Application of furostanol dioscin compound in preparation of selective SGLT-2 inhibition medicine

Abstract

The invention relates to application of a furostanol dioscin compound shown in a general formula (I) in preparation of a selective SGLT-2 (sodium-glucose cotransporter 2) inhibition medicine, and further relates to a medicine composition containing the compound. The compound and the pharmaceutical composition containing the compound can treat diseases such as diabetes mellitus and / or heart failure by selectively inhibiting SGLT-2. # imgabs0 #

Description

[0001] This application claims priority to a Chinese application filed on June 12, 2023, with application number 202310689036.4, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to use of a compound in preparing a selective SGLT-2 (sodium-dependent glucose transporters 2, sodium-glucose co-transporter 2) inhibitory drug. Background Art

[0003] SGLT (sodium-dependent glucose transporters) is a type of sodium-glucose co-transporter, which mainly has two subtypes, SGLT-1 and SGLT-2. SGLT-1 is mainly distributed in the brush border of the small intestine and the S3 segment farther away from the proximal tubule of the kidney, and is expressed in small amounts in the heart and trachea. It is a high-affinity, low-transport capacity transporter. SGLT-2 is mainly distributed in the S1 segment of the proximal tubule of the kidney. It is a low-affinity, high-transport capacity transporter. Its main physiological function is to complete the reabsorption of 90% of glucose in the glomerular filtrate in the proximal tubule of the kidney. Studies have found that loss of SGLT-1 activity can lead to severe diarrhea. Therefore, SGLT inhibitors with poor selectivity for SGLT-1 and SGLT-2 have greater adverse reactions due to simultaneous inhibition of SGLT-1 and SGLT-2.

[0004] SGLT-2 selective inhibitors can inhibit the renal reabsorption of glucose in a targeted manner, allowing excess glucose to be excreted from the urine, lowering blood sugar, and becoming a new type of anti-diabetic drug. Diabetes is a common independent risk factor for cardiovascular and cerebrovascular diseases. Heart failure (heart failure) is referred to as HF, which means that due to the disorder of the heart's contractile function and (or) diastolic function, the venous return blood cannot be fully discharged from the heart, resulting in blood congestion in the venous system and insufficient blood perfusion in the arterial system, thus causing a syndrome of cardiac circulatory disorders. Most heart failures start with left heart failure. Heart failure is divided into heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF) according to the left ventricular ejection fraction (LVEF).

[0005] Large-scale clinical data show that SGLT-2 inhibitors can reduce the risk of heart failure hospitalization by 30-35% and improve clinical outcomes in patients with different types of heart failure, including HFrEF and HFpEF. [1-5] SGLT-2 inhibitors have been included in European guidelines for the treatment of heart failure [6] ; And the study showed that the significant effect of SGLT-2 inhibitors on heart failure is not related to diabetes [7-10] .

[0006] Natural products have always been an important source of drugs for disease prevention and treatment, with a long history and solid foundation. Although synthetic drugs account for a considerable proportion in drug research and development, many drugs used in clinical practice are directly or indirectly derived from natural products. Natural products are still one of the main sources of drugs or lead compounds for the treatment of major diseases. It is of great significance to find selective SGLT-2 inhibitory components in natural products.

[0007] References:

[0008] [1] Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).

[0009] [2]Neal,B.et al.Canagliflozin and cardiovascular and renal events intype 2diabetes.N.Engl.J.Med.377,644–657(2017).

[0010] [3]Wiviott,S.D.et al.Dapagliflozin and cardiovascular outcomes intype 2diabetes.N.Engl.J.Med.380,347–357(2019).

[0011] [4]Perkovic,V.et al.Canagliflozin and renal outcomes in type2diabetes and nephropathy.N.Engl.J.Med.380,2295–2306(2019).

[0012] [5]Das,S.R.et al.2020expert consensus decision pathway on noveltherapies for cardiovascular riskreduction in patients with type2diabetes.J.Am.Coll.Cardiol.76,1117–1145(2020).

[0013] [6]McDonagh,T.A.et al.2021ESC Guidelines for the diagnosis andtreatment of acute and chronic heart failure:developed by the Task Force forthe diagnosis and treatment of acute and chronic heart failure of theEuropean Society of Cardiology(ESC)with the special contribution of the HeartFailure Association(HFA)of the ESC.Eur.Heart J.42,3599–3726(2021).

[0014] [7]Joshi, S. S., Singh, T., Newby, D. E. & Singh, J. S. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart 107, 1032–1038 (2021).

