Combination use of a nitroketone compound or a pharma- ceutically acceptable salt thereof with an SGLT-2 inhibitor

Abstract

The present invention provides a combination therapy of a nitroketone compound or its pharma- ceutically acceptable salt with an SGLT-2 inhibitor. Research has shown that the combination of the nitroketone compound TBN and TN-2 with an SGLT-2 inhibitor can synergistically lower blood glucose levels, reduce 24-hour urinary microalbumin and urinary albumin-creatinine ratio in db / db mice, and have a protective effect on the kidney. The inventors also unexpectedly found that the combination of a nitroketone compound with an SGLT-2 inhibitor can reduce the risk of urinary and reproductive tract infections caused by SGLT-2 receptor inhibitors.

Description

[Technical field]

[0001] The present invention relates to the field of biomedicine technology, and relates to a combination of drugs, in particular to a combination of a nitroketone compound or a pharma- ceutically acceptable salt thereof with an SGLT-2 inhibitor. [Background technology]

[0002] Diabetes is a group of metabolic diseases characterized by hyperglycemia. According to data released by the International Diabetes Federation in 2019, there are currently 463 million people with diabetes in the world, and it is predicted that by 2030, there will be 578 million people with diabetes worldwide, and this number will further increase to 700 million by 2045. China is the country with the most diabetes patients in the world, and the number of people with type 2 diabetes has already exceeded 120 million. Long-term high blood sugar levels damage large and small blood vessels, endangering tissues and organs such as the heart, brain, kidneys, surrounding nerves, eyes, and feet. According to statistics from the World Health Organization, there are more than 100 types of diabetic complications, making it the most common disease among currently known complications. Clinical data shows that 10 years after the onset of diabetes, 30-40% of patients will develop at least one complication. Traditional hypoglycemic drugs, such as insulin, biguanides, thiazolylene diketones, insulin secretagogues, α-glucosidase inhibitors, DPP-4 enzyme inhibitors, etc., are often limited to hypoglycemic effects and often fail to provide patients with comorbid benefits.

[0003] What makes it different from traditional diabetes-lowering drugs is the SGLT-2 inhibitor, whose Chinese name is “ SGLT-2 inhibitors are sodium-dependent glucose transporters 2 inhibitors, which inhibit glucose reabsorption by the kidney and reduce blood glucose by excreting excess glucose in the urine. SGLT-2 inhibitors have potential renal function protective effects in patients with mild to moderate renal insufficiency, and can improve proteinuria in diabetic patients and delay the progression of nephropathy. Clinical studies have shown that SGLT-2 inhibitors have a certain degree of acute kidney injury within 1-2 months of administration, which then gradually recovers and shows a renal protective effect one year later (David ZI Cherney,Francesco Cosentino,2 Samuel Dagogo-Jack,et al. Ertugliflozin and Slope of Chronic eGFR Prespecified Analyses from the Randomized VERTIS CV Trial, Clin J Am Soc Nephrol[J]. 2021 Sep;16(9):1345-1354).

[0004] Because SGLT-2 inhibitors can provide renal benefits while lowering glucose levels, in 2015, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) both recommended SGLT-2 inhibitors as second- or third-line treatments for type 2 diabetes, and they can be used in combination with metformin or other glucose-lowering drugs.

[0005] During clinical use, SGLT-2 inhibitors not only lower blood glucose levels, but also have renal protective mechanisms, providing new possibilities for the clinical treatment of diabetic complications. However, SGLT-2 inhibitors can increase urinary glucose excretion, increase local glucose concentrations in the urogenital tract, and increase the opportunities for bacterial and fungal infections. Summary of the Invention

[0006] In order to solve the problems in the prior art, the present invention aims to provide a composition, a kit and a combination of active ingredients in the manufacture of medicines for preventing or treating diabetes and its complications, and its use.Research shows that the combination of the nitroketone compound of the present invention or its pharmacologic acceptable salt with SGLT-2 inhibitor can enhance renal protective effect, and at the same time further reduce IL-6 level, and the results suggest that the combination can reduce the risk of urogenital infection of SGLT-2 inhibitor, which has important clinical significance.

