Glycoside derivatives, their manufacturing methods, and applications

Abstract

The present invention provides glycoside derivatives, their preparation methods, and applications. Specifically, the present invention provides glycoside derivatives that are compounds represented by the following formula I or pharmaceutically acceptable salts thereof. The glycoside derivatives according to the present invention can be used to treat type II diabetes or type I diabetes. JPEG2023551441000082.jpg4278

Description

[Technical Field]

[0001] cross reference This application was filed with the China National Intellectual Property Administration on November 19, 2020, claiming priority to Chinese Patent Application No. 202011302722.4, titled "Glycoside derivatives, methods for producing the same, and applications," the contents of which are incorporated herein by reference in their entirety.

[0002] This invention relates to the field of chemical technology, particularly to glycoside derivatives, their production methods, and applications. [Background technology]

[0003] Currently, out of more than 400 million people worldwide with diabetes, approximately 110 million are in China, making the market value for diabetes medications high. Diabetes is a chronic, comprehensive disease characterized primarily by impaired glucose metabolism resulting from absolute or relative insulin deficiency or decreased sensitivity of target cells to insulin. Among these, the development of type 2 diabetes is the result of the combined action of peripheral insulin resistance and β-cell dysfunction.

[0004] The design concept of this invention originates from the mango leaf used in traditional Chinese medicine. Mango leaves are used in folk medicine to lower blood sugar levels. Modern pharmacological research has shown that the blood sugar-lowering active ingredient in mango leaves is the natural product mangiferin. The compound of this invention was obtained by two series of structural optimizations using mangiferin as the lead compound.

[0005] According to the literature, mangiferin exerts a direct blood glucose-lowering effect by enhancing the regenerative capacity of insulin cells, insulin levels, insulin sensitivity, and glucose utilization. It has also been reported that intraperitoneal injection of mangiferin may significantly reduce the amount of glycated hemoglobin in diabetic rats affected by oxidative damage. Furthermore, mangiferin has been reported to have some therapeutic effect on diabetic nephropathy, and may delay cardiovascular disease under oxidative stress caused by diabetes.

[0006] However, mangiferin has drawbacks, including low water solubility, low oral bioavailability, and a relatively mild blood glucose-lowering effect. Therefore, the inventors optimized the structure of mangiferin with the aim of improving its pharmacokinetic properties and increasing its bioavailability, thereby enhancing its efficacy in lowering blood glucose levels and reducing the risk of diabetic complications, while also reducing toxic side effects in humans.

[0007] Because the chemical structure of mangiferin is similar to that of SGLT-2 inhibitor compounds, which are hypoglycemic drugs, the chemical structure of mangiferin was optimized to target SGLT-2 for therapeutic effect. In vitro screening for SGLT-2 target inhibitory activity revealed a series of compounds with good hypoglycemic activity, and further in vivo animal studies confirmed that this series of compounds is effective in both type 1 and type 2 diabetes animal models. Furthermore, it offers a statistically significant advantage compared to dapagliflozin.

[0008] SGLT-2 inhibitors, a class of blood glucose-lowering drugs, have the advantage of being beneficial to the cardiovascular system compared to other blood glucose-lowering drugs. However, conventional SGLT-2 inhibitor compounds are still unsatisfactory in terms of biological activity, duration of action, and safety. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] This invention has been made in view of the above circumstances, and aims to provide an SGLT-2 inhibitor compound that has high therapeutic efficacy, high safety, a long duration of action, and requires fewer doses for the patient. [Means for solving the problem]

[0010] To solve the above technical problems, the present invention provides glycoside derivatives which are compounds represented by the following formula I or pharmaceutically acceptable salts thereof.

[0011] [ka]

[0012] In the formula, A is an oxygen atom, -(CH2) m - or -NH-, where m is 1, 2, or 3. B is an oxygen atom or a sulfur atom, R1, R2, R3, R4, R5, and R6 are independently hydrogen, hydroxyl group, carboxyl group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH2-aryl group, -OCH2-heteroaryl group, -O-heterocyclyl group, -OCH2-heterocyclyl group, ester group, and -NR. 11 R 11a , as well as selected from the group consisting of 3 to 14 membered heterocyclyl groups containing 1 to 4 heteroatoms selected from N, O, S, SO and / or SO2, Alternatively, R1 and R2 together form a heterocyclyl group, cycloalkyl group, aryl group, or heteroaryl group condensed on a benzene ring, and / or R3 and R4 together form a cyclopentyl group or oxacyclopentyl group condensed on a benzene ring. R7, R8, R9, R 10 These are independently selected from the group consisting of hydrogen, hydroxyl group, alkyl group, alkoxy group and alkylthio group, The aforementioned R 11 , R11a is independently selected from the group consisting of a hydrogen atom and an alkyl group, wherein the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH2-aryl group, -OCH2-heteroaryl group, -O-heterocyclyl group, -OCH2-heterocyclyl group, ester group, -NR 11 R 11a , heterocyclyl group, and alkylthio group may be further substituted by one or more substituents selected from the group consisting of halogen, hydroxy group, amino group, carboxy group, cyano group, alkyl group, alkoxy group, and nitro group.

[0013] More preferably, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH2-aryl group, -OCH2-heteroaryl group, -O-heterocyclyl group, -OCH2-heterocyclyl group, ester group, -NR 11 R 11a , heterocyclyl group, and alkylthio group may be further substituted by one or more substituents selected from the group consisting of halogen, hydroxy group, amino group, carboxy group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, and nitro group.

[0014] Preferably in the present invention, A is an oxygen atom or -CH2-.

[0015] Preferably in the present invention, B is an oxygen atom.

