Compound 7-3A for reducing blood fat and application thereof

Abstract

The invention relates to a compound 7-3A for reducing blood fat and application of the compound 7-3A. The structure of the compound 7-3A is shown as a formula (1). Formula (1). The invention also relates to the following application of the compound as shown in the formula (1): (1) preparing a medicine or preparation for controlling and / or reducing the body weight of a hyperlipidemia patient; (2) preparing medicines or preparations for controlling and / or reducing the serum triglyceride (TG) level of hyperlipidemia patients; and (3) preparing a medicine or a preparation for inhibiting very low density lipoprotein (VLDL) of hyperlipidemia patients from transferring endogenous triglyceride.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical biotechnology, and specifically relates to a compound 7-3A that lowers blood lipids and its applications. Background Technology

[0002] Elevated low-density lipoprotein cholesterol (LDL-C) or plasma triglycerides (TG) are important risk factors for atherosclerosis. Statins are first-line treatments for the prevention and treatment of atherosclerotic cardiovascular disease, primarily working by lowering LDL-C levels. However, approximately 25% of high-risk cardiovascular patients do not experience significant lipid-lowering effects despite receiving adequate doses of statins. Some patients are intolerant to statins, experiencing adverse reactions such as myalgia and rhabdomyolysis. [1] Therefore, numerous trials have been exploring new targets and therapies for lowering LDL-C.

[0003] Proprotein convertase subtilisin 9 (PCSK9) is a newly discovered drug target for lowering LDL-C levels, discovered in 2003, and drugs targeting it have already been developed and marketed. PCSK9 is a proprotein convertase expressed in large quantities in the liver. The main physiological function of PCSK9 is to promote the degradation of LDLR. LDL-C in the blood can be cleared from the liver through the specific binding of its receptor (LDLR). In the liver, PCSK9 specifically recognizes and binds to the LDLR epidermal growth factor A (EGF-A) on the surface of liver cells. Subsequently, the PCSK9 / LDLR complex enters the cell and, via the endosomal lysosomal pathway, PCSK9 and LDLR are jointly degraded in lysosomes, leading to an increase in LDL-C levels. Therefore, inhibiting PCSK9 can significantly reduce LDL-C levels.

[0004] Currently, there are three main known strategies for inhibiting PCSK9: 1. Inhibiting the binding of PCSK9 to LDLR on the cell surface; 2. Interfering with the maturation and secretion of PCSK9; 3. Inhibiting the synthesis and expression of PCSK9 at the mRNA or protein level. [2] .

[0005] Currently, two human monoclonal antibodies (Mabs) were launched in 2015 as novel PCSK9 inhibitors: Evolocumab and Alirocumab, for the treatment of primary hypercholesterolemia or mixed dyslipidemia in adults (which can be used in combination with statins or other lipid-lowering drugs). [3,4]These drugs primarily employ strategy 1 to prevent PCSK9 from binding to LDLR. Additionally, Inclisiran, a small interfering RNA currently in Phase III clinical trials, is the first small molecule interfering RNA drug for regulating blood lipids. It is administered subcutaneously and employs strategy 3 to directly inhibit the synthesis and expression of PCSK9. [5] .

[0006] Large molecule antibody drugs and interfering RNA require injection, which is inconvenient for long-term administration of dyslipidemia, a chronic condition, and antibody preparations are currently expensive. In recent years, researchers have focused on developing small molecule PCSK9 inhibitors. However, due to the relatively flat surface of the PCSK9 protein's catalytic domain, the development of small molecules that directly inhibit protein-protein interactions is difficult. Therefore, many small molecule inhibitors with other mechanisms have been developed. Berberine (BBR) was one of the earliest reports to possess PCSK9 inhibitory activity, exerting its effect by inhibiting PCSK9 transcription. [6] Currently, a small molecule corydaline derivative, CVI-LM001, has entered Phase I clinical trials. [2] Corydaline is a naturally extracted acetylcholinesterase inhibitor, and its CVI-LM001 structure is very similar to berberine. Pfizer's PF-06815345 is a novel type of inhibitor obtained through screening and lead optimization; it is a PCSK9 mRNA translation inhibitor. [7] Other studies have attempted to indirectly inhibit the binding of PCSK9 and LDLR by utilizing the grooves near the EGF-A binding domain of PCSK9 and LDLR, through small molecule bonding that induces protein allosteric changes. [8] .