[0007] In order to achieve the above object, the technical aspects of the present invention are as follows: A first aspect of the present invention provides a composition comprising: (A) a first active ingredient which is a nitroketone compound or a pharma- ceutically acceptable salt; (B) A second active ingredient that is an SGLT-2 inhibitor. The nitroketone compounds of the present invention have a structure represented by general formula (I): [ka] Where: R1 is a hydrogen atom, a methyl group, or [ka] and; R2, R3 are the same or different and are each independently selected from hydrogen or a C1-C6 alkyl group; R4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; and R5 is sec-butyl, isobutyl, tert-butyl or cyclohexyl.

[0008] In the nitroketone compound of the present invention, R2 and R3 are the same or different and are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and n-pentyl; R1 is hydrogen, a methyl group, [ka] It is. Further, the nitroketone compounds of the present invention are selected from the following structural formulas: [ka] .

[0009] According to some embodiments of the invention, the SGLT-2 inhibitor is selected from Dapagliflozin, Canagliflozin, Empagliflozin (abbreviated as Empag), Ipragliflozin, Luseogliflozin, Tofogliflozin, Ertugliflozin, Sergliflozin Etabonate, Sotagliflozin, Rongliflozin L-Pyroglutamic Acid, Wangliflozin, Tagliflozin, Gagliflozin, Henggliflozin, or combinations thereof.

[0010] A second aspect of the invention provides a medicine chest characterised in that it comprises: (A) a first formulation containing the nitroketone compound or a pharma- ceutically acceptable salt thereof; (B) A second formulation comprising an SGLT-2 inhibitor, the SGLT-2 inhibitor being selected from the group consisting of Dapagliflozin, Canagliflozin, Empagliflozin (abbreviated as Empag), Ipragliflozin, Luseogliflozin, Tofogliflozin, Ertugliflozin, Sergliflozin etabonate, Sotagliflozin, Rongliflozin L-Pyroglutamic Acid Salt, and the like. Acid, Wangliflozin, Tagliflozin, Gagliflozin, Henggliflozin, or a combination thereof. (C) Instructions. The medicine chest of the present invention is a carrier for storing or transporting medicines.

[0011] A third aspect of the present invention provides a pharmaceutical composition comprising: (A) a first active ingredient comprising the above nitroketone compound or a pharma- ceutically acceptable salt thereof; (B) a second active ingredient comprising an SGLT-2 inhibitor, the SGLT-2 inhibitor being selected from the group consisting of Dapagliflozin, Canagliflozin, Empagliflozin (abbreviated as Empag), Ipragliflozin, Luseogliflozin, Tofogliflozin, Ertugliflozin, Sergliflozin etabonate, Sotagliflozin, Rongliflozin L-Pyroglutamic Acid Salt, and the like. Acid, Wangliflozin, Tagliflozin, Gagliflozin, Henggliflozin, or a combination thereof. (C) A pharma- ceutically acceptable carrier.

[0012] A fourth aspect of the invention provides pharmaceutical combinations.

[0013] The nitroketone compound or its pharma- ceutically acceptable salt is used in combination with a drug containing an SGLT-2 inhibitor in the manufacture of a drug for preventing or treating chronic kidney disease.Furthermore, the nitroketone compound or its pharma-ceutically acceptable salt is used in combination with a drug containing an SGLT-2 inhibitor in the manufacture of a drug for preventing or treating diabetes or / and its complications.

[0014] The diabetic complications of the present invention are one or more of diabetic hypertension, diabetic nephropathy, diabetic reproductive tract infection, diabetic retinal lesions, diabetic cataracts, and diabetic neuropathy.

[0015] The drug containing an SGLT-2 inhibitor includes an SGLT-2 inhibitor and may also include (other) hypoglycemic agents or / and antihypertensive agents. The (other) hypoglycemic agents are selected from one or more combinations of insulin, biguanides, thiazolylene diketones, insulin secretagogues, α-glucosidase inhibitors, DPP-4 enzyme inhibitors, glucosidase inhibitors, and dipeptide peptidase inhibitors. The antihypertensive agents are selected from one or more combinations of angiotensin receptor blockers and angiotensin converting enzyme inhibitors.