[0016] Preferably in the present invention, R1, R2, R3, R4, R5, and R6 are independently hydrogen, a hydroxyl group, a carboxyl group, a halogen, -CN, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C16 alkoxyalkoxy group, a C3-C6 cycloalkyl group, a C6-C12 aryl group, a C2-C12 heteroaryl group, an -O-C6-C12 aryl group, an -O-C2-C12 heteroaryl group, an -OCH2-C6-C12 aryl group, an -OCH2-C2-C12 heteroaryl group, an -O-C2-C6 heterocyclyl group, an -OCH2-C2-C6 heterocyclyl group, a C1-C6 ester group, or an -NR 11 R 11a , as well as selected from the group consisting of 3-14 membered heterocyclyl groups containing 1-4 heteroatoms selected from N, O, S, SO and / or SO2.

[0017] Here, the R 11 , R 11a R is independently selected from the group consisting of a hydrogen atom and an alkyl group, and more preferably a hydrogen atom or a C1-C6 alkyl group. In some specific embodiments of the present invention, the R 11 , R 11a The group is independently selected from the group consisting of H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl, and isohexyl group.

[0018] More preferably, R1, R2, R3, R4, R5, and R6 are independently hydrogen, hydroxyl group, carboxyl group, fluorine, chlorine, bromine, -CN, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methoxymethoxy group, ethoxymethoxy group, ethoxyethoxy group, n-propoxymethoxy group, isopropoxymethoxy group, n-propoxyethoxy group, isopropoxyethoxy group, cyclopropyl group, methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, pyri -OCH2-pyridyl group, -OCH2-pyridinyl group, -OCH2-pyridinyl group, -OCH2-pyridinyl group, -OCH2-pyridinyl group, -OCH2-pyridinyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl group, -OCH2-thienyl Selected from the group consisting of -OCH2-furanyl group, -OCH2-oxazolyl group, -OCH2-thiazolyl group, -OCH2-imidazolyl group, -OCH2-triazolyl group, methyl ester group, ethyl ester group, isopropyl ester group, sulfonic acid ester group, amino group, hexahydropyridyl group, hexahydropyradinyl group, morpholinyl group, tetrahydropyrrolyl group, and tetrahydrooxazolyl group.

[0019] In the present invention, one or more hydrogen atoms of the above group may be further substituted with one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and nitro groups.

[0020] More preferably, the substituent is selected from the group consisting of fluorine, chlorine, bromine, hydroxyl group, amino group, carboxyl group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, and nitro group.

[0021] In some specific embodiments of the present invention, the phenoxy group is, specifically,

[0022] [ka] And so on.

[0023] In some specific embodiments of the present invention, the above-mentioned -O-C2~C12 heteroaryl group is, specifically,

[0024] [ka] And so on.

[0025] In some specific embodiments of the present invention, the above--OCH2-C6~C12 aryl group is specifically PhCH2O-,

[0026] [ka] And so on.

[0027] In some specific embodiments of the present invention, the above-mentioned -OCH2-C2~C12 heteroaryl group is, specifically,

[0028] [ka] And so on.

[0029] In some specific embodiments of the present invention, the above C6-C12 aryl group is specifically a phenyl group, a p-methylphenyl group, a p-fluorophenyl group, an o-chlorophenyl group, an m-methoxyphenyl group, or

[0030] [ka] And so on.

[0031] In some specific embodiments of the present invention, the above C2-C12 heteroaryl groups are, specifically,

[0032] [ka] And so on.

[0033] In some specific embodiments of the present invention, the above C1-C6 alkyl groups are specifically -CF3, CHF2, CH2F, etc.

[0034] In some specific embodiments of the present invention, the above C1-C6 alkoxy groups are specifically -OCHF2, -OCF3, and the like.

[0035] In some specific embodiments of the present invention, the above-mentioned C2-C16 alkoxyalkoxy groups are specifically methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, and the like.

[0036] In some specific embodiments of the present invention, the above-mentioned -O-C2~C6 heterocyclyl group is specifically:

[0037] [ka] And so on.

[0038] In some specific embodiments of the present invention, the above C1-C6 ester groups are, specifically,

[0039] [ka] And so on.

[0040] Some specific embodiments of the present invention, the above-NR 11 R 11a Specifically, the amino group,

[0041] [ka] And so on.

[0042] In some specific embodiments of the present invention, a 3-14 membered heterocyclyl group containing 1-4 heteroatoms selected from N, O, S, SO and / or SO2 is specifically:

[0043] [ka] And so on.

[0044] In some specific embodiments of the present invention, R1 and R2 together form a 3-14 membered heterocyclyl group, a C3-C6 cycloalkyl group, a C6-C12 aryl group, or a C2-C12 heteroaryl group containing 1-4 heteroatoms selected from N, O, S, SO, and / or SO2, which are condensed on a benzene ring.

[0045] Preferably in the present invention, R1 and R2 together form a cyclohexyl group, phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyrrolyl group, thienyl group, furanyl group, oxazolyl group, thiazolyl group, imidazolyl group, triazolyl group, hexahydropyridyl group, hexahydropyrazine group, morpholinyl group, tetrahydropyrrolyl group, tetrahydrooxazolyl group, or dioxane condensed on a benzene ring.

[0046] The dioxane is preferably 1,4-dioxane, i.e., a dioxane group.

[0047] In the present invention, preferably R7, R8, R9, R10 These are independently selected from the group consisting of hydrogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group.

[0048] More preferably, R7, R8, R9, R 10 The group is independently selected from the group consisting of hydrogen, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, hydroxymethyl group, hydroxyethyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t-butylthio group, n-pentylthio group, isopentylthio group, and n-hexylthio group.

