103] Therefore, the composition of the present invention can be usefully used for the prevention or treatment of osteomuscular obesity syndrome (OSO), which requires simultaneous inhibition of fat accumulation and protection of bone and muscle tissue.

[0104] The pharmaceutical composition of the present invention can suppress weight gain in a menopausal obesity model without significant changes in the average daily dietary intake or the dietary efficiency index (FER). This suggests that the effect of the composition may be mediated by a metabolic regulatory mechanism rather than simple appetite suppression.

[0105] Conventional appetite suppressants act on the central nervous system to inhibit appetite, but this commonly leads to cardiovascular side effects (such as palpitations and hypertension) and central nervous system side effects (such as anxiety and insomnia). Additionally, while fat absorption inhibitors block fat absorption in the gastrointestinal tract, they are accompanied by gastrointestinal side effects such as diarrhea and oily stools, as well as a risk of fat-soluble vitamin deficiency. Furthermore, when hormone regulators are used, various side effects have been reported, including nausea, vomiting, a risk of pancreatitis, and muscle loss. Moreover, conventional obesity treatments primarily induce weight loss through appetite suppression, inhibition of fat absorption, or hormone regulation mechanisms, focusing on reducing already accumulated fat. However, this approach has limitations as it involves the reduction of muscle and bone tissue, and it is particularly difficult to effectively treat complex metabolic diseases such as osmotic obesity syndrome.

[0106] On the other hand, the pharmaceutical composition of the present invention can help bone formation by inhibiting the activity of PPARγ, a transcription factor related to adipocyte differentiation, while simultaneously increasing the expression of a bone formation marker selected from the group consisting of RUNX2 (runt-related transcription factor 2), BMP2 (bone morphogenetic protein 2), and osteocalcin, which are transcription factors related to osteocytes differentiation. The stem cells may include mesenchymal stem cells, hematopoietic stem cells, adipose stem cells, bone marrow stem cells, etc.

[0107] Unlike conventional technologies that simply reduce fat accumulation, this mechanism of action regulates the balance between fat, bone, and muscle tissues during the cell differentiation stage, thereby inhibiting the reduction of muscle and bone tissues that may occur during the weight loss process.

[0108] In addition, through the mechanism of action described above, the pharmaceutical composition of the present invention can exhibit the effect of normalizing energy metabolism in the body beyond simple weight loss to reduce blood glucose concentration and total cholesterol levels, and thereby contribute to the improvement of various metabolic diseases including diabetes, dyslipidemia, and fatty liver.

[0109] Specifically, the diabetes includes type 1 diabetes, type 2 diabetes, insulin-resistant diabetes, and gestational diabetes; the dyslipidemia includes hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterolemia, and high low-density lipoprotein (LDL) cholesterolemia; and the fatty liver may be non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0110] In addition, the pharmaceutical composition of the present invention exhibits the effect of inhibiting the accumulation of adipose tissue while maintaining or increasing bone tissue and muscle tissue by regulating the differentiation balance of mesenchymal stem cells, and accordingly, it can be effectively applied not only to pathological conditions such as menopausal obesity and high-fat diet-induced obesity, but also to complex diseases such as osteosarcoma-obesity syndrome.

[0111] The above pharmaceutical composition may exhibit effects of inhibiting fat accumulation in the body, inhibiting bone tissue reduction, and inhibiting muscle mass reduction. In particular, since the composition of the present invention can induce weight loss while preventing muscle and bone loss that commonly occurs during the process of weight loss, it can be usefully used for the prevention or treatment of various metabolic diseases, including osteosarcopenic obesity syndrome.

[0112] In particular, the above composition can exhibit the effect of inhibiting weight gain and reducing fat accumulation in an obesity model induced by a high-fat diet and a menopausal obesity model induced by ovariectomy, while simultaneously inhibiting the reduction of bone and muscle tissue. In addition, the above composition can exhibit the effect of improving metabolic diseases by improving serum glucose and cholesterol levels without affecting dietary intake.