[0007] References: [1] Su T, Zhang P, Wang Z, Research progress of alicumab as a proprotein convertase subtilisin 9 inhibitor, Progress in Cardiovascular Diseases, 2016, 37 (1), 78-80. [2] -2Shengtao Xu, Shanshan Luo, Zheying Zhu, et al, Small molecules as inhibitors of PCSK9: Current status and future challenges, European Journal of Medicinal Chemistry, 162 (2019) 212-233. [3] Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term Low-DensityLipoprotein Cholesterol-Lowering Efficacy, Persistence,and Safety ofEvolocumab in Treatment of Hypercholesterolemia: Results Up to 4 YearsFromthe Open-LabelOSLER-1 Extension Study [J]. JAMA Cardiol, 2017, 2(6):598-607. [4] Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety ofalirocumab in reducing lipids and cardiovascular events [J]. N Engl J Med,2015, 372(16):1489-1499. [5] Nishikido T, Ray KK, Non-antibody Approaches to ProproteinConvertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides,Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Basedon New Discoveries, Front Cardiovasc Med. 2018; 5: 199. [6] J. Cameron, T. Ranheim, M.A. Kulseth, T.P. Leren, K.E. Berge,Berberine decreases PCSK9 expression in HepG2 cells, Atherosclerosis 201(2008) 266-273. [7] -8Allyn T. Londregan, Liuqing Wei, Jun Xiao, et al, SmallMolecule Proprotein Convertase Subtilisin / Kexin Type 9 (PCSK9) Inhibitors:Hit to Lead Optimization of Systemic Agents, J. Med. Chem. 2018, 61, 5704−5718 [8] -9T.E. Barta, JW Bourne, KD Monroe, MM Muehlemann, A.Pandey, S. Bowers, Phenylpiperazine Proprotein Convertase Subtilisin / kexinType 9 (PCSK9) Modulators and Their Use, 02 March, 2017. WO 2017 / 034997 A1. Summary of the Invention

[0008] This invention first relates to the use of compound 7-3A, as shown in formula (1), in the preparation of drugs for lowering blood lipids. Equation (1) .

[0009] This invention also relates to the following applications of compound 7-3A: (1) Prepare drugs or formulations for controlling and / or reducing the weight of patients with hyperlipidemia; (2) To prepare drugs or preparations for controlling and / or reducing serum triglyceride (TG) levels in patients with hyperlipidemia; (3) Prepare drugs or preparations that inhibit the transport of endogenous triglycerides by very low density lipoprotein (VLDL) in patients with hyperlipidemia.

[0010] The present invention also relates to a drug or drug composition comprising: (1) A therapeutically effective amount of compound 7-3A; (2) Necessary pharmaceutical excipients.

[0011] The drug or drug composition is an orally administered drug or drug composition.

[0012] The drug or drug composition mentioned above is: (1) Drugs or drug combinations that lower blood lipids, or (2) Drugs or drug combinations that control and / or reduce the weight of patients with hyperlipidemia, or (3) Drugs or drug combinations that control and / or reduce serum triglyceride (TG) levels in patients with hyperlipidemia, or (4) Drugs or drug combinations that inhibit the transport of endogenous triglycerides by very low density lipoprotein (VLDL) in patients with hyperlipidemia.

[0013] This invention also relates to a compound 7-3A for lowering blood lipids, the structure of which is shown in the following formula. .

[0014] The beneficial effects of this invention are as follows: (1) Compound 7-3A is a novel potential compound that has never been used in the development of lipid-lowering drugs. This study shows that, based on the previous lead compound IMB-7C5, this compound has significant advantages in terms of safety, efficacy, and therapeutic index.

[0015] (2) This study confirms that oral administration of compound 7-3A can significantly reduce serum triglyceride (TG) levels by inhibiting the transport of endogenous triglycerides (TG) by very low density lipoprotein (VLDL); thereby controlling and reducing the weight of hyperlipidemic animals and improving hyperlipidemic complications. Attached Figure Description

[0016] Figure 1 The effect of different concentrations of compound 7-3A on the weight of golden hamsters.