[0049] In some specific embodiments of the present invention, the glycoside derivative is a compound represented by the following formula Ia or a pharmaceutically acceptable salt thereof:

[0050] [ka] In the formula, R1, R2, R3, R4, R5, R6, R 10 The definition is the same as above, and therefore the explanation will be omitted here.

[0051] Preferably, R 10 This is a hydroxymethyl group or a methylthio group.

[0052] In some specific embodiments of the present invention, the glycoside derivative is a compound represented by the following formula II or a pharmaceutically acceptable salt thereof.

[0053] [ka] In the formula, A is an oxygen atom, -(CH2) m - or -NH-, where m is 1, 2, or 3. B is an oxygen atom or a sulfur atom, R3, R4, R5, and R6 are independently hydrogen, hydroxyl group, carboxyl group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH2-aryl group, -OCH2-heteroaryl group, -O-heterocyclyl group, -OCH2-heterocyclyl group, ester group, and -NR. 11 R 11a , as well as selected from the group consisting of 3 to 14 membered heterocyclyl groups containing 1 to 4 heteroatoms selected from N, O, S, SO and / or SO2, R 10 It is selected from the group consisting of hydrogen, hydroxyl group, alkyl group, alkoxy group and alkylthio group, The aforementioned R 11 , R 11a These are independently selected from the group consisting of hydrogen atoms and alkyl groups, Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH2-aryl group, -OCH2-heteroaryl group, -O-heterocyclyl group, -OCH2-heterocyclyl group, ester group, -NR 11 R 11a The heterocyclyl group and alkylthio group may be further substituted with one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, alkyl groups, alkoxy groups, and nitro groups.

[0054] More preferably, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH2-aryl group, -OCH2-heteroaryl group, -O-heterocyclyl group, -OCH2-heterocyclyl group, ester group, -NR 11 R11a The heterocyclyl group and alkylthio group may be further substituted with one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and nitro groups.

[0055] In the present invention, preferably, A is an oxygen atom or -CH2-.

[0056] In the present invention, B is preferably an oxygen atom.

[0057] Preferably in the present invention, R3, R4, R5, and R6 are independently hydrogen, a hydroxyl group, a carboxyl group, a halogen, -CN, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C16 alkoxyalkoxy group, a C3-C6 cycloalkyl group, a C6-C12 aryl group, a C2-C12 heteroaryl group, an -O-C6-C12 aryl group, an -O-C2-C12 heteroaryl group, an -OCH2-C6-C12 aryl group, an -OCH2-C2-C12 heteroaryl group, an -O-C2-C6 heterocyclyl group, an -OCH2-C2-C6 heterocyclyl group, a C1-C6 ester group, or an -NR 11 R 11a Furthermore, selected from the group consisting of 3-14 membered heterocyclyl groups containing 1-4 heteroatoms selected from N, O, S, SO, and / or SO2.

[0058] Here, the R 11 , R 11a R is independently selected from the group consisting of a hydrogen atom and an alkyl group, and more preferably a hydrogen atom or a C1-C6 alkyl group. In some specific embodiments of the present invention, the R 11 , R 11a The group is independently selected from H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, or isohexyl group.

[0059] More preferably, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, a hydroxyl group, a carboxyl group, a halogen, -CN, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C2-C16 alkoxyalkoxy group.

[0060] More preferably, R3 is selected from the group consisting of C1-C3 alkyl groups and C1-C3 alkoxy groups. R4, R5, and R6 are hydrogen.

[0061] The C1-C3 alkyl group and C1-C3 alkoxy group may be further substituted with one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, and nitro groups.

[0062] More preferably, R3, R4, R5, and R6 are independently hydrogen, hydroxyl group, carboxyl group, fluorine, chlorine, bromine, -CN, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methoxymethoxy group, ethoxymethoxy group, ethoxyethoxy group, n-propoxymethoxy group, isopropoxymethoxy group, n-propoxyethoxy group, isopropoxyethoxy group, cyclopropyl group, methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, and pyridyl -OCH2-pyridyl group, pyridinyl group, pyrrolyl group, thienyl group, furanyl group, oxazolyl group, thiazolyl group, imidazolyl group, triazolyl group, phenoxy group, pyridyloxy group, pyridinyloxy group, pyrrolyloxy group, furanyloxy group, thienyloxy group, oxazolyloxy group, benzyloxy group, -OCH2-pyridyl group, -OCH2-pyridinyl group, -OCH2-pyrrolyl group, -OCH2-thienyl The group is selected from the group consisting of -OCH2-furanyl group, -OCH2-oxazolyl group, -OCH2-thiazolyl group, -OCH2-imidazolyl group, -OCH2-triazolyl group, methyl ester group, ethyl ester group, isopropyl ester group, sulfonic acid ester group, amino group, hexahydropyridyl group, hexahydropyradinyl group, morpholinyl group, tetrahydropyrrolyl group, and tetrahydrooxazolyl group.

[0063] In the present invention, one or more hydrogen atoms of the above group may be further substituted with one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and nitro groups.

[0064] More preferably, the substituent is selected from the group consisting of fluorine, chlorine, bromine, hydroxyl group, amino group, carboxyl group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, and nitro group.

[0065] In some embodiments of the present invention, A is -(CH2)- or an oxygen atom, B is an oxygen atom, R1 and R2 together form a 5-6 membered heterocyclyl group condensed on a benzene ring, or a cyclobutanyl group condensed on a benzene ring, and the 5-6 membered heterocyclyl group is a 5-6 membered heterocyclyl group containing one or two heteroatoms selected from O and S. R3 is CH3 (CH2) n -, CH3(CH2) n Selected from the group consisting of O- and halogens, n is selected from 0, 1, 2, and 3. R4 is hydrogen, Alternatively, R3 and R4 may combine to form a cyclopentyl group or oxacyclopentyl group condensed on a benzene ring. R5 and R6 are hydrogen. R7, R8, and R9 are hydroxyl groups. R 10 The group is selected from the group consisting of hydroxyalkyl groups, alkoxy groups, and alkylthio groups.