[0113]

[0114] In this specification, the term "pharmaceutical composition" may refer to a molecule or compound that imparts several beneficial effects upon administration to a subject. The beneficial effects may include enabling diagnostic decisions; improving a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder, or disease; and generally addressing a disease, symptom, disorder, or pathological condition.

[0115] In this specification, the term "composition" refers to a composition that can be administered parenterally during clinical administration and can be used in the form of a general pharmaceutical formulation. Parenteral administration may refer to administration via routes other than oral administration, such as rectal, intravenous, peritoneal, intramuscular, arterial, transdermal, nasal, inhalation, ocular, and subcutaneous. When the above-described pharmaceutical composition of the present invention is used as a pharmaceutical product, it may additionally contain one or more active ingredients exhibiting the same or similar functions.

[0116] The types of pharmaceutical active ingredients capable of delivering the above active ingredients into an organism may include anticancer agents, contrast agents (dye), hormone preparations, anti-hormone preparations, vitamin preparations, calcium preparations, mineral preparations, sugar preparations, organic acid preparations, protein amino acid preparations, detoxifiers, enzyme preparations, metabolic preparations, diabetes concomitant preparations, tissue revitalization agents, chlorophyll preparations, pigment preparations, tumor agents, tumor therapeutic agents, radiopharmaceuticals, tissue cell diagnostic agents, tissue cell therapeutic agents, antibiotic preparations, antiviral agents, combination antibiotic preparations, chemotherapy agents, vaccines, toxins, toxoids, antitoxins, leptospira serum, blood preparations, biological preparations, analgesics, immunogenic molecules, antihistamines, allergy preparations, non-specific immunogenic preparations, anesthetics, stimulants, psychotropic agents, small molecule compounds, nucleic acids, aptamers, antisense nucleic acids, oligonucleotides, peptides, siRNA, and microRNA, etc.

[0117] The above pharmaceutical composition may be prepared by additionally including one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may include saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures of one or more of these components, and other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added as needed. Additionally, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate the composition into injectable formulations such as aqueous solutions, suspensions, and emulsions, or into pills, capsules, granules, or tablets. Furthermore, the composition may be preferably formulated according to each disease or component by appropriate methods in the art.

[0118] When formulating the above pharmaceutical composition, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspension solvents. Witepsol, macrogol, Tween 61, cacao oil, lyulin oil, glycerogelatin, etc. may be used as bases for suppositories.

[0119] In order to increase stability or absorption, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers may be used as pharmaceutical agents in the above pharmaceutical composition.

[0120]

[0121] In addition to including a compound of Formula 1 as an active ingredient, the pharmaceutical composition of the present invention may further include suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceuticals. Carriers, excipients, and diluents that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0122] When formulating the pharmaceutical composition of the present invention, it is prepared using diluents or excipients such as commonly used fillers, volume expanders, binders, humectants, disintegrants, and surfactants. Solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules, and these solid dosage forms are prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the composition of the present invention. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid dosage forms for oral administration include suspensions, liquid formulations, emulsions, and syrups, and may include various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0123] The above "pharmaceuticalally acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals within the scope of pure medical judgment without causing excessive toxicity, irritation, or allergic reactions, and does not adversely affect the biological activity and physicochemical properties of the parent compound. The above pharmaceutically acceptable salt is well known in the art. The salt may be prepared in the same reaction system during the final separation and purification of the compound of the present invention, or separately by reacting it with an inorganic base or an organic base. Suitable addition salt forms include, for example, alkali metal salts and alkaline earth metal salts (calcium salts, etc.) such as ammonium salts, lithium, sodium, potassium, magnesium, calcium, etc., salts with organic bases, for example, primary, secondary, and tertiary aliphatic and aromatic amines, for example, methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucarmine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydravamin salts, and salts with amino acids such as arginine and lysine.

[0124] In the present invention, the hydrate or solvate of the compound of Formula 1 and / or Formula 2 can be prepared by conventional methods, for example, by dissolving the base compound of Formula 1 and / or Formula 2 in a solvent such as water, methanol, ethanol, acetone, or 1,4-dioxane, and then adding a free acid or free base, followed by crystallization or recrystallization.