[0016] The biguanides are one or more combinations selected from metformin, phenylethyl biguanide, and butadiguanide. The insulin secretagogue is one or more combinations selected from toluenesulfobutylurea, hexourea acetate, terasulfoneurea, chlorosulfonepropionurea, glipyrazine, glycerinurea, glilemeurea, glisit, gliquinone, ligurene, and naglyne. The thiazolylene diketones are one or more combinations selected from traglitazone, roglitazone, piraglitazone, and cycloglitazone. The α-glucose glycan inhibitor is one or more combinations selected from migretanol, accabose, and voglibose. The DPP-4 enzyme inhibitor is one or more combinations selected from cigretin, zagretin, vigretin, ligretin, or aggretin.

[0017] The combinations of the present invention may be administered simultaneously or separately.

[0018] The present invention also provides use of the above nitroketone compound or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the prophylaxis and / or treatment of genital tract infections by SGLT-2 inhibitors.

[0019] The dosage of the SGLT-2 inhibitor according to the present invention can be determined by the clinician based on the severity of the disease, the response of the disease, the toxicity associated with any treatment, the age of the patient, the weight of the patient and the health condition of the patient, and the specific administration method and administration frequency can follow the usual administration method of these drugs in the art. For example, the dosage of the SGLT-2 inhibitor according to the present invention can be 0.5 mg-500 mg of the SGLT-2 inhibitor per person per day. The preferred dose range of the SGLT-2 inhibitor engeletin is 1 mg-100 mg / day, more preferably 1 mg-50 mg / day, such as 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25 or 50 mg of engeletin / day. The preferred dose range of the Calgary net of the SGLT-2 inhibitor is 50 mg-500 mg / day, more preferably 50 mg-300 mg / day, such as 50, 100, 150, 200, 250 or 300 mg / day. The preferred dose range of the SGLT-2 inhibitor dapagliflozin is 1 mg-200 mg / day, more preferably 1 mg-100 mg / day, for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25, 50 or 100 mg dapagliflozin / day. The specific dosage can be determined based on the severity of the disease, the response of the disease, the toxicity associated with any treatment, the age and health condition of the patient. The specific method and frequency of administration can be the usual administration method of SGLT-2 inhibitors, for example, once or more times a day.

[0020] The amount of the nitroketone compound or a pharma- ceutical acceptable salt thereof of the present invention to be used may be 100-3000 mg / person / time, for example 300-1200 mg / person / time (1-3 times a day) as nitroketone azine (abbreviated as TBN). The preferred dosage range of nitroketamine (abbreviated as TBN) is 100 mg-3000 mg / day, more preferably 300-2400 mg / day, such as 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900 or 3000 mg / day. The specific dosage can be determined based on the severity of the disease, the response of the disease, the toxicity associated with any treatment, the age and health of the patient. The specific method and frequency of administration can be the usual administration method of nitroketamine (TBN), for example, one or more times per day.

[0021] According to some embodiments of the present invention, the nitroketone compound can be formulated into a pharmaceutical composition as an active pharmaceutical preparation using a pharma- ceutically acceptable carrier. The pharmaceutical composition can be any composition suitable for oral, sublingual, local inhalation (nose spray), rectal, intramuscular, dermal, subcutaneous or intravenous administration. The amount of the composition required for treatment varies depending on the route of administration, the nature of the treatment situation, the age and health of the patient, and is ultimately determined by the attending clinician. The desired dose can be provided twice, three times, or multiple times (at appropriate intervals) per day to achieve or meet the need for treatment.

[0022] The term "pharmaceutical acceptable carrier" as used in the present invention refers to a substance that does not inhibit the physiological action of nitroketone compounds and is non-toxic to mammals, including humans. In one embodiment, a pharmaceutical composition is prepared using tetradinitropine (TBN) and a pharmaceutical acceptable carrier. The pharmaceutical composition can be prepared in the form of a solid, capsule, pill, suppository, liquid (e.g., injection), oil, emulsion, spray, gel, aerosol, inhalant or patch, including but not limited to a solid.

[0023] Research shows that the nitroketone compounds of the present invention, TBN and TN-2, when used in combination with SGLT-2 inhibitors, can jointly lower blood glucose and simultaneously reduce urinary microalbumin and urinary albumin creatinine ratio in db / db mice 24 hours, thus realizing renal protective effect. Clinical trial results are also presented, showing that the nitroketone compounds of the present invention, when used in combination with SGLT-2 inhibitors, can significantly increase the reduction extent of UACR, thus realizing synergistic renal protective effect.