[0066] In another embodiment of the present invention, A is -(CH2)- or an oxygen atom, B is an oxygen atom, R1 and R2 together form a 5-6 membered heterocyclyl group condensed on a benzene ring, or a cyclobutanyl group condensed on a benzene ring, and the 5-6 membered heterocyclyl group is a 5-6 membered heterocyclyl group containing 1 or 2 oxygen atoms. R3 is CH3 (CH2) n -, CH3(CH2) nSelected from the group consisting of O- and halogens, n is selected from 0, 1, 2, and 3. R4 is hydrogen, Alternatively, R3 and R4 may combine to form a cyclopentyl group or oxacyclopentyl group condensed on a benzene ring. R5 and R6 are hydrogen. R7, R8, and R9 are hydroxyl groups. R 10 The group is selected from the group consisting of a hydroxymethyl group, a methoxy group, and a methylthio group.

[0067] In some embodiments of the present invention, A is an oxygen atom, B is an oxygen atom, R1 is selected from the group consisting of C1-C3 alkoxy groups. R2 is hydrogen, R3 is selected from halogens, preferably fluorine, chlorine, or bromine. R4 is hydrogen, R5 and R6 are hydrogen. R7, R8, and R9 are hydroxyl groups. R 10 The group is selected from hydroxyalkyl groups, preferably a hydroxymethyl group.

[0068] In some specific embodiments of the present invention, the phenoxy group is, specifically,

[0069] [ka] And so on.

[0070] In some specific embodiments of the present invention, the above-mentioned -O-C2~C12 heteroaryl group is, specifically,

[0071] [ka] And so on.

[0072] In some specific embodiments of the present invention, the above--OCH2-C6~C12 aryl group is specifically PhCH2O-,

[0073] [ka] And so on.

[0074] In some specific embodiments of the present invention, the above-mentioned -OCH2-C2~C12 heteroaryl group is, specifically,

[0075] [ka] And so on.

[0076] In some specific embodiments of the present invention, the above C6-C12 aryl group is specifically a phenyl group, a p-methylphenyl group, a p-fluorophenyl group, an o-chlorophenyl group, an m-methoxyphenyl group, or

[0077] [ka] And so on.

[0078] In some specific embodiments of the present invention, the above C2-C12 heteroaryl groups are, specifically,

[0079] [ka] And so on.

[0080] In some specific embodiments of the present invention, the above C1-C6 alkyl groups are specifically -CF3, CHF2, CH2F, etc.

[0081] In some specific embodiments of the present invention, the above C1-C6 alkoxy groups are specifically -OCHF2, -OCF3, and the like.

[0082] In some specific embodiments of the present invention, the above-mentioned C2-C16 alkoxyalkoxy groups are specifically methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, and the like.

[0083] In some specific embodiments of the present invention, the above-mentioned -O-C2~C6 heterocyclyl group is specifically:

[0084] [ka] And so on.

[0085] In some specific embodiments of the present invention, the above C1-C6 ester groups are, specifically,

[0086] [ka] And so on.

[0087] Some specific embodiments of the present invention, the above-NR 11 R 11a Specifically, the amino group,

[0088] [ka] And so on.

[0089] In some specific embodiments of the present invention, the above 3- to 14-membered heterocyclyl group comprising 1 to 4 heteroatoms selected from N, O, S, SO and / or SO2 is specifically:

[0090] [ka] And so on.

[0091] Preferably in the present invention, the R 10This is selected from the group consisting of hydrogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group.

[0092] More preferably, R 10 This is selected from the group consisting of hydrogen, a hydroxyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group, and a C1-C3 alkylthio group.

[0093] The C1-C3 alkyl group, C1-C3 alkoxy group, or C1-C3 alkylthio group may be further substituted with one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, and nitro groups.

[0094] More preferably, the R 10 The group is selected from the group consisting of hydrogen, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, hydroxymethyl group, hydroxyethyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t-butylthio group, n-pentylthio group, isopentylthio group, and n-hexylthio group.

[0095] In some specific embodiments of the present invention, the glycoside derivative is a compound having any of the following structures or a pharmaceutically acceptable salt thereof:

[0096] [ka]

[0097] [ka]

[0098] [ka]

[0099] In some specific embodiments of the present invention, the glycoside derivative is a compound having any of the following structures or a pharmaceutically acceptable salt thereof:

[0100] [ka]

[0101] In some specific embodiments of the present invention, the glycoside derivative is a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0102] [ka]

[0103] A second object of the present invention is to provide a method for producing the glycoside derivative described above, which includes producing a compound represented by formula Ia from a compound represented by formula III via a deprotection reaction.

[0104] [ka] In the formula, the definitions of A, B, R1, R2, R3, R4, R5, and R6 are the same as above, and their explanation is omitted here.

[0105] R 10 It is a hydroxymethyl group.

[0106] R 12These are alkyl groups (for example, C1-C6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl groups), TMS- (trimethylsilyl group), Bn- (benzyl group), formyl group, Ac- (acetyl group), THP- (tetrahydropyranyl group), MOM- (methoxymethyl group), or TBDMS- (t-butyldimethylsilyl group).