[0017] Figure 2 The effect of different concentrations of compound 7-3A on the TG content of golden hamsters.

[0018] Figure 3 The effect of different concentrations of compound 7-3A on the distribution of TG in serum lipoproteins in golden hamsters.

[0019] Figure 4 Effects of different concentrations of compound 7-3A on body weight of C57BL / 6J mice.

[0020] Figure 5 Effects of different concentrations of compound 7-3A on blood lipids in C57BL / 6J mice.

[0021] Figure 6 Cytotoxicity assay of compound 7-3A. Detailed Implementation

[0022] Experimental Materials and Methods Supplement the necessary experimental consumables and reagents as needed. The Yangshen drug IMB-7C5 (C5) is compound (7030B-C5) in the applicant's prior work 201910410812.6, and its structural formula is as follows: 2. Hyperlipidemia animal model (golden hamsters fed a high-fat diet) A suitable animal model is a primary factor in investigating the function and mechanism of compounds regulating lipid metabolism. Compared to other animal models, Syrian golden hamsters share more similarities with humans in lipid metabolism, such as using LDL as the main circulating lipoprotein, the presence of cholesterol transporter protein (CETP) in serum, and specific expression of ApoB100 in the liver. Furthermore, the hyperlipidemia model in this animal is established quickly. This study used LVG Syrian golden hamsters purchased from Vital River Pharmaceuticals in Beijing. Related animal experiments followed the experimental protocol approved by the Experimental Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and the hamsters were housed at the Experimental Animal Center of the Institute of Medicinal Biotechnology under suitable conditions with free access to food and water. All surgical procedures were performed under anesthesia, and postoperative analgesia was administered. Animal welfare principles were strictly adhered to during the experiment to minimize animal suffering. The hamsters were fed a high-fat diet (HFD, containing 0.25% cholesterol, 20% fat, and 40% fructose). Blood samples were taken every two weeks to measure plasma cholesterol and triglyceride levels. A significant increase in blood lipids after four weeks of feeding confirmed successful model establishment.

[0023] 3. Hyperlipidemia animal model (C57BL / 6J mice fed a high-fat diet) The C57BL / 6J mouse genome has a well-defined sequence and is widely used to establish various disease-related transgenic mouse models, such as the ApoE KO high-fat mouse model, which is commonly used for studies on lipid metabolism. In this study, C57BL / 6J mice were purchased from Vital River Pharmaceuticals in Beijing. Animal experiments were conducted in accordance with the experimental protocols approved by the Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and the mice were housed at the Institute's Experimental Animal Center under suitable conditions with free access to food and water. All surgical procedures were performed under anesthesia, and postoperative analgesia was administered. Animal welfare principles were strictly adhered to throughout the experiment, and every effort was made to minimize animal suffering. The mice were fed a high-fat diet (HFD, containing 0.15% cholesterol and 20% lard). Blood samples were taken every two weeks to measure plasma cholesterol and triglyceride levels. A significant increase in blood lipids after six weeks of feeding confirmed successful model establishment.

[0024] 4. Detection of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG). Blood was collected from the orbital vein to obtain plasma samples from each group of animals. The samples were centrifuged at 800 g for 3 minutes to collect serum samples. Serum samples were then analyzed using the following kits according to their instructions: Cholesterol Assay Kit (CHOD-PAP method, Zhong Sheng Bei Kong 100020080), High-Density Lipoprotein Cholesterol Assay Kit (Direct Method - Catalase Clearance Method, Zhong Sheng Bei Kong 100020235), Low-Density Lipoprotein Cholesterol Assay Kit (Direct Method - Surfactant Clearance Method, Zhong Sheng Bei Kong 100020245), and Triglyceride Assay Kit (GPO-PAP method, Zhong Sheng Bei Kong 100020090). The results were calibrated using the included standards. Samples were analyzed using a fully automated biochemical analyzer 7100. Non-high-density lipoprotein cholesterol (NDL-C) content was calculated by subtracting HDL-C from TC, which includes LDL-C and VLDL-C.

[0025] 5. FPLC method for separating serum lipoproteins In this study, different lipoproteins in serum were separated using the Akta instrument, and the contents of TC and TG in each lipoprotein component were determined using the above-mentioned TC and TG detection kits. Specifically, the following steps were taken: (1) The serum from each mouse in each group was mixed in equal volumes into one tube and filtered through a 0.22 μm filter.