[0024] The Chinese Expert Consensus (2019 edition) and the Chinese Clinical Guideline for Prevention and Treatment of Diabetes and Kidney Disease (2019 edition) point out that the effect of SGLT-2 inhibitors in lowering blood glucose levels has many advantages over other oral hypoglycemic drugs, and this advantage becomes more obvious the longer the treatment time, but it can increase the risk of urinary tract and genital tract infections, mainly because this type of drug can increase the excretion of urinary glucose while increasing the proliferation of bacteria due to high urinary glucose. For the signal strength comparison of urinary tract infection, dapagliflozin > canagliflozin > englin (see Chen Qiying (Wang Pian "Qi"), Li Yimin, Zhang Yin. Analysis and study of sodium-glucose cotransporter protein-2 inhibitor side effects by FAERS [J]. Chinese Modern Applied Pharmacology, 2021, 38(14):1729-1733). According to overseas research, diabetes can increase the risk of genital infection, and the new glucose-lowering drug SGLT-2 inhibitors make urinary tract and reproductive system infections more likely to occur due to their unique glucose-lowering mechanism (see Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obets Metab. 2017 Mar, 19(3):348-355). The risk of SGLT-2 inhibitor-associated urinary tract infections was significantly higher in female patients than in male patients (see Shen J, Yang J, Zhao BA Survey of the FDA's Adverse Event Reporting System Database Concerning Urogenital Tract Infections and Sodium Glucose Cotransporter-2 Inhibitor Use. Diabetes Ther. 2019 Jun, 10(3):1043-1050).

[0025] Urinary tract infection is an inflammatory disease caused by the growth and proliferation of various pathogenic microorganisms in the urinary tract. Clean midstream urine culture is an important basis for diagnosing urinary tract infection. However, it takes about 3-4 days to culture urine bacteria, which cannot provide clinical basis for timely diagnosis. In addition, colony counting during the culture process does not meet the standard, and contamination is likely to occur, resulting in inaccurate results. Therefore, clinical diagnosis of urinary tract infection requires more specific and sensitive indicators.

[0026] A large amount of research at home and abroad has shown that the content of interleukin-6 (IL-6) is highly correlated with urogenital tract infection, and can be used as a marker for the early diagnosis of urogenital tract infection. (Rashid MH, Sparrow NA, Anwar F, Guidry G, Covarrubias AE, Pang H, Bogguri C, Karumanchi SA, Lahiri S. Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection. J Neuroinflammation. 2021 Oct 28;18(1):247, Peng Xuan (Wang Xuan in the "Sweep" character), Ke Guibao, et al., Changes and clinical significance of serum peptide, IL-6, and PCT levels in patients with urinary tract infection [J], Practical Clinical Medicine, 2017, 01:13-15, Sun Yuyan (three fire characters), Ding Sanzhen, et al., The relationship between urinary bacterial distribution and serum IL-6 in female type 2 diabetes patients [J], Chinese Journal of Microecology, 2021, 33(10):1170-1175). The inventors unexpectedly discovered that the nitroketone compounds of the present invention (such as TBN and TN-2) alone or in combination with SGLT-2 inhibitors (such as englycine) can significantly reduce the content of IL-6 in the serum of model animals. The nitroketone compounds of the present invention can be used in combination with SGLT-2 inhibitors to reduce the risk of urinary tract infections caused by SGLT-2 inhibitors. The nitroketone compounds of the present invention may act as serum IL-6 antagonists and may also be used to treat reproductive tract infections associated with diabetes.

[0027] The use of nitroketamine or a pharma- ceutical acceptable salt thereof in the manufacture of an oral pharmaceutical formulation for preventing or treating chronic kidney disease is characterized by administering an oral pharmaceutical formulation prepared mainly from nitroketamine in a unit dose form, the formulation containing a therapeutically effective amount of nitroketamine or a pharma- ceutical acceptable salt thereof, the therapeutically effective amount being about 600-2400 mg per day, which can effectively treat, prevent, inhibit, reduce the risk of, delay the onset, and / or delay the progression of chronic nephropathy.

[0028] According to different embodiments, the therapeutically effective amount may be about 600-1200 mg per day, about 1200-2400 mg per day, about 600 mg per day, about 1200 mg per day, or about 2400 mg per day.