[0107] R 12 If it is TMS- or TBDMS-, the deprotection reagent is, for example, TBAF. 12 When is Bn-, the conditions for the deprotection reaction are H2 / Pd-C, H2 / Pt-C, or H2 / Pd(OH)2-C, etc. One example is R 12 If the compound is Ac-, the conditions for the deprotection reaction are either strongly basic conditions (e.g., aqueous sodium hydroxide solution or aqueous potassium hydroxide solution) or strongly acidic conditions. For example, R 12 If is THP- or MOM-, the deprotection reaction conditions are acidic (e.g., aqueous hydrochloric acid solution, ethyl hydroxide solution (HCl(g) / SiO), methanol hydroxide solution (HCl(g) / CH3OH), ethanol hydroxide solution (HCl(g) / EtOH), or dioxane hydroxide solution (HCl(g) / Dioxane)). As an example, R 12 If the group is a methyl group or the like, the deprotection reagent is concentrated hydrochloric acid, hydrobromic acid, concentrated sulfuric acid, or boron tribromide.

[0108] In the above manufacturing method, in a preferred embodiment, the compound represented by formula III is produced from the compound represented by formula IV.

[0109] [ka] Here, A, B, R1, R2, R3, R4, R5, R6, R 12 The definition is the same as above, and therefore the explanation will be omitted here.

[0110] For example, the reaction conditions for producing the compound represented by formula III from the compound represented by formula IV are BF3.Et2O.

[0111] In the above manufacturing method, as a preferred embodiment, the compound represented by formula IV is produced by reacting the compound represented by formula V with the compound represented by formula VI.

[0112] [ka] Here, A, B, R1, R2, R3, R4, R5, R6, R 12 The definition is the same as above, and therefore the explanation will be omitted here.

[0113] R 13 These are -H, -F, -Cl, -Br, -I, -OMs, -OTs, and -OTf.

[0114] Reaction reagents for producing the compound represented by formula IV from the compound represented by formula V and the compound represented by formula VI include, for example, LDA (lithium diisopropylamide) or n-BuLi (n-butyllithium).

[0115] In some specific embodiments of the present invention, the reaction pathway of the glycoside derivative is as follows:

[0116] [ka]

[0117] In some specific embodiments of the present invention, the reaction pathway of the glycoside derivative is as follows:

[0118] [ka]

[0119] The present invention provides another method for producing the glycoside derivatives described above, comprising producing a compound represented by formula Ia below from a compound represented by formula VII below through a sulfurization reaction and a deprotection reaction.

[0120] [ka] Here, the definitions of A, B, R1, R2, R3, R4, R5, and R6 are the same as above, and their explanation is omitted here.

[0121] R 10 This is a methylthio group.

[0122] Preferably, B is an oxygen atom.

[0123] R 12 These are alkyl groups (for example, C1-C6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl groups), TMS- (trimethylsilyl group), Bn- (benzyl group), formyl group, Ac- (acetyl group), THP- (tetrahydropyranyl group), MOM- (methoxymethyl group), or TBDMS- (t-butyldimethylsilyl group).

[0124] For example, the sulfurizing agent in the aforementioned sulfurization reaction is thiourea.

[0125] For example, R 12 If it is TMS- or TBDMS-, the deprotection agent is TBAF. 12 When is Bn-, the conditions for the deprotection reaction are, for example, H2 / Pd-C, H2 / Pt-C, or H2 / Pd(OH)2-C. 12 If the compound is Ac-, for example, the conditions for the deprotection reaction are either strongly basic conditions (e.g., aqueous sodium hydroxide solution or aqueous potassium hydroxide solution) or strongly acidic conditions. 12If the compound is THP- or MOM-, for example, the conditions for the deprotection reaction are acidic conditions (e.g., aqueous hydrochloric acid, ethyl hydroxide solution (HCl(g) / SiO), methanol hydroxide solution (HCl(g) / CH3OH), ethanol hydroxide solution (HCl(g) / EtOH), or dioxane hydroxide solution (HCl(g) / Dioxane)). 12 If the group is a methyl group, for example, the deprotection reagents are concentrated hydrochloric acid, hydrobromic acid, concentrated sulfuric acid, or boron tribromide.

[0126] In the above manufacturing method, as a preferred embodiment, the compound represented by formula VII is produced from the compound represented by formula VIII.

[0127] [ka] Here, the definitions of A, B, R1, R2, R3, R4, R5, and R6 are the same as above, and their explanation is omitted here.

[0128] For example, the reaction conditions for producing the compound represented by formula VII from the compound represented by formula VIII are AC2O, DMAP, and TEA.

[0129] In the above manufacturing method, as a preferred embodiment, the compound represented by formula VIII is produced from the compound represented by the following formula IX.

[0130] [ka] Here, the definitions of A, R1, R2, R3, R4, R5, and R6 are the same as above, and their explanation is omitted here.

[0131] For example, the conditions for producing the compound of formula VIII from the compound represented by formula IX are AcOH and H2O.

[0132] In the above manufacturing method, as a preferred embodiment, the compound represented by formula IX is produced by reacting the compound represented by the following formula V with the compound represented by the following formula X, followed by a reduction reaction.

[0133] [ka] Here, the definitions of A, R1, R2, R3, R4, R5, and R6 are the same as above, and their explanation is omitted here.

[0134] R 13 These are -H, -F, -Cl, -Br, -I, -OMs, -OTs, and -OTf.

[0135] For example, the catalyst used in the reaction between the compound represented by formula V and the compound represented by formula X is t-BuMgCl.

[0136] For example, the conditions for the above reduction reaction are CeCl3 and NaBH4.