[0026] (2) Turn on the Akta instrument, put tube a1 into PBS (Ph7.4), tube a2 into water, and tubes b1 and b2 into 20% ethanol for a long time (all liquids are filtered through a 0.22 μm filter). Use a syringe to remove air bubbles from the system.

[0027] (3) Before use, flush the system and replace the corresponding liquid in all 4 pumps (pump wash), set the system flow rate to 0.5 ml / min, and connect the Superose 6 Increase 10 / 300 GL column.

[0028] (4) Run Colunm prep and flush the system with water at a flow rate of 0.5 ml / min (flush for 1.5 column volumes).

[0029] (5) When separating the first sample, run First Sample Application. The system first equilibrates the column with PBS at a rate of 0.5 Ml / min. During the column equilibration, the sample is loaded. After the column is equilibrated for one column volume, the system automatically injects the sample and elutes it with PBS at a flow rate of 0.25 Ml / min. At the same time, prepare collection tubes. Collect 0.3 ml of the eluent in each ep tube, for a total of 63 fractions.

[0030] (6) Run the Rest Sample Application for the remaining samples (equilibrate only 0.1 column volume before system injection). Rinse the injection loop with water before each injection, and inject PBS to replace the liquid in the injection loop before injecting the next sample.

[0031] (7) After the experiment, rinse the system with water and 20% ethanol in sequence (rinse one column volume each time), and remove the column. Finally, put a1, a2, b1, and b2 into 20% ethanol to rinse the pump and system, so that all pipelines are filled with 20% ethanol.

[0032] (8) The contents of the corresponding indicators of the sample were determined on the fully automated biochemical analyzer 7100.

[0033] 6. MTT method The MTT assay, also known as the MTT colorimetric assay, is a method for detecting the effect of drugs on cell growth and survival. MTT can be reduced by succinate dehydrogenase in the mitochondria of living cells, forming water-insoluble blue-purple crystals called formazan, which are deposited in the cells. Dead cells do not exhibit this phenomenon. After the formazan is dissolved in DMSO, the absorbance at a wavelength of 490 nm is measured. Within a certain range, the amount of formazan is directly proportional to the number of living cells; therefore, the OD value can reflect the number of living cells. The specific operation is as follows: (1) HepG2 cells were subjected to a concentration of 4.5 × 10⁻⁶ cells. 5 The density is applied to a 96-well plate.

[0034] (2) After 24 h, the old culture medium in the well was aspirated, and the corresponding concentration of compound diluted in MEM culture medium was added. The mixture was then incubated in an incubator for 24 h.

[0035] (3) Add 10 μl of 5 mg / ml MTT solution to each well (final concentration is 0.5 mg / ml) and incubate in an incubator for 4 h.

[0036] (4) Discard the liquid in the well, add 100 μl / well of DMSO, and after all the crystals in the well are dissolved, detect them with an ELISA reader (490 nm).

[0037] (5) Calculate cell viability: Cell viability = (absorbance of drug-treated group / absorbance of control group) × 100%.

[0038] Example 1: Lipid-lowering effect of compound 7-3A in golden hamsters Golden hamsters were selected first to evaluate the in vivo lipid-regulating and anti-atherosclerotic activities of compound 7-3A.

[0039] Eight-week-old male golden hamsters were fed a normal diet (chow) and a high-fat diet (HFD, containing 0.25% cholesterol, 20% fat, and 40% fructose) for five weeks, respectively. Medications were administered via gavage. Specific drug concentrations and groupings were determined. Figure 1-3 (The abbreviations in parentheses are used in the illustrations below:) Normal diet group (chow): chow diet High-fat diet group (HFD): HFD diet 7-3A low-dose group (3A (L)): HFD + 10 mg / kg 7-3A 7-3A High-Dose Group (3A (H)): HFD + 50 mg / kg 7-3A IMB-7C5 group (C5): HFD + 50 mg / kg IMB-7C5.

[0040] 1.1 Effects of the compound on the body weight of golden hamsters From the start of the experiment, the weight of golden hamsters was measured weekly. The results showed that the weight of hamsters in each group gradually increased over time. The high-dose 7-3A group showed the most significant weight decrease, exhibiting a significant inhibitory effect in the second week of administration. The activity of 7-3A was particularly significant, and was superior to the previously reported active lead compound IMB-7C5. Figure 1 * indicates p < 0.05.