[0015] [8]de Leeuw, A. E. & de Boer, R. A. Sodium-glucose cotransporter2 inhibition: cardioprotection by treating diabetes—a translational viewpoint explaining its potential salutary effects. Eur. Heart J. Cardiovasc. Pharmacother. 2, 244–255 (2016).

[0016] [9]Arnold, J. M. O. et al. Prevention of heart failure in patients in the heart outcomes prevention evaluation (HOPE) study. Circulation 107, 1284–1290 (2003).

[0017]

[10] NAVIGATOR Study Group, McMurray, J. J. et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N. Engl. J. Med. 362, 1477–1490 (2010). Summary of the Invention

[0018] The technical problems to be solved by the present invention include that when SGLT inhibitor drugs are used to treat diabetes and / or heart failure, due to the lack of selectivity for SGLT-2, SGLT inhibitor drugs also have high inhibition on SGLT-1, resulting in severe diarrhea and other side effects, and the problem that the symptoms of diabetes and / or heart failure cannot be effectively treated. In order to solve this technical problem, it is necessary to provide more drugs that are selective for SGLT-2 for optional use, especially to provide drugs that are selective for SGLT-2 based on natural drugs. The present invention provides a use of a compound as shown in the general formula (I) and a pharmaceutically acceptable salt thereof in the preparation of a selective SGLT-2 inhibitory drug; and provides a use of a compound as shown in the above general formula and a pharmaceutically acceptable salt thereof in the preparation of a drug and / or a pharmaceutical composition for treating diabetes and / or heart failure.

[0019] Specifically, the present invention provides the following technical solutions:

[0020] Technical solution (1): Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a SGLT-2 selective inhibitory drug:

[0021]

[0022] Wherein, R1 is any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a straight-chain or branched glycoside group formed by three monosaccharides, and a straight-chain or branched oligosaccharide glycoside group formed by polymerization of 4 to 9 monosaccharides.

[0023] The monosaccharide is independently selected from any one or a combination of more than one of glucose, rhamnose, galactose, mannose, xylose or arabinose;

[0024] represents a single bond or a double bond,

[0025] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0026] Technical solution (2): Use of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a SGLT-2 selective inhibitory drug:

[0027]

[0028] Wherein, R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a straight-chain or branched glycoside group formed by three monosaccharides, and a straight-chain or branched oligosaccharide glycoside group formed by four or five monosaccharides.

[0029] The monosaccharide is independently selected from any one or a combination of more than one of glucose, rhamnose, galactose, mannose, xylose or arabinose;

[0030] represents a single bond or a double bond,

[0031] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0032] Technical solution (3): The use according to technical solution (1) or (2), characterized in that R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, and a straight-chain or branched glycoside group formed by three monosaccharides, and the monosaccharides are independently selected from glucose or rhamnose;

[0033] represents a single bond or a double bond,

[0034] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0035] Technical solution (4): The use according to technical solution (3), characterized in that:

[0036] R1 is selected from:

[0037]

[0038] represents a single bond or a double bond,

[0039] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0040] Technical solution (5): The use according to technical solution (4), wherein the compound represented by general formula (I) is any one of the following compounds:

[0041]

[0042]

[0043] Technical solution (6): A pharmaceutical composition for selective inhibition of SGLT-2, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier:

[0044]

[0045] Wherein, R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a straight-chain or branched glycoside group formed by three monosaccharides, and a straight-chain or branched oligosaccharide glycoside group formed by 4-9 monosaccharides.

[0046] The monosaccharide is independently selected from any one or a combination of more than one of glucose, rhamnose, galactose, mannose, xylose and arabinose;

[0047] represents a single bond or a double bond,

[0048] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0049] Technical solution (7): The pharmaceutical composition according to technical solution (6), characterized in that R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, and a straight-chain or branched glycoside group formed by three monosaccharides, four monosaccharides, or five monosaccharides, and the monosaccharides are independently selected from glucose or rhamnose;

[0050] represents a single bond or a double bond,

[0051] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0052] Technical solution (8): The pharmaceutical composition according to technical solution (7), characterized in that:

[0053] R1 is selected from:

[0054]

[0055] represents a single bond or a double bond,

[0056] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0057] Technical solution (9): According to the pharmaceutical composition of technical solution (6), wherein the compound represented by general formula (I) is any one of the following compounds:

[0058]

[0059] Technical solution (10): The pharmaceutical composition according to technical solution (6), wherein the pharmaceutical composition optionally contains two or more of the following compounds:

[0060]

[0061] Technical solution (11): A pharmaceutical composition according to any one of technical solutions (6) to (10), wherein the pharmaceutical composition is an injection or an oral preparation;

[0062] Preferably, the oral preparation is any one of a mixture, tincture, pill, pellet, powder, granule, tablet, micropill, microcapsule, capsule, soft capsule, suspension and syrup; wherein the capsule includes, for example, a hard capsule dosage form and the like.