[0137] In some specific embodiments of the present invention, the reaction pathway of the glycoside derivative is as follows:

[0138] [ka]

[0139] A third object of the present invention is to provide an intermediate compound or a salt thereof having a structure represented by the following formula IV:

[0140] [ka] In the formula, the above A, B, R1, R2, R3, R4, R5, R6, R 12 The definition is the same as above, and therefore the explanation will be omitted here.

[0141] Furthermore, the present invention provides another intermediate compound or salt thereof having a structure represented by the following formula IX:

[0142] [ka] In the formula, the definitions of A, R1, R2, R3, R4, R5, and R6 are the same as above, and their explanation is omitted here.

[0143] In some specific embodiments of the present invention, the above intermediate has one of the following structures:

[0144] [ka]

[0145] A fourth object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned glycoside derivative or a glycoside derivative produced by the above-mentioned production method, and a pharmaceutically acceptable carrier, excipient, diluent, auxiliary agent, medium, or a combination thereof.

[0146] In the present invention, the types of carriers, excipients, diluents, auxiliaries, and media are not particularly limited, and examples include carriers, excipients, diluents, auxiliaries, and media that are well known to those skilled in the art and applicable.

[0147] A fifth object of the present invention is to provide applications of the above-mentioned glycoside derivative, or the glycoside derivative produced by the above-mentioned production method, or the above-mentioned pharmaceutical composition in the manufacture of pharmaceuticals for preventing, treating, or alleviating diabetes and its complications.

[0148] In the present invention, the above-mentioned diabetes can be selected from type 1 diabetes and type 2 diabetes, and is preferably type 2 diabetes.

[0149] The above complications are preferably cardiovascular diseases caused by type II diabetes.

[0150] The glycoside derivatives provided in the present invention, or glycoside derivatives produced by the above production method, or the pharmaceutical compositions can be used to improve blood glucose control or protect cardiovascular health in adult patients with type II diabetes, and can rapidly and safely lower blood glucose without causing a risk of hypoglycemia.

[0151] In the present invention, the glycoside derivative can be used in combination with other drugs for preventing, treating, or alleviating diabetes and its complications.

[0152] A sixth object of the present invention is to provide a method for preventing, treating, or alleviating diabetes and its complications, comprising contacting a biological sample or a patient with the above-described glycoside derivative, or a glycoside derivative produced by the above-described manufacturing method, or the above-described pharmaceutical composition. In a particular embodiment, the method for preventing, treating, or alleviating diabetes and its complications comprises applying the glycoside derivative according to the present invention, or a glycoside derivative produced by the above-described manufacturing method, or the above-described pharmaceutical composition to a patient in need thereof.

[0153] Compared to the prior art, the present invention provides a glycoside derivative having a structure represented by formula I or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0154] Compared to the prior art, the present invention has the following technical advantages. 1. The present invention provides a novel glycoside derivative having a therapeutic effect on type II diabetes. Compared to the prior art, the glycoside derivative according to the present invention has a superior therapeutic effect on type II diabetes, whether used in high, medium, or low doses.

[0155] 2. The method for producing glycoside derivatives according to the present invention uses inexpensive and readily available chemical products as starting materials, and since the synthesis yield at each step is high, production costs are low and it is more suitable for industrial production. [Modes for carrying out the invention]

[0156] term: Unless otherwise specified, terms used in this application, encompassing the specification and claims, are defined as follows. Note that, unless otherwise specified, nouns not modified by numbers in the specification and attached claims may generally refer to plural items. Unless otherwise specified, methods commonly used in biochemistry and pharmacology, such as mass spectrometry, nuclear magnetism, and HPLC, are used.

[0157] As used herein, the term “alkyl group” is intended to encompass branched and linear saturated aliphatic hydrocarbon groups having a given number of carbon atoms. For example, “C1-C6 alkyl group” means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, and neopentyl). Preferred alkyl groups are C1-C6 alkyl groups, and more preferred alkyl groups are C1-C4 alkyl groups.

[0158] The terms "alkoxy group" or "alkyloxy group" refer to an -O-alkyl group. "C1-C6 alkoxy group" (or alkyloxy group) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Preferred alkoxy groups are C1-C6 alkoxy groups, and more preferred alkoxy groups are C1-C4 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy groups (e.g., n-propoxy and isopropoxy groups) and t-butoxy groups. Similarly, "alkylthio group" or "thioalkoxy group" represents the alkyl group defined above having a predetermined number of carbon atoms linked via crosslinked sulfur, for example, methyl-S- or ethyl-S-.

[0159] The term "carbonyl group" refers to an organic functional group (C=O) formed by the double bond between two atoms, carbon and oxygen.

[0160] The term "aryl group" refers to a monocyclic, bicyclic, or tricyclic cyclic system having a total of 5 to 12 ring members, wherein at least one ring in the cyclic system is an aromatic ring, and each ring in the cyclic system contains 3 to 7 ring constituent atoms. A monocyclic aryl refers to a phenyl group. Bicyclic and aryls with two or more rings refer to naphthyl groups, anthracenyl groups, etc. Furthermore, this aryl bicyclic ring may be formed by condensing a cycloalkyl group, a cycloalkenyl group, or a cycloalkynyl group onto a benzene ring. The aryl group is preferably a C6 to C12 aryl group. In specific embodiments of the present invention, "aryl group" refers to an aromatic cyclic system including, but not limited to, phenyl, biphenyl, indenyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl groups. The term "aralkyl group" or "arylalkyl group" refers to an alkyl group residue bonded to an aryl ring, and non-limiting examples include benzyl and phenethyl groups. The fused aryl group can be bonded to another group at an appropriate position on a cycloalkyl or aromatic ring. For example, the arrow lines drawn from the ring system represent bonds that can be attached to any suitable ring atom.