[0041] 1.2 Effects of the compound on triglyceride levels in golden hamsters Serum triglyceride (TG) levels are closely related to atherosclerosis and are an important biochemical indicator reflecting lipid metabolism; elevated TG levels are a risk factor for cardiovascular disease. Therefore, we measured serum TG levels in golden hamsters in each group (blood samples were collected via the retroocular vein at 0, 2, and 4 weeks of high-fat diet feeding, centrifuged, and analyzed using a TG detection kit). The results showed: After 4 weeks of feeding on a high-fat diet, compared with the normal diet (chow) control group, the serum TG level in the HFD group mice was significantly increased (approximately 3-fold). 50 mg / kg 7-3A significantly inhibited the HFD-induced increase in serum TG levels, while 50 mg / kg IMB-7C5 had no significant activity. Figure 2 ** indicates p < 0.01).

[0042] Triglycerides (TG) and very low-density lipoproteins (VLDL) are closely related in lipid metabolism. VLDL is the main transport carrier of TG, and the primary function of VLDL synthesis in the liver is to transport endogenous TG to peripheral tissues; approximately 50-60% of VLDL particles are TG. When liver TG synthesis increases, VLDL synthesis and secretion also increase accordingly, leading to elevated plasma TG levels. Clinically, elevated plasma TG levels usually reflect abnormal VLDL metabolism and are one of the core characteristics of metabolic syndrome. It is a cardiovascular disease Independent risk factors for the disease Therefore, we further used FPLC to separate the serum lipoproteins (mainly very low-density lipoprotein VLDL, low-density lipoprotein LDL, and high-density lipoprotein HDL) of the above-mentioned groups of golden hamsters according to their size, and measured the TG content in each lipoprotein component. At the end of the experiment, the results were measured after 4 weeks of high-fat diet. ).

[0043] The results show: Compounds 7-3A can significantly inhibit the increase in TG content in very low-density lipoprotein (VLDL) induced by HFD, and their activity is superior to C5 ( Figure 3 ).

[0044] Example 2: Lipid-lowering activity of compound 7-3A in C57BL / 6J mice The lipid-lowering effect and mechanism of 7-3A were preliminarily analyzed using C57BL / 6J mice. Eight-week-old male C57BL / 6J mice were fed a high-fat diet (containing 0.15% cholesterol and 20% lard) for 6 weeks, and the drug was administered via gavage. Specific drug concentrations and groupings are as follows (…). Figure 4-6 (The abbreviations in parentheses are used in the illustrations). Control group (veh): HFD diet 7-3A low-dose group (3A (L)): HFD + 10 mg / kg 7-3A 7-3A High-Dose Group (3A (H)): HFD + 50 mg / kg 7-3A IMB-7C5 group (C5): HFD + 50 mg / kg IMB-7C5.

[0045] 2.1 Effect of 7-3A on body weight of C57BL / 6J mice After the experiment began, the mice were weighed every two weeks. The results showed that the weight of each group of mice gradually and steadily increased over time. However, after 4 weeks of 7-3A administration, the weight of the mice decreased significantly. Figure 4 The weight-reduction activity of 7-3A is superior to that of C5, which is consistent with the effect of 7-3A on golden hamsters in Example 1.

[0046] 2.2 Effects of 7-3A on lipid levels in C57BL / 6J mice The effects of compound 7-3A on serum and liver cholesterol levels in C57BL / 6J mice were further investigated. The results showed that... The 50 mg / kg 7-3A (7-3A (H)) group showed significantly better activity in reducing serum TC, non-HDL-C, and TG than IMB-7C5. This result indicates that compound 7-3A can significantly reduce blood lipids, and its activity in reducing serum TC, non-HDL-C, and TG is significantly better than that of IMB-7C5. Figure 5 ).