[0029] Furthermore, the oral pharmaceutical formulation for preventing or treating chronic kidney disease comprises an SGLT-2 inhibitor, which is selected from dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sergliflozin etabonate, sotagliflozin, longliflozin-L-pyroglutamate, wangliflozin, tagliflozin, gagliflozin, hengliflozin, or a combination thereof.

[0030] According to one embodiment of the present invention, the complication of chronic kidney disease of the present invention is one or more of diabetes mellitus complicated with chronic kidney disease and chronic kidney disease complicated with infection. [Brief description of the drawings]

[0031] [Figure 1] 24-hour urinary microalbumin content of mice in different groups in Example 1. [Diagram 2] Blood glucose levels of mice in different groups in Example 1. [Diagram 3]IL-6 levels in serum of mice in different groups in Example 1. [Figure 4] IL-1β levels in serum of mice in different groups in Example 1. [Diagram 5] FIG. 2 shows serum urea nitrogen levels in mice from different groups in Example 1. [Figure 6] Triglyceride levels in serum of mice in different groups in Example 1. [Figure 7] Blood glucose levels of mice in different groups in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The present invention will be described in detail below with reference to specific examples, but it should be noted that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Except for special descriptions, all the parts in the present invention are by weight, and all the percentages are by mass.

[0033] In the examples of the present invention, wt / wt refers to wild type mice, ig means gastric irrigation, and po means oral administration.

[0034] Example 1 Grouping and pharmacological study of TBN and TN-2 administered alone and in combination with empagliflozin in spontaneous type 2 diabetes model mice db / db mice are type 2 diabetic mice caused by a defect in the leptin receptor gene located on chromosome 4, and begin to show polydipsia, polyphagia, polyuria, and obesity from the age of 4 weeks. As the mice age, they develop obvious characteristics such as hyperglycemia, hyperlipidemia, and insulin resistance, and the pathogenesis is very similar to that of type 2 diabetic patients. As diabetes worsens, db / db mice develop a series of complications, and the main pathology of renal tissue changes to renal globule interstitial expansion, renal globule basement membrane thickening, and excessive accumulation of extracellular matrix, making them a good model for studying the early morphological changes of DKD kidneys.

[0035] (1) Animal grouping and administration are shown in Table 1 below.

[0036] [Table 1]

[0037] Six-week-old db / db mice were adaptively treated for 1 w (i.e., 7 wk of age) with repeated administration of TBN and TN-2 alone or in combination with Empagliflozin twice daily (fixed times of 9:00-10:00 in the morning and 3:00-4:00 in the afternoon, 6-h intervals) for 6 w.

[0038] (2) Pharmacodynamic studies Blood glucose testing During the experiment, blood was collected from the tail vein before the start of administration (when the mice were 7 weeks old) and the mouse blood glucose levels were measured. After the end of administration (when the mice were 13 weeks old, i.e., the end of the experiment), serum was collected and the blood glucose levels of the mice in each group were measured using a fully automated biochemical analyzer.

[0039] Detection of 24-hour urinary microalbumin The db / db mice were subjected to 24-h urinary microalbumin detection at 4 and 6 weeks after drug treatment. Mice in each group were placed in metabolic cages and allowed to drink water ad libitum. 24-h urine samples were collected and centrifuged to measure the 24-h urinary microalbuminuria levels in each group of mice using an ELISA kit.

[0040] Detection of serum IL-6 and IL-1β levels After 6 weeks of administration, the collected whole blood was left to stand at room temperature for 1 hour, then spun in a centrifuge at 3000 rpm for 10 minutes, and the upper layer of serum was removed and placed in an EP tube and frozen in a refrigerator at -20°C. The levels of IL-6 and IL-1β in the serum of mice from each group were detected using an ELISA kit.

[0041] The 24-h urinary microalbumin levels in mice treated with TBN, TN-2, and Empagliflozin alone or in combination are shown in Figure 1. Co-administration of TBN and Empagliflozin and co-administration of TN-2 and Empagliflozin further reduced the 24-h urinary microalbumin levels compared to the single-administration groups.

[0042] The blood glucose levels of mice administered TBN, TN-2, and Empagliflozin alone or in combination are shown in Figure 2. Both combined administration of TBN and Empagliflozin and combined administration of TN-2 and Empagliflozin were able to effectively lower blood glucose levels.