[0125] Additionally, compounds of Formula 1 and / or Formula 2 may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may exist. Accordingly, the compounds of the present invention include each isomer or a mixture of these isomers. Furthermore, different isomers may be separated or decomposed by conventional methods, or any isomer may be obtained by conventional synthesis methods or by stereospecific or asymmetric synthesis. Additionally, the compounds of the present invention include radioactive derivatives of compounds represented by the formulas, and these radioactive compounds are useful in the field of biological research.

[0126]

[0127] According to one embodiment of the present invention, the present invention provides a health functional food composition for the prevention or improvement of metabolic diseases comprising a lapaconitine derivative represented by Chemical Formula 1 as an active ingredient. The lapaconitine derivative included in the health functional food composition may be a compound represented by Chemical Formula 1, and preferably may be a compound represented by Chemical Formula 2, but is not limited thereto.

[0128] The above-mentioned health functional food composition may additionally include various food-grade acceptable additives in addition to the active ingredient. For example, the additives may include, but are not limited to, sweeteners, flavorings, colorings, preservatives, acidulants, stabilizers, emulsifiers, thickeners, or mixtures thereof. Furthermore, the above-mentioned health functional food composition may be manufactured in various forms, for example, tablets, capsules, powders, granules, pills, liquids, jellies, stick-type products, or beverages, but is not limited thereto.

[0129] The above-mentioned health functional food composition may have the effect of inhibiting fat accumulation in the body, inhibiting bone tissue reduction, and inhibiting muscle mass reduction.

[0130] In addition, the above-described health functional food composition may be characterized by preventing or improving osteosarcopenic obesity syndrome, which is accompanied by one or more diseases selected from the group consisting of obesity, sarcopenia, osteopenia, and osteoporosis, by simultaneously inducing inhibition of body fat accumulation, inhibition of bone tissue reduction, and increase in muscle mass. Specifically, the above-described pharmaceutical composition may be characterized by preventing or improving osteosarcopenic obesity syndrome, which is characterized by the complex occurrence of obesity, sarcopenia, and osteopenia, or the complex occurrence of obesity, sarcopenia, and osteoporosis.

[0131] Regarding the active ingredients of the above-mentioned health functional food composition and their effects, the matters described in the above-mentioned pharmaceutical composition may be applied identically or similarly, provided that such matters do not conflict with the essential matters of the invention.

[0132] In this specification, the term "food" means a natural product or processed product containing one or more nutrients, preferably one that has undergone some degree of processing to become edible, and is used in a conventional sense and is not particularly limited in type, and the food composition may include food, food additives, health functional foods, and beverages.

[0133]

[0134] According to one embodiment of the present invention, the present invention provides a food composition for the prevention or improvement of metabolic diseases comprising a lapaconitine derivative represented by Formula 1 as an active ingredient. The lapaconitine derivative included in the food composition may be a compound represented by Formula 1, and preferably may be a compound represented by Formula 2, but is not limited thereto.

[0135] In addition to the active ingredient, the above food composition may additionally include various ingredients commonly used in food manufacturing. For example, the above food composition may include carbohydrates, proteins, fats, vitamins, minerals, dietary fiber, flavorings, sweeteners, colorings, stabilizers, or mixtures thereof, but is not limited thereto.

[0136] The above food composition may be manufactured in various food forms, for example, in the form of a beverage, confectionery, dairy product, or processed meat product, but is not limited thereto. Specifically, the food composition in the form of a beverage may be manufactured in the form of a functional beverage, tea, juice, or health drink, and the food composition in the form of a confectionery may be manufactured in the form of a biscuit, cookie, or snack. In addition, the food composition in the form of a dairy product may be manufactured in the form of yogurt, cheese, or fermented milk, and the food composition in the form of a processed meat product may be manufactured in the form of a sausage, ham, or other processed meat product.