[0047] Example 3: Toxicity and Therapeutic Index Study of Compound 7-3A 3.1 MTT assay for cytotoxicity of compounds (TC50) First, HepG2 cells were used, and the cytotoxicity of the compound was detected using the MTT assay. HepG2 cells were cultured at 4.5 × 10⁻⁶ cells / year. 5 The cells were seeded at a density of 7-3A in 96-well plates. Different concentrations of 7-3A were incubated with HepG2 cells for 24 h. Then, 10 μl of 5 mg / ml MTT solution (final concentration 0.5 mg / ml) was added, and the cells were incubated for 4 h. DMSO was added to dissolve the formazan crystals, and the absorbance of different cells was measured at 490 nm to detect the effect of the compound on the growth status and survival rate of HepG2 cells.

[0048] The results show that ( Figure 6 ): (1) When the compound concentration was <100 μM, the cell viability after treatment with compound 7-3A was more than 90% of that of the control group, confirming its TC 50 >100 μM indicates that 7-3A has no significant effect on cell growth; (2) TC of IMB-7C5 50 The concentration is approximately 33.4 μM. In summary, compound 7-3A exhibits lower toxicity, significantly superior to IMB-7C5.

[0049] 3.2 Acute toxicity test in animals (mice) The toxic response of experimental animals after a single or multiple drug treatments within 24 hours is evaluated by observing the subsequent poisoning symptoms or the number of deaths. The median lethal dose (LD50) in mice is calculated to assess the toxic effects of the compound and to provide a dosage reference for subsequent experiments. This is a commonly used indicator for evaluating drug toxicity.

[0050] C57BL / 6J mice were administered compound 7-3A by gavage at different concentrations (100 mg / kg, 250 mg / kg or 500 mg / kg) for a single time. The mice were then observed for 7 days at different time points.

[0051] The results (Table 1) showed that mice treated with compound 7-3A did not exhibit abnormal phenotypes and all survived.

[0052] therefore, The maximum tolerated dose of 7-3A is greater than 500 mg / kg, which is significantly better than that of IMB-7C5 (whose maximum tolerated dose is approximately...). 300 mg / kg .

[0053] 3.3 Therapeutic Index (TI) Detection The therapeutic index (TI) is a commonly used indicator for evaluating drug safety, usually expressed as the median lethal dose (TC). 50 ) and half effective amount (IC) 50 The ratio of ( ) indicates that the higher the activity or the lower the toxicity of a compound, the higher its therapeutic index, meaning it has greater potential for further development and application.

[0054] The therapeutic index of compound 7-3A is shown in Table 2.2. It shows that the PCSK9 transcriptional repression activity of 7-3A and 7-5D is comparable to that of IMB-7C5, while the cytotoxicity and acute animal toxicity are significantly reduced. Their therapeutic index is significantly better than that of the lead compound IMB-7C5.

[0055] Table 1. Statistical Table of Compound Therapeutic Index Finally, it should be noted that the above embodiments are only used to help those skilled in the art understand the essence of the present invention, and are not intended to limit the scope of protection of the present invention.

Claims

1. The application of compound 7-3A shown in formula (1) in the preparation of drugs for lowering blood lipids, Equation (1) .

2. The following applications of compound 7-3A shown in formula (1): (1) Prepare drugs or formulations for controlling and / or reducing the weight of patients with hyperlipidemia; (2) To prepare drugs or preparations for controlling and / or reducing serum triglyceride (TG) levels in patients with hyperlipidemia; (3) Prepare drugs or preparations that inhibit the transport of endogenous triglycerides by very low density lipoprotein (VLDL) in patients with hyperlipidemia.

3. A drug or drug composition comprising: (1) A therapeutically effective amount of compound 7-3A; (2) Necessary pharmaceutical excipients.

4. The drug or drug composition according to claim 3, characterized in that, The drug or drug composition is an orally administered drug or drug composition.

5. The drug or drug composition according to claim 3 or 4, characterized in that, The drug or drug composition mentioned above is: (1) Drugs or drug combinations that lower blood lipids, or (2) Drugs or drug combinations that control and / or reduce the weight of patients with hyperlipidemia, or (3) Drugs or drug combinations that control and / or reduce serum triglyceride (TG) levels in patients with hyperlipidemia, or (4) Drugs or drug combinations that inhibit the transport of endogenous triglycerides by very low density lipoprotein (VLDL) in patients with hyperlipidemia.

6. A compound 7-3A for lowering blood lipids, the structure of which is shown in the following formula. 。

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