[0043] The serum IL-6 levels in mice treated with TBN, TN-2, and Empagliflozin alone or in combination are shown in Figure 3. Combined administration of TBN and Empagliflozin, as well as combined administration of TN-2 and Empagliflozin, significantly reduced serum IL-6 levels.

[0044] The levels of IL-1β in the serum of mice treated with TBN, TN-2, and Empagliflozin alone or in combination are shown in Figure 4. Combined administration of TBN and Empagliflozin, as well as combined administration of TN-2 and Empagliflozin, can significantly reduce the levels of IL-1β in the serum.

[0045] Values ​​are presented as mean ± SEM. ### P < 0.001 compared with the db / m group; * P < 0.05, ** P < 0.01, *** P < 0.001 compared with the db / db group. & P < 0.05, &&& P < 0.001 compared with empagliflozin 2.5 mg / kg group.

[0046] See Table 2 below for specific results regarding the rate of change in blood glucose, urinary microalbumin, and serum IL-6 and IL-1β levels in model groups administered TBN and Empagliflozin of the present invention alone or in combination.

[0047] [Table 2]

[0048] As is clear from Table 2, when the nitroketone compound TBN of the present invention is used in combination with the SGLT-2 inhibitor Empagliflozin, the degree of reduction in blood glucose level can be increased, and in particular, the degree of reduction in blood glucose level in the TBN 10 mg / kg + Empagliflozin 2.5 mg / kg group is superior to the sum of the TBN 10 mg / kg group and the Empagliflozin 2.5 mg / kg group. After the combination, whether in the TBN 10 mg / kg + Empagliflozin 2.5 mg / kg group or the TBN 30 mg / kg + Empagliflozin 2.5 mg / kg group, the degree of reduction in urinary protein can be increased, and the degree of reduction in both groups is superior to the sum of the TBN 10 mg / kg group and the Empagliflozin 2.5 mg / kg group. After the combination, whether in the TBN 10 mg / kg + Empagliflozin 2.5 mg / kg group or the TBN 30 mg / kg + Empagliflozin 2.5 mg / kg group, the degree of reduction in urinary protein can be increased, and the degree of reduction in both groups is superior to the sum of the TBN 10 mg / kg group and the Empagliflozin 2.5 mg / kg group. After combination use, whether in the TBN 10 mg / kg + Empagliflozin 2.5 mg / kg group or the TBN 30 mg / kg + Empagliflozin 2.5 mg / kg group, the reduction in IL-6 could be increased, and the reduction in both groups was superior to the sum of the TBN 10 mg / kg group and the Empagliflozin 2.5 mg / kg group.

[0049] All SGLT-2 inhibitor drugs achieve blood glucose lowering function by increasing urinary glucose excretion, and high urinary glucose also increases urinary tract infection caused by bacterial proliferation in the urogenital tract, resulting in related inflammation. The combination of the nitroketone compound of the present invention with SGLT-2 inhibitors further reduces the level of IL-6, and the results suggest that the nitroketone compound of the present invention can reduce the risk of infection in the urogenital system caused by SGLT-2 inhibitor drugs, which has important clinical significance.

[0050] Measurement of serum urea nitrogen and triglyceride levels in db / db mice After anesthetizing the mice, blood was collected from the abdominal aorta, left to stand for 1 h, centrifuged at 3000 rpm for 10 min, and stored at -80°C. The levels of urea nitrogen and triglyceride in the serum were measured using a fully automated biochemical analyzer, and the results are shown in Figure 5-6.

[0051] Example 2 Grouping and pharmacodynamic study of TBN and canagliflozin administered alone or in combination in DKD model mice Animal groupings and treatments are shown in Table 3 below.

[0052] [Table 3]

[0053] Six-week-old db / db mice were adaptively dosed for 1 w (i.e., 7 wk of age) and then administered TBN, canagliflozin, or both, in combination. TBN was administered twice a day (9:00-10:00 a.m. and 3:00-4:00 p.m., 6-h intervals) and canagliflozin was administered once a day (9:00-10:00 a.m., 6-h intervals) for 8 w of continuous treatment.

[0054] According to the method of Example 1, blood was collected from the tail vein before the start of administration (mouse 7 weeks old) and the blood glucose content of the mouse was measured. After the end of administration (mouse 15 weeks old, i.e., the end of the experiment), serum was collected and the blood glucose level of the mouse of each group was measured using a fully automatic biochemical analyzer (the results are shown in Figure 7). As is clear from Figure 7, the combined use of TBN and Canagliflozin can effectively lower the blood glucose level.