[0137] Foods to which the composition of the present invention can be added include, for example, various types of food, beverages, chewing gum, candy, tea, vitamin complexes, functional foods, etc. Additionally, in the present invention, food includes, but is not limited to, special nutritional foods (e.g., infant formula, baby food, etc.), processed meat products, fish products, tofu products, jelly products, noodles (e.g., ramen, noodles, etc.), health supplements, seasoning foods (e.g., soy sauce, soybean paste, red pepper paste, mixed sauce, etc.), sauces, confectionery products (e.g., snacks), dairy products (e.g., fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various types of kimchi, pickled vegetables, etc.), beverages (e.g., fruit and vegetable beverages, soy milk, fermented beverages, ice cream, etc.), natural seasonings (e.g., ramen soup, etc.), vitamin complexes, alcoholic beverages, alcoholic drinks, and other health supplements. The above-mentioned food, beverage, or food additive may be manufactured by conventional manufacturing methods.

[0138] In addition, the above food composition may have the effect of inhibiting body fat accumulation, inhibiting bone tissue reduction, and inhibiting muscle mass reduction.

[0139] Regarding the active ingredients of the above food composition and their effects, the matters described in the above pharmaceutical composition may be applied identically or similarly, provided that such matters do not conflict with the essential matters of the invention.

[0140]

[0141] In addition, the present invention provides a method for preventing or treating a metabolic disease, comprising the step of administering a lafaconitine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof. In one embodiment, the lafaconitine derivative of Formula 1 may be a compound represented by Formula 2 below. Furthermore, the metabolic disease may be obesity, diabetes, hyperlipidemia, dyslipidemia, metabolic syndrome, insulin resistance syndrome, non-alcoholic fatty liver disease, sarcopenic obesity, hypertension, atherosclerosis, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, senile obesity, hereditary obesity, or fatty liver disease. By administering the above, the accumulation of body fat may be inhibited, and the reduction of muscle mass and bone tissue may be inhibited.

[0142] In addition, the present invention provides a lafaconitine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of metabolic diseases. In one embodiment, the lafaconitine derivative of Formula 1 may be a compound represented by Formula 2. The compounds of the present invention may have specialized uses for the prevention or treatment of metabolic diseases, particularly in patients with osteosarcopenic obesity (OSO) or menopausal women at high risk of reduced muscle mass and bone density due to estrogen deficiency.

[0143]

[0144] The present invention will be explained in detail below through examples, manufacturing examples, and experimental examples.

[0145] Meanwhile, the claims of the present invention are not limited to the following examples, manufacturing examples, and experimental examples, but should be interpreted to include all objects falling within the equivalent category.

[0146]

[0147] <Preparation Example 1> Preparation of QG30-OB Powder

[0148] 1-1. Preparation of Rapaconitine Derivatives (LADs) from Rapaconitine

[0149] A rapaconitine derivative (LAD) was prepared from rapaconitine using the following method.

[0150] 400 mL of dimethylformamide (DMF) was added to 50 g of rapaconitine hydrobromide, followed by the addition of 72.6 g of phenyliodine diacetate, and the mixture was stirred at 40°C for 10 minutes. Subsequently, 800 mL of ethyl acetate and 160 mL of an aqueous sodium bicarbonate solution were added. The DMF was then removed by washing twice with 500 mL of water, and the organic layer was separated. Anhydrous magnesium sulfate was added to the separated organic layer, and after drying, the mixture was filtered under reduced pressure. The filtrate was subjected to vacuum distillation to remove the solvent, and the crude product was obtained by vacuum drying for 6 hours. The product was dissolved in a minimal amount in an ethyl acetate / heptane (2:1, v / v) mixed solvent and loaded onto a silica gel 60 column equilibrated with the same solvent. The main peak was then eluted, and the result was vacuum distilled to obtain 20 g of rapaconitine derivative (LAD).

[0151]

[0152] 1-2. Manufacture of QG30-OB from LAD

[0153] QG30-OB was prepared from a rapaconitine derivative (LAD) using the following method.