[0161] The term "cycloalkyl group" refers to monocyclic or bicyclic cyclic alkyl groups. Monocyclic cyclic alkyl groups include, but are not limited to, C3-C8 cyclic alkyl groups including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl groups. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl group." Bicyclic cyclic alkyl groups include bridged rings, spiro rings, or fused ring cycloalkyl groups. Cycloalkyl groups are preferably C3-C6 cycloalkyl groups.

[0162] Examples of "halo" or "halogen" include fluorine, chlorine, bromine, and iodine. A "haloalkyl group" is intended to encompass branched and linear saturated aliphatic hydrocarbon groups having a predetermined number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl groups. Another example of a haloalkyl group is a "fluoroalkyl group" intended to encompass branched and linear saturated aliphatic hydrocarbon groups having a predetermined number of carbon atoms and substituted with one or more fluorine atoms.

[0163] A "haloalkoxy group" or "haloalkyloxy group" refers to a haloalkyl group as defined above, having a predetermined number of carbon atoms bonded via a crosslinking oxygen atom. For example, "C1-C6 haloalkoxy group" is intended to include haloalkoxy groups of C1, C2, C3, C4, C5, and C6. Examples of haloalkoxy groups include, but are not limited to, the trifluoromethoxy group, the 2,2,2-trifluoroethoxy group, and the pentafluoroethoxy group. Similarly, a "haloalkylthio group" or "thiohaloalkoxy group" represents a haloalkyl group as defined above, having a predetermined number of carbon atoms bonded via a crosslinking sulfur atom, for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0164] The term "heteroaryl group" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic ring, or a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered aromatic polycyclic heterocycle, which is fully unsaturated or partially unsaturated and contains a carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. Examples of "heteroaryl groups" include any of the following polycyclic groups, in which any heterocycle as defined above in these polycyclic groups is condensed to a benzene ring, and the nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR (where R is H or another substituent as defined)). The heterocycle can be linked to its side groups with any heteroatoms or carbon atoms that result in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. Nitrogen in the heterocycle may optionally be quaternized. Preferably, if the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. Preferred heteroaryl groups are 5- to 12-membered heteroaryl groups. Examples of heteroaryl groups include acridinyl group, azetidinyl group, azosine group, benzimidazolyl group, benzofuranyl group, benzothiofuranyl group, benzothienyl group, benzoxazolyl group, benzoxazolinyl group, benzothiazolyl group, benzotriazolyl group, benzotetrazolyl group, benzoisoxazolyl group, benzoisothiazolyl group, benzimidazolinyl group, carbazolyl group, 4aH-carbazolyl group, carbolinyl group, chromanyl group, chromenyl group, sinnolinyl group, decahydroquinolinyl group, 2H,6H-1,5,2-dithiadinyl group, dihydrofluoro[2,3-b] Tetrahydrofuranyl group, furanyl group, furazanyl group, imidazolidinyl group, imidazolinyl group, imidazolyl group, 1H-indazolyl group, imidazopyridyl group, indolenyl group, dihydroindolyl group, indolyl group, 3H-indolyl group, isatinoyl group, isobenzofuranyl group, isochromanyl group, isoindazolyl group, isodihydroindolyl group, isoindolyl group, isoquinolinyl group, isothiazolyl group, isothiazolopyridyl group, isoxazolyl group, isoxa Zolopyridyl group, methylenedioxyphenyl group, morpholinyl group, diazanaphthyl group, octahydroquinolinyl group, oxadiazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazolopyridyl group, oxazolidinyl group, perimidinyl group, oxyindolyl group, pyrimidinyl group, phenanthrolinyl group, phenanthrolinyl group, phenazinyl group, phenothiazinyl group, phenoxadiyl group, phenoxazinyl Group, phthalazinyl group, piperazinyl group, piperidine group, piperidinol group, 4-piperidinol group, piperonyl group, pteridinyl group, prinyl group, pyranyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolopyridyl group, pyrazolyl group, pyridadinyl group, pyridoxazolyl group, pyridimidazolyl group, pyridothiazolyl group, pyridyl group, pyrimidinyl group, pyrrolidinyl group, pyrrolidinyl group, 2-pyrrolidonyl group, 2H-pyrrolyl group, pyrrolyl group, quinazolinyl group, quinolinyl group, 4H-quinadinyl group, quinoxalinyl group, quinuclidinyl group, te Trazolyl group, tetrahydrofuranyl group, tetrahydroisoquinolinyl group, tetrahydroquinolinyl group, 6H-1,2,5-thiadiadinyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl group, thiazolyl group, thienyl group, thiazolopyridyl group, thienohiazolyl group, thienoxazolyl group, thienoimidazolyl group, thienyl group, triazinyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, 1,2,5-triazolyl group, 1,3,Examples of heteroaryl groups include, but are not limited to, 4-triazolyl groups and xanthenyl groups, quinolinyl groups, isoquinolinyl groups, phthalazinyl groups, quinazolinyl groups, indolyl groups, isoindolyl groups, isodihydroindolyl groups, 1H-indazolyl groups, benzimidazolyl groups, 1,2,3,4-tetrahydroquinolinyl groups, 1,2,3,4-tetrahydroisoquinolinyl groups, 5,6,7,8-tetrahydroquinolinyl groups, 2,3-dihydrobenzofuranyl groups, chromanyl groups, 1,2,3,4-tetrahydroquinoxalinyl groups, and 1,2,3,4-tetrahydroquinazolinyl groups. In the present invention, the heteroaryl group is preferably a C2-C12 heteroaryl group or a C5-C12 heteroaryl group.