[0055] Example 3 Clinical trial study on the combination of TBN and SGLT-2 inhibitors (hereafter abbreviated as SGLT2i) The present invention employs a multi-center, randomized, double-blind, placebo-parallel controlled design. Subjects: Patients with type 2 diabetic nephropathy were included in the study (all of whom signed informed consent) and had a urinary microalbumin / urinary creatinine ratio (UACR) of ≥ 30 mg / g and < 300 mg / g in at least two of the three morning urine samples taken during the screening period.

[0056] [Table 4]

[0057] The administration period of the present invention: 180 days of continuous administration. In this embodiment, SGLT 2 i is a commercially available SGLT 2 i, and is selected from Engagement Net, Dagret Net, or Cagret Net. Engagement is 10 mg once a day, Dagret is 10 mg once a day, and Cagret is 100 mg once a day. Of the three subjects in the 300 mg TBN + SGLT 2 i group, one took engretin, two subjects took dagretin, all three subjects in the 600 mg TBN + SGLT 2 i group took dapagliflozin, of the four subjects in the 1200 mg TBN + SGLT 2 i group, two took kagrelin, one took engrelin, one took dagrelin, and one subject in the SGLT 2 i group took dapagliflozin.

[0058] The UACR relative baseline change results for the TBN group (67 subjects) are shown in Table 5 below.

[0059] [Table 5]

[0060] The results of the change in UACR from baseline in the combination administration group (11 subjects) are shown in Table 6 below.

[0061] [Table 6]

[0062] From the results of Tables 5 and 6, the combined use of the nitroketone compound TBN of the present invention and SGLT2i for 90 days / 180 days significantly increased the reduction in UACR compared with the use of TBN or SGLT2i alone, achieving a synergistic effect.

Claims

1. A composition comprising: a first active ingredient which is a nitroketone compound or a pharma- ceutically acceptable salt thereof; and a second active ingredient which is an SGLT-2 inhibitor; and The nitroketone compound has a structure represented by the general formula (I): 【Chemistry 1】 Where: R1 is a hydrogen atom, a methyl group, or 【Chemistry 2】 and R 2, R 3 are the same or different and each independently selected from hydrogen or a C 1-C 6 alkyl group; R 4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; R 5 is sec-butyl, isobutyl, tert-butyl or cyclohexyl; preferably, R 2, R 3 of the nitroketone compound are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl; R 1 is hydrogen, a methyl group, or 【Chemistry 3】 and preferably the nitroketone compound is selected from the following structural formulas: 【Chemistry 4】 。

2. 2. The composition of claim 1, wherein the SGLT-2 inhibitor is selected from Dapagliflozin, Canagliflozin, Empagliflozin (abbreviated as Empag), Ipragliflozin, Luseogliflozin, Tofogliflozin, Ertugliflozin, Sergliflozin Etabonate, Sotagliflozin, Rongliflozin L-Pyroglutamic Acid, Wangliflozin, Tagliflozin, Gagliflozin, Henggliflozin, or a combination thereof.

3. A medicine cabinet, comprising: A first formulation comprising a therapeutically effective amount of a first active agent according to claim 1; A second formulation comprising a therapeutically effective amount of a second active agent according to claim 1, wherein the SGLT-2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sergliflozin etabonate, sotagliflozin, longliflozin-L-pyroglutamate, wangliflozin, tagliflozin, gagliflozin, hengliflozin, or a combination thereof; Instructions.

4. A pharmaceutical composition, comprising: a therapeutically effective amount of the first active agent of claim 1; A second formulation comprising a therapeutically effective amount of a second active agent according to claim 1, wherein the SGLT-2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sergliflozin etabonate, sotagliflozin, longliflozin-L-pyroglutamate, wangliflozin, tagliflozin, gagliflozin, hengliflozin, or a combination thereof; A pharma- ceutically acceptable carrier.

5. 2. Use of the composition of claim 1 in the manufacture of a medicine, wherein the nitroketone compound or a pharma- ceutically acceptable salt is used in combination with a drug including an SGLT-2 inhibitor for the prevention and treatment of diabetes and its complications.