[0154] 130 mL of ethanol and 9 mL of purified water were added to the rapaconitine derivative (LAD) of Example 1-1, and the mixture was cooled to 0°C. Subsequently, 2.9 g of sodium hydroxide was added, and the mixture was stirred at room temperature for 12 hours. After the reaction, the ethanol was removed by vacuum distillation. Then, 9.6 mL of purified water and 36 mL of dichloromethane were added for washing. Next, 2.4 g of ammonium chloride was dissolved in 8.4 mL of purified water and added, and the pH was adjusted to 9 to 10. Then, 54 mL of isopropanol / dichloromethane (85:15, v / v) was added for extraction, and 6 mL of an aqueous sodium chloride solution was added, followed by re-extraction using 54 mL of the same mixed solvent. 2 g of anhydrous magnesium sulfate was added to the separated organic layer, dried, and then filtered under reduced pressure. The solvent was removed by vacuum distillation of the filtrate, and the mixture containing QG30-OB was obtained by vacuum drying for 6 hours.

[0155]

[0156] <Experimental Example 1> Confirmation of Body Weight Inhibition Effect in High-Fat Diet-Induced (HFD) Obese Mice

[0157] Using the following method, the effect of QG30-OB on inhibiting weight gain in a high-fat diet-induced obesity model was confirmed.

[0158] C57BL / 6 mice were used as experimental animals, and the groups were organized as follows:

[0159] (1) Control group, (2) HFD group (high-fat diet control group), (3) HFD + QG30-OB 60 mg / kg administration group, (4) HFD + QG30-OB 150 mg / kg administration group, and (5) HFD + QG30-OB 300 mg / kg administration group.

[0160] To induce obesity, experimental animals were fed a high-fat diet (HFD) for 8 weeks. QG30-OB was orally administered once a day to the test groups at concentrations of 60, 150, and 300 mg / kg, respectively.

[0161] As a result, as shown in Figure 1, the HFD group fed a high-fat diet showed significant weight gain compared to the Control group fed a normal diet. On the other hand, in the test group administered QG30-OB, a tendency for weight gain to be significantly suppressed was observed starting from the 4th week of administration. In addition, as shown in Figure 2, an analysis of terminal body weight at the end of the experiment (week 8) revealed that the QG30-OB group showed a concentration-dependent weight loss effect compared to the HFD group. Meanwhile, as shown in Figure 3, no significant difference was observed between the experimental groups in the average daily dietary intake measured during the experiment. Furthermore, a comparison of net weight gain (as shown in Figure 4) also showed that the QG30-OB group exhibited a tendency for weight gain to be suppressed compared to the HFD group.

[0162] From the above results, it was confirmed that QG30-OB effectively suppresses weight gain induced by a high-fat diet without affecting dietary intake. Through this, it was confirmed that the composition can exert an obesity-improving effect not through an appetite-suppressing mechanism, but through a mechanism of regulating energy metabolism or inhibiting fat accumulation in the body.

[0163]

[0164] <Experimental Example 2> Confirmation of Weight Control Effect in Ovariectomy-Induced (OVX) Obesity Model

[0165] Using the following method, the effect of QG30-OB on inhibiting weight gain in a menopausal obesity model was confirmed.

[0166] C57BL / 6 female mice were used as experimental animals, and the groups were organized as follows:

[0167] (1) Sham group (control group without oophorectomy), (2) OVX group (group with oophorectomy), (3) QG30-OB 20 mg / kg administration group, (4) QG30-OB 60 mg / kg administration group, and (5) QG30-OB 200 mg / kg administration group.

[0168] To establish a menopausal obesity model, the ovaries of experimental animals were resected bilaterally (ovariectomy, OVX). After an obesity induction period of 8 weeks following ovariectomy, QG30-OB was orally administered once daily to the test groups at concentrations of 20, 60, and 200 mg / kg, respectively, for 10 weeks. During the experiment, body weight was measured regularly once a week, the weights of bone, fat, and muscle tissues were measured, and the expression of obesity-related factors in the serum was analyzed. The results are shown in Figures 5 to 7.

[0169] As a result, as shown in Figure 5, the OVX group showed a tendency for body weight to increase compared to the Sham group. On the other hand, in the test group administered QG30-OB, a tendency for significant inhibition of body weight gain was observed starting from the third week of administration. In addition, as shown in Figure 6, no statistically significant difference was observed between the experimental groups when comparing the average daily food intake measured during the experimental period. No significant difference was also confirmed between the groups when analyzing the Food Efficiency Ratio (FER) in Figure 7, which indicates the correlation between body weight change and food intake.