[0063] Technical solution (12): According to the pharmaceutical composition according to any one of technical solutions (6) to (11), the carrier is selected from any one or more substances in the group consisting of a binder, a filler, a disintegrant, a lubricant, a glidant, a surfactant, a wetting agent, an antioxidant and a coating agent.

[0064] In the above pharmaceutical composition, examples of optional carriers include: the binder can be selected from polyvinyl pyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose; the filler can be selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch or pregelatinized starch; the disintegrant can be selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or sodium starch glycolate; the lubricant can be selected from magnesium stearate or sodium stearyl fumarate; the glidant can be selected from colloidal silicon dioxide or talc.

[0065] As for the above-mentioned various carriers, any known or commercially available carriers routinely used by those skilled in the art can be used in the medicine or pharmaceutical composition of the present invention to prepare medicines in various dosage forms.

[0066] Technical solution (13): The use according to any one of technical solutions (1) to (5) or the pharmaceutical composition according to any one of technical solutions (6) to (12), characterized in that the drug or the pharmaceutical composition is used to treat diabetes, diabetic nephropathy and / or cardiovascular and cerebrovascular diseases;

[0067] Preferably, the diabetes is type 2 diabetes, and the cardiovascular and cerebrovascular disease is heart failure;

[0068] Further preferably, the heart failure includes heart failure with reduced ejection fraction, heart failure with intermediate ejection fraction or heart failure with preserved ejection fraction.

[0069] Definition of terms:

[0070] The following terms and the like are used to describe the present invention. It should be understood that terms not specifically defined are given a meaning consistent with the use of the terms in the context of the present invention as understood by those of ordinary skill in the art.

[0071] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation carrier or excipient that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.

[0072] Beneficial technical effects achieved:

[0073] The compound of the present invention has selective SGLT-2 inhibitory activity and can reduce adverse reactions such as diarrhea caused by the inhibition of SGLT-1 activity compared with non-selective SGLT inhibitors, and can be used to prepare drugs for treating diabetes and / or heart failure. DETAILED DESCRIPTION

[0074] In order to solve the problem that the SGLT inhibitor drugs for treating diabetes and / or heart failure in the prior art have high inhibition of SGLT-1, resulting in severe diarrhea, and cannot effectively treat the symptoms of diabetes and / or heart failure, the present invention provides an alternative to SGLT-2 selective inhibitor drugs, and provides the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a selective SGLT-2 inhibitor drug.

[0075]

[0076] R1 is any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a glycoside group formed by three monosaccharides, and a linear or branched oligosaccharide glycoside group formed by polymerization of 4 to 9 monosaccharides.

[0077] In one embodiment, the oligosaccharide glycoside group is a linear or branched oligosaccharide composed of 4 or 5 monosaccharides, and the monosaccharides are independently selected from any one or a combination of more than one of glucose, rhamnose, galactose, mannose, xylose or arabinose;

[0078] represents a single bond or a double bond,

[0079] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0080] In a preferred embodiment of the present invention, the present invention provides the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a selective SGLT-2 inhibitory drug,

[0081] R1 is selected from:

[0082]

[0083] represents a single bond or a double bond,

[0084] when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

[0085] In a more preferred embodiment of the present invention, the present invention provides use of any of the following compounds or pharmaceutically acceptable salts thereof in the preparation of a selective SGLT-2 inhibitory drug:

[0086]

[0087]

[0088] Among them, Compounds 1 to 5 are compounds known in the prior art and can be commercially obtained;

[0089] The present invention also provides a pharmaceutical composition, which comprises the compound represented by the above formula (I) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0090] The following examples illustrate that the compounds of the present invention or their pharmaceutically acceptable salts, or pharmaceutical compositions can be used to treat diabetes, cardiovascular and cerebrovascular diseases.