6. 6. The use according to claim 5, wherein the diabetic complications are one or more of diabetic hypertension, diabetic nephropathy, diabetic reproductive tract infection, diabetic retinal lesions, diabetic cataracts, and diabetic neuropathy.

7. The use according to claim 5 or 6, wherein the reagent comprising an SGLT-2 inhibitor further comprises a hypoglycemic agent and / or an antihypertensive agent. Here, the insulin, biguanides, thiazolylene diketones, insulin secretagogues, α-glucosidase inhibitors, DPP-4 enzyme inhibitors, glucosidase inhibitors, dipeptide peptidase inhibitors, or combinations thereof are selected from the group consisting of insulin, biguanides, metformin, phenylethylbiformin, butadiformin, or combinations thereof. The insulin secretagogues are preferably selected from toluenesulfobutylurea, hexyl acetate, tert-sulfone urea, chlorosulfone propionate urea, glipyrazine, The thiazolylene diketones are selected from traglitazone, roglitazone, piraglitazone, cycloglitazone. The α-glucose glycan inhibitors are selected from migretanol, accabose, voglibose, or combinations thereof. The DPP-4 enzyme inhibitors are selected from cigretin, zagretin, vigretin, ligretin, aggretin, or combinations thereof. wherein the antihypertensive agent is selected from an angiotensin receptor blocker, an angiotensin converting enzyme inhibitor, or a combination thereof.

8. Use of a nitroketone compound or a pharma- ceutically acceptable salt thereof in the prophylaxis and / or treatment of SGLT-2 inhibitor-induced reproductive tract infections. The nitroketone compound has a structure represented by the general formula (I): 【Chemistry 5】 where R 1 is hydrogen, a methyl group, or 【Chemistry 6】 and R 2 , R 3 are the same or different and each independently represents hydrogen or C 1 -C 6 R is selected from alkyl groups; 4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; R 5 is sec-butyl, isobutyl, tert-butyl or cyclohexyl, preferably R 2 , R 3 are the same or different and are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and n-pentyl; R 1 is a hydrogen atom, a methyl group, or 【Chemistry 7】 Preferably, the nitroketone compound is selected from the following structural formulas: 【Chemistry 8】 Preferably, the SGLT-2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sergliflozin etabonate, sotagliflozin, longliflozin-L-pyroglutamate, wangliflozin, tagliflozin, gagliflozin, hengliflozin, or combinations thereof.

9. Use of a nitroketone compound or a pharma- ceutically acceptable salt thereof in an antagonistic drug for the production of interleukin-6; The nitroketone compound has a structure represented by the general formula (I): 【Chemistry 9】 Here, R 1 is a hydrogen atom, a methyl group, or 【Chemistry 10】 and R 2, R 3 are the same or different and each independently selected from hydrogen or a C 1-C 6 alkyl group; R 4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; R 5 is sec-butyl, isobutyl, tert-butyl or cyclohexyl; preferably, R 2, R 3 of the nitroketone compound are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl; R 1 is hydrogen, a methyl group, or 【Chemistry 11】 and preferably the nitroketone compound is selected from the following structural formulas: 【Chemistry 12】

10. 1. Use of nitroketamine or a pharma- ceutical acceptable salt thereof in the manufacture of a medicament for preventing or treating chronic kidney disease and its complications, said medicament being an oral pharmaceutical formulation comprising a therapeutically effective amount of nitroketamine or a pharma- ceutical acceptable salt thereof, said therapeutically effective amount being about 600-2400 mg per day; The structure of said nitroazine is as follows: 【Chemistry 13】

11. The use according to claim 10, wherein the therapeutically effective amount is about 600-1200 mg per day.

12. The use according to claim 10, wherein the therapeutically effective amount is about 1200-2400 mg per day.

13. The use according to any one of claims 10 to 12, wherein the complication of chronic nephropathy is diabetes mellitus-complicated chronic nephropathy, chronic nephropathy-complicated infection, or a combination thereof.

14. The use according to any one of claims 10-13, wherein the oral dosage formulation further comprises an SGLT-2 inhibitor, wherein the SGLT-2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sergliflozin etabonate, sotagliflozin, longliflozin-L-pyroglutamate, wangliflozin, tagliflozin, gagliflozin, hengliflozin, or a combination thereof.

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