[0170] From the above results, it was confirmed that QG30-OB effectively suppresses weight gain caused by menopause without a change in dietary intake. Through this, it was confirmed that the composition can improve menopausal obesity not through appetite control via central nervous system inhibition, but through mechanisms of regulating energy metabolism or inhibiting fat accumulation.

[0171]

[0172] <Experimental Example 3> Confirmation of Efficacy in Inhibiting Fat Increase and Bone and Muscle Decrease in an Ovariectomy-Induced (OVX) Obesity Model

[0173] Using the following method, the effects of QG30-OB on fat, bone, and muscle tissue in a menopausal obesity model were confirmed.

[0174] C57BL / 6 female mice were used as experimental animals, and the groups were organized as follows:

[0175] (1) Sham group, (2) OVX group, (3) QG30-OB 20 mg / kg administration group, (4) QG30-OB 60 mg / kg administration group, and (5) QG30-OB 200 mg / kg administration group.

[0176] To establish a menopausal obesity model, the oophoresis was performed on experimental animals, and an obesity induction period of 8 weeks was applied after ovariectomy. The test groups were orally administered QG30-OB once daily for 10 weeks at concentrations of 20, 60, and 200 mg / kg, respectively. During the experiment, body weight was measured regularly once a week, and food intake was recorded daily. After the experiment, the animals were sacrificed to measure the weight of abdominal adipose tissue, and the weight of bone tissue, including the femur, and muscle tissue was analyzed. The results are shown in Figures 8 to 10.

[0177] As a result, as shown in Figure 8, a decreasing trend in the weight of abdominal adipose tissue was observed in the QG30-OB administration group compared to the OVX group. Additionally, as shown in Figure 9, the weight of bone tissue (femur) showed a decreasing trend in the OVX group, whereas this decrease was inhibited in the QG30-OB administration group. Meanwhile, as shown in Figure 10, a decreasing trend in the weight of muscle tissue reduced by OVX was observed in the QG30-OB administration group.

[0178] From the above results, it was confirmed that QG30-OB inhibits fat accumulation that increases in obese states, while simultaneously mitigating the reduction of bone and muscle tissue that may accompany weight loss or the progression of obesity. Through this, it was confirmed that the present composition can exhibit a favorable tissue-protective effect distinct from the muscle and bone loss that may be problematic with existing GLP-1 class obesity treatments. Furthermore, the compound of the present invention not only protects against bone and muscle loss that may accompany weight control but also exhibits selective metabolic modulation that contributes to maintaining or increasing muscle mass. Through this, it can be seen that a composition containing the compound of the present invention as an active ingredient can be usefully applied to patients with osteosarcopenic obesity, who are clinically vulnerable to bone and muscle loss.

[0179]

[0180] <Experimental Example 4> Analysis of Obesity-Related Factors in an Ovariectomy-Induced (OVX) Obesity Model

[0181] Using the following method, we confirmed whether QG30-OB causes toxicity or inflammatory side effects in metabolism-related organs and immune-related organs even under conditions of high-dose or long-term administration.

[0182] C57BL / 6 female mice were used as experimental animals, and the groups were organized as follows:

[0183] (1) Sham group, (2) OVX group, (3) QG30-OB 20 mg / kg administration group, (4) QG30-OB 60 mg / kg administration group, and (5) QG30-OB 200 mg / kg administration group.

[0184] To establish a menopausal obesity model, the oophores of experimental animals was bilateral, followed by an obesity induction period of 8 weeks. The test groups were orally administered QG30-OB once daily for 10 weeks at concentrations of 20, 60, and 200 mg / kg, respectively. The results are shown in Figures 11 to 13. After the experiment, serum was isolated to measure serum glucose and total cholesterol concentrations. Additionally, the weight of the liver and spleen was measured to determine the effects of the drug on major organs.

[0185] As a result, as shown in Figure 11, a decreasing trend in serum glucose concentration was observed in the test group administered QG30-OB compared to the OVX group. In addition, as shown in Figure 12, a decreasing trend in serum total cholesterol (T-CHO) was also confirmed, particularly in the 60 mg / kg administration group. Meanwhile, as shown in Figure 13, no significant difference in liver and spleen weight was observed between the QG30-OB administration group and the OVX group.