[0091] Example 1: Preparation and structure confirmation of compound 6

[0092] Compound preparation method:

[0093] 6kg of commercially available Rhizoma Dioscoreae (Chinese Pharmacopoeia 2020, Part I, pages 279-280) slices were extracted three times with water. The first time, 8 times of drinking water was added and boiled for 4 hours. The second and third times, 6 times of drinking water were added and boiled for 3 hours. The extracts were combined and concentrated and dried to obtain 1278g of Rhizoma Dioscoreae extract. 1278g of the Rhizoma Dioscoreae extract was taken and dispersed in 11100ml of water. It was extracted with ethyl acetate (7500ml×4 times) and n-butanol (7500ml×5 times) in turn. The ethyl acetate extract was concentrated and dried to obtain 102g and 503g of n-butanol extract.

[0094] Take 200g of the above n-butanol extract and perform silica gel column chromatography (Φ10.5cm×52cm, 2000g), eluting with chloroform-methanol-water (9:1:0.1), each bottle receiving 500ml of eluent, and a total of 160 portions (bottles) were collected. The combined fractions determined by thin layer chromatography were combined with bottles 138 to 143, and concentrated and dried to obtain 2.6g. Further silica gel column chromatography (Φ3.1cm×19cm, 90g) was performed, eluting with chloroform-methanol (4:1) water saturated solution to obtain 19mg of the target product.

[0095] Compound structure confirmation:

[0096] ESI-MS m / z:761[M+Na] + , 739[M+H] + , confirmed molecular weight is 738; high resolution mass spectrum 761.40919 [M+Na] + Confirm its molecular formula: C 39 H 62 O 13 .

[0097] 1 H NMR (400MHz, C5D5N): δ0.75(3H,s,CH3-18), δ0.94(3H,s,CH3-19), δ1.05(3H,d,J=4,CH3-27), δ1.67(3H,s,CH3-21), δ4.87and 5.08(each 1H, d, J = 8Hz, H-1'andH-1”), δ5.34 (1H, br, s, H-6).

[0098] 13 C NMR, carbon signals of sapogenin C-1 to C-27: δ = 37.29, 30.06, 78.33, 39.16, 140.71, 121.53, 32.18, 31.27, 50.06, 36.84, 21.08, 39.47, 43.23, 54.75, 34.29, 84.28, 64.30, 13.96, 19.23, 103.39, 11.63, 152.20, 33.20, 23.51, 31.31, 74.77, 17.17.

[0099] 13 C NMR, carbon signals of sugar C-1' to C-6': δ = 102.42, 75.03, 77.88, 71.52, 78.45, 62.67; C-1" to C-6": δ = 104.73, 75.17, 78.36, 71.52, 78.45, 62.67.

[0100] 13 The C NMR spectrum showed a total of 39 carbon signals, of which 12 were carbon signals of sugars (2 hexoses) and 27 were carbon signals of diosgenin. Only glucose was detected by acid hydrolysis, and both hexoses were glucose. 1 HNMR (400 MHz, C5D5N): δ0.75 (3H, s, CH3-18), δ0.94 (3H, s, CH3-19), δ1.67 (3H, s, CH3-21), δ1.05 (3H, d, J=4, CH3-27), showing the four methyl proton signals of dioscorea steroidal sapogenin. 13C NMR spectrum δ140.71 (C-5), δ121.53 (C-6) and 1 The HNMR spectrum δ5.34 (1H, br, s, H-6) shows the signal of the steroidal sapogenin 5-6 double bond, δ103.39 (C-20), δ152.20 (C-22) show the signal of the steroidal sapogenin 20-22 double bond. 13 C NMR spectra δ78.33 (C-3) and δ74.77 (C-26) showed that the steroidal sapogenin C-3 and C-26 positions were connected with sugars. 13 C NMR spectra of δ75.03 (C-2') and δ71.52 (C-4') showed that there was no sugar attached to the C-2' and C-4' positions of the C-3 glucose. 1 The coupling constants of the two sugar terminal protons δ4.87 and 5.08 (each 1H, d, J = 8 Hz, H-1' and H-1") in the HNMR spectrum show that the configurations of the two glucoses are both β-type. The compound was identified as: 26-O-β-D-pyranoglucopyranosyl-(25R)-furosta-Δ5,20(22)-diene-3β,26-dihydroxy-3-O-β-D-pyranoglucopyranoside, and its structural formula is as follows:

[0101]

[0102] The ESI-MS instrument model is Waters Vion IMS QTof ultra-high resolution liquid-mass spectrometer; 1 H NMR and 13 The instrument model used in the C NMR experiment is: Bruker Avance III 400M nuclear magnetic spectrometer.