[0186] From the above results, it was confirmed that QG30-OB improves blood glucose control by reducing serum glucose concentration and alleviates dyslipidemia by lowering total cholesterol levels. Furthermore, it was confirmed to have excellent safety, as it did not induce significant changes in the weight of major metabolic and immune-related organs, such as the liver and spleen, even with high-dose or long-term administration.

[0187]

[0188] In summary, the above experimental examples confirmed whether a rapaconitine derivative (QG30-OB) could inhibit weight gain in a high-fat diet (HFD)-induced obese mouse model (Experimental Example 1); it was confirmed that in an ovariectomy (OVX) menopausal obese mouse model, the weight increase caused by OVX was significantly inhibited in the QG30-OB administration group, but there was no significant change in food intake (Experimental Example 2); it was confirmed that QG30-OB reduced the accumulation of abdominal fat tissue but inhibited or restored the reduction of bone and muscle tissue (Experimental Example 3); and it was confirmed that QG30-OB reduced serum glucose and total cholesterol levels, but no significant change was observed in the weight of major organs such as the liver and spleen, thus maintaining safety (Experimental Example 4).

[0189] Accordingly, the above composition can inhibit abdominal fat accumulation that increases in obese conditions, while simultaneously inhibiting or mitigating the decrease in muscle and bone tissue that may accompany weight loss or the progression of obesity; thus, it can be usefully applied in menopausal or senile obesity conditions where muscle mass and bone tissue are vulnerable.

[0190] Furthermore, the above composition can improve diabetes and dyslipidemia by reducing serum glucose and total cholesterol (T-CHO) levels, and can demonstrate excellent safety by not exhibiting significant toxicity to major metabolic and immune organs such as the liver and spleen even when administered at high doses or for a long period.

[0191] In addition, the above composition significantly inhibits the hypertrophy and accumulation of adipose tissue, while simultaneously blocking, through an independent mechanism, the decrease in bone tissue density (osteopenia) and muscle mass (sarcopenia) that may inevitably accompany obesity or rapid weight loss.

[0192] In addition, the above composition provides excellent effects in the prevention or treatment of osteosarcopenic obesity (OSO), which is characterized by a combination of obesity, sarcopenia, and osteopenia, and has a differentiated technical advantage that can overcome the problems of bone density and muscle loss caused by existing GLP-1 receptor agonist class therapies.

[0193] Based on the above results, the composition comprising the rapaconitine derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient has pharmaceutical utility in preventing or treating metabolic diseases through a multi-target metabolic regulatory effect that inhibits fat accumulation in the body while simultaneously inhibiting the reduction of muscle and bone tissue, and can be considered to have utility as a food or health functional food for preventing or improving metabolic diseases.

[0194]

[0195] The present invention has been described above with reference to its preferred embodiments. Those skilled in the art will understand that the present invention may be embodied in modified forms without departing from the essential characteristics of the invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the invention is defined by the claims, not by the foregoing description, and all variations within the scope of the claims should be interpreted as being included in the invention.

[0196] The scope of the present invention is defined by the claims set forth below, and all modifications or variations derived from the meaning and scope of the claims and equivalent concepts thereof should be interpreted as being included within the scope of the present invention.

Claims

1. A pharmaceutical composition for the prevention or treatment of metabolic diseases comprising, as an active ingredient, a rapaconitine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In Chemical Formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxyalkyl, dihydroxyalkyl, aryl, arylalkyl, aminoalkyl, alkylaminoalkyl, acylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, allyl, and heterocyclic groups.

2. In Paragraph 1, The rapaconitine derivative of the above chemical formula 1 is characterized as being a compound represented by chemical formula 2, Pharmaceutical composition for the prevention or treatment of metabolic diseases. [Chemical Formula 2] 3. In Paragraph 1 or 2, The above metabolic disease is, Characterized by obesity, diabetes, hyperlipidemia, dyslipidemia, metabolic syndrome, insulin resistance syndrome, non-alcoholic fatty liver disease, sarcopenic obesity, hypertension, atherosclerosis, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, senile obesity, hereditary obesity, or fatty liver. Pharmaceutical composition for the prevention or treatment of metabolic diseases.

4. In Paragraph 3, The above obesity is, Characterized by menopausal obesity, high-fat diet-induced obesity, abdominal obesity, visceral obesity, childhood obesity, senile obesity, hereditary obesity, or osteosarcopenic obesity (OSO) syndrome, Pharmaceutical composition for the prevention or treatment of metabolic diseases.

5. In Paragraph 1 or 2, The above composition is, Characterized by preventing or treating osteomuscular obesity syndrome, which is accompanied by one or more diseases selected from the group consisting of obesity, sarcopenia, osteopenia, and osteoporosis, by simultaneously inducing inhibition of body fat accumulation, inhibition of bone tissue reduction, and increase in muscle mass. Pharmaceutical composition for the prevention or treatment of metabolic diseases.

6. A health functional food composition for the prevention or improvement of metabolic diseases comprising a rapaconitine derivative represented by Chemical Formula 1 as an active ingredient: [Chemical Formula 1] In Chemical Formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxyalkyl, dihydroxyalkyl, aryl, arylalkyl, aminoalkyl, alkylaminoalkyl, acylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, allyl, and heterocyclic groups.

7. In Paragraph 6, The rapaconitine derivative of the above chemical formula 1 is characterized as being a compound represented by chemical formula 2, Health functional food composition for the prevention or improvement of metabolic diseases. [Chemical Formula 2] 8. In Paragraph 6 or 7, The above composition is, Characterized by preventing or improving osteomuscular obesity syndrome, which is accompanied by one or more diseases selected from the group consisting of obesity, sarcopenia, osteopenia, and osteoporosis, by simultaneously inducing inhibition of body fat accumulation, inhibition of bone tissue reduction, and increase in muscle mass. Health functional food composition for the prevention or improvement of metabolic diseases.

9. A food composition for the prevention or improvement of metabolic diseases comprising a rapaconitine derivative represented by Chemical Formula 1 as an active ingredient: [Chemical Formula 1] In Chemical Formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxyalkyl, dihydroxyalkyl, aryl, arylalkyl, aminoalkyl, alkylaminoalkyl, acylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, allyl, and heterocyclic groups.

10. In Paragraph 9, The rapaconitine derivative of the above chemical formula 1 is characterized as being a compound represented by chemical formula 2, Food composition for the prevention or improvement of metabolic diseases. [Chemical Formula 2] 11. A step comprising administering a lapaconitine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof, Methods for preventing or treating metabolic diseases: [Chemical Formula 1] In Chemical Formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxyalkyl, dihydroxyalkyl, aryl, arylalkyl, aminoalkyl, alkylaminoalkyl, acylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, allyl, and heterocyclic groups.

12. In Paragraph 11, A lapaconitine derivative of Chemical Formula 1 is characterized as being a compound represented by Chemical Formula 2, Methods for the prevention or treatment of metabolic diseases. [Chemical Formula 2] 13. In Paragraph 11 or 12, The above entity is, Characterized as being a postmenopausal woman at risk of muscle mass loss or bone density loss, or a patient with osteosarcopenic obesity syndrome, Methods for the prevention or treatment of metabolic diseases.

14. A lapaconitine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of metabolic diseases: [Chemical Formula 1] In Formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxyalkyl, dihydroxyalkyl, aryl, arylalkyl, aminoalkyl, alkylaminoalkyl, acylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, allyl, or heterocyclic groups.

15. A compound for use or a pharmaceutically acceptable salt thereof, characterized in that, in claim 14, the rapaconitine derivative of Formula 1 is a compound represented by Formula 2. [Chemical Formula 2] 16. A compound or a pharmaceutically acceptable salt thereof for use, characterized in that, in paragraph 14 or 15, the subject of prevention or treatment is a menopausal woman or a patient with musculoskeletal obesity syndrome at risk of muscle mass loss or bone density loss.

Images