[0103] Example 2: Experimental study on the inhibition of SGLT-1 and SGLT-2 activity by compounds 1 to 6

[0104] 1.1 Instruments and Materials

[0105] Experimental instrument: PerkinElmer1450-023

[0106] Experimental Materials:

[0107] Compounds 1 to 5, Dapagliflozin (commercially available standard product), and Compound 6 (prepared in Example 1);

[0108] NIH3T3-hSGLT1 stable strain, NIH3T3-hSGLT2 stable strain (cell lines were provided by the National Center for Drug Screening);

[0109] Methyl-α-D-[U-14 C]pyranoglucoside (methyl-α-D-[U- 14 C]glucopyranoside)(PerkinElmer)

[0110] Methyl sulfoxide (Genebase,ProdNo:0231)

[0111] DMEM-(High glucose and FBS)(gibico)

[0112] 1.2 Sample processing

[0113] The sample was dissolved with DMSO and stored at low temperature. The concentration of DMSO in the final system was controlled within a range that would not affect the detection activity.

[0114] 1.3 Experimental process

[0115] Construction of experimental cell lines: Human SGLT-1 and SGLT-2 genes were cloned into eukaryotic expression vectors, and transfected into NIH3T3 cells, respectively. NIH3T3 cells stably expressing SGLT-1 and SGLT-2 (NIH3T3-hSGLT1, NIH3T3-hSGLT2) were obtained through antibiotic screening and RT-PCR and Western-blot identification.

[0116] Sample activity determination:

[0117] (1) 96-well plates were coated with 0.2% gelatin and kept at 37°C. They were then washed once with PBS before use.

[0118] (2) NIH3T3-hSGLT1 and NIH3T3-hSGLT2 cells were plated in 96-well plates at 30,000 cells / well with 100 μl of culture medium per well.

[0119] (3) The medium was changed on the second day and sodium butyrate was added to the culture medium at a final concentration of 2 mM.

[0120] (4) On the third day, the medium was changed and sodium butyrate was added to the culture medium at a final concentration of 2 mM.

[0121] (5) KRH-Na + The cells were washed three times with 100 μl of each of the KRH-acetylcholine solution and then incubated with 50 μl of each for 30 min.

[0122] (6) Compound preparation:

[0123] Single concentration inhibition rate determination: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 and Dapagliflozin (positive drug) were dissolved in DMSO to prepare stock solutions; then the stock solution of Compound 1 was stained with KRH-Na + The stock solution of compound 2 was diluted to 400 μM with KRH-Na + The stock solution of compound 3 was diluted to 100 μM with KRH-Na + The stock solution of compound 4 was diluted to 100 μM with KRH-Na + The stock solution of compound 5 was diluted to 400 μM with KRH-Na + The stock solution of compound 6 was diluted to 100 μM with KRH-Na + Dapagliflozin (positive drug) stock solution was diluted to 100 μM with KRH-Na + Dilute to 100 nM, then KRH-Na + The compound concentration in the assay was the test concentration, and the DMSO content was 0.1%.

[0124] IC50 determination: Compounds 1 to 6 and Dapagliflozin (positive drug) were taken, and the test compounds and positive drugs were dissolved in DMSO at appropriate concentrations, and the test compounds and positive drugs were diluted with DMSO to form 6 concentration gradients; the above compound solutions were added to KRH-Na + At this time, KRH-Na + The compound concentration in the assay was the test concentration, and the DMSO content was 0.1%.

[0125] (7) The cells were replaced with 50 μl KRH-Na containing the target concentration of compound or positive drug. + or KRH-choline chloride, add uptake buffer (KRH-Na + Add methyl-α-D-[U- 14 C]pyranoglucoside (methyl-α-D-[U- 14 C]glucopyranoside) and 1 mM methyl-α-D-pyranoglucoside; KRH-acetylcholine solution was used instead of KRH-Na for nonspecific absorption + ) 10 μl per well.

[0126] (8) Wash three times with 100 μl PBS and dry; add 50 μl lysis solution to each well and lyse for about 15 minutes, then add 150 μl scintillation fluid to each well, cover with membrane, press flat, shake on a shaker to mix, centrifuge at 4°C, 1200 r / min for 5 minutes. Take out and measure the reading by liquid scintillation counting.

[0127] 1.4 Calculation of inhibition rate and IC50 value

[0128] (1) Calculation method of inhibition rate:

[0129] Set the reading of the DMSO control well to L Control The reading of the compound well is L Sample The choline well reading as background is L Background The inhibition rate (Inhibition%) of each sample at each concentration was calculated according to the following formula:

[0130]

[0131] (2) IC50 calculation method:

[0132] The IC50 value of the sample was calculated by nonlinear fitting using GraphpadPrism4 calculation software, using the sigmoidaldose-response (variable slope) fitting model and setting the bottom and top of the fitting curve to 0 and 100.

[0133] 1.5 Experimental Results

[0134] The activity data of Compounds 1 to 6 in inhibiting SGLT-1 and SGLT-2 measured in the above experiments are shown in Table 1 below.

[0135] Table 1 Inhibition of SGLT-1 and SGLT-2 activities by single concentrations of compounds 1 to 6

[0136]

[0137] 1.6 Conclusion

[0138] The experiments confirmed that compounds 1 to 6 had almost no inhibitory activity on SGLT-1, but had significant inhibitory activity on SGLT-2; compounds 1 to 6 had highly selective SGLT-2 inhibitory activity.

Claims

1. Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a SGLT-2 selective inhibitory drug: in, R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a straight-chain or branched glycoside group formed by three monosaccharides, and a straight-chain or branched oligosaccharide glycoside group formed by polymerization of 4 to 9 monosaccharides. The monosaccharide is independently selected from any one or a combination of more than one of glucose, rhamnose, galactose, mannose, xylose or arabinose; represents a single bond or a double bond, when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

2. Use of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a SGLT-2 selective inhibitory drug: in, R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a straight-chain or branched glycoside group formed by three monosaccharides, and a straight-chain or branched oligosaccharide glycoside group formed by four or five monosaccharides, The monosaccharide is independently selected from any one or a combination of more than one of glucose, rhamnose, galactose, mannose, xylose or arabinose; represents a single bond or a double bond, when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

3. The use according to claim 1 or 2, characterized in that R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, and a straight-chain or branched glycoside group formed by three monosaccharides, wherein the monosaccharide is independently selected from glucose or rhamnose; represents a single bond or a double bond, when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

4. The use according to claim 3, characterized in that R1 is selected from: represents a single bond or a double bond, when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

5. The use according to claim 4, wherein The compound represented by the general formula (I) is any one of the following compounds:

6. A pharmaceutical composition for selective inhibition of SGLT-2, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier: in, R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a straight-chain or branched glycoside group formed by three monosaccharides, and a straight-chain or branched oligosaccharide glycoside group formed by 4-9 monosaccharides. The monosaccharide is independently selected from any one or a combination of more than one of glucose, rhamnose, galactose, mannose, xylose and arabinose; represents a single bond or a double bond, when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

7. The pharmaceutical composition according to claim 6, characterized in that R1 is selected from any one of hydrogen, a monosaccharide group, a glycoside group formed by two monosaccharides, a straight-chain or branched glycoside group formed by three monosaccharides, four monosaccharides or five monosaccharides, wherein the monosaccharides are independently selected from glucose or rhamnose; represents a single bond or a double bond, when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

8. The pharmaceutical composition according to claim 7, characterized in that R1 is selected from: represents a single bond or a double bond, when When is a single bond, R2 is a hydroxyl group; When it is a double bond, R2 does not exist.

9. The pharmaceutical composition according to claim 6, wherein The compound represented by the general formula (I) is any of the following compounds:

10. The pharmaceutical composition according to claim 6, wherein The pharmaceutical composition optionally contains two or more of the following compounds:

11. The pharmaceutical composition according to any one of claims 6 to 10, wherein The pharmaceutical composition is one of an injection or an oral preparation; Preferably, the oral preparation is any one of a mixture, a tincture, a pill, a pellet, a powder, a granule, a tablet, a micropill, a microcapsule, a capsule, a soft capsule, a suspension and a syrup.

12. The pharmaceutical composition according to claims 6-11, wherein The carrier is selected from any one or more substances in the group consisting of a binder, a filler, a disintegrant, a lubricant, a glidant, a surfactant, a wetting agent, an antioxidant, a plasticizer, a sweetener, a colorant and a coating agent.

13. The use according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 6 to 12, characterized in that: The drug or the pharmaceutical composition is used to treat diabetes, diabetic nephropathy and / or cardiovascular and cerebrovascular diseases; Preferably, the diabetes is type 2 diabetes, and the cardiovascular and cerebrovascular disease is heart failure; Further preferably, the heart failure includes heart failure with reduced ejection fraction, heart failure with intermediate ejection fraction or heart failure with preserved ejection fraction.

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