[0165] As used herein, the terms “heterocyclyl group” or “heterocycloalkyl group” refer to monocyclic heterocycloalkyl systems or bicyclic heterocycloalkyl systems. A monocyclic heterocycloalkyl group refers to a 3- to 8-membered saturated or unsaturated but non-aromatic cyclic alkyl group comprising at least one selected from O, N, S, and P. Preferred heterocycloalkyl groups are 3- to 12-membered heterocyclyl groups or 3- to 6-membered heterocyclyl groups, with the preferred heterocyclyl group being the -O-C2-C6 heterocyclyl group.

[0166] As used herein, the term "substitution" means that at least one hydrogen atom is substituted by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound.

[0167] If any variable appears one or more times in any composition or formula of a compound, its definition at each occurrence is independent of its definition at all other occurrences. Therefore, for example, if a group is shown to be substituted with 0, 1, 2, or 3 R groups, that group may be substituted with up to 3 R groups, and each R group is independently selected from those defined as R at each occurrence. Furthermore, combinations of substituents and / or variables are only permitted if such combinations result in a stable compound.

[0168] As used herein, the term “patient” refers to an organism treated by the method of the present invention. Such organisms are preferably mammals (e.g., mice, monkeys, horses, cattle, pigs, dogs, cats, etc.), but are not limited to these, and most preferably refer to humans.

[0169] As used herein, the term “effective dose” means the amount of a drug or agent (i.e., a compound according to the present invention) that elicits a biological or medical response in a tissue, system, animal, or human, as determined by a researcher or clinician. Furthermore, the term “therapeutic effective dose” means the amount that, compared to a corresponding subject who has not received the above dose, results in improvement, treatment, cure, prevention or reduction of a disease, illness, or side effect, or a reduction in the rate of progression of a disease or illness. An effective dose may be given in one or more doses, applications, or applications and is not intended to be limited by a particular formulation or route of administration. The term also encompasses effective doses within the range that result in an enhancement of normal physiological function.

[0170] As used herein, the term “treatment” encompasses any effect resulting from the improvement of a disease, disorder, or disability, such as reduction, decrease, regulation, improvement, or elimination, or improvement of its symptoms. As used herein, by administering a compound or pharmaceutical composition, a disease, symptoms, or condition can be improved, in particular by improving its severity, delaying its onset, slowing the progression of the disease, or shortening the duration of the disease. This can be due to circumstances related to the administration, whether fixed or temporary, continuous or intermittent. As used herein, the term “prevention” means preventing, blocking, or eliminating the onset of a disease or symptoms before they occur, or hindering or slowing the progression of the disease.

[0171] As used herein, the term "pharmaceutical composition" refers to a composition that is a combination of an activator and an inactive or active carrier, particularly applicable in vivo or ex vivo for the diagnosis or treatment of a disease.

[0172] The terms “medicinal” or “pharmaceutically acceptable” are used herein to mean, within reasonable medical judgment, compounds, substances, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions and / or other problems or complications, and that are appropriate in terms of a reasonable benefit / risk ratio.

[0173] As used herein, “pharmaceutically acceptable carrier” and “medicinal carrier” mean medicinal substances, compositions, or media such as liquid or solid fillers, diluents, excipients, manufacturing aids (e.g., lubricants, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid) or solvent encapsulants, relating to the transport or delivery of active compounds from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and harmless to the patient.

[0174] To further illustrate the present invention, the glycoside derivatives provided in the present invention, their manufacturing methods, and applications will be described in detail below with reference to examples.

[0175] Preparation of the example: Example 1: Preparation of Compound 1

[0176] [ka]

[0177] (1) Under stirring conditions, Cu(AcO)2 (1.97 g, 10.836 mmol, 1.1 equivalent) and pyridine (2.34 g, 29.552 mmol, 3 equivalents) were added to a solution of 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (2.30 g, 12.806 mmol, 1.3 equivalents) and 5-bromo-2-methoxyphenol (2.00 g, 9.851 mmol, 1.00 equivalent) in dichloromethane (50.00 mL), and the mixture was stirred at room temperature under an air atmosphere for 48 hours. 100 mL of H2O was added to the mixture. The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic phase was washed with saturated saline solution (1 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain 6-(5-bromo-2-methoxyphenoxy)-2,3-dihydro-1,4-benzodioxane (1134 mg, yield 34.14%) as a grayish-white solid.

[0178] The reaction pathway is as follows:

[0179] [ka]

[0180] (2) Under nitrogen protection and stirring conditions, n-BuLi (0.24 mL, 0.594 mmol, 2.00 equivalents) was added dropwise to a solution of 6-(5-bromo-2-methoxyphenoxy)-2,3-dihydro-1,4-benzodioxane (100.00 mg, 0.297 mmol, 1.00 equivalent) in tetrahydrofuran (1.00 mL) at a dropping temperature of -78 °C. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 1 hour. A solution of (3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxane-2-one (479.26 mg, 0.890 mmol, 3.00 equivalents) in tetrahydrofuran (1.00 mL) was added dropwise to the above mixture at a dropping temperature of -78 °C. The resulting mixture was stirred at -78 °C for an additional 1 hour. The reaction system was warmed to room temperature, and the reaction was quenched with saturated NH4Cl(aq.) at room temperature. The resulting mixture was extracted with EA (2 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled under reduced pressure to concentrate. The crude product was used directly in the next step without further purification.

[0181] The reaction pathway is as follows:

[0182]

Chemical formula

[0183] (3) Under nitrogen protection and stirring conditions, BF3-Et2O was added dropwise to a solution of (3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]-2-[3-(2,3-dihydro-1,4-benzodioxin-6-oxyl)-4-methoxyphenyl]oxan-2-ol (540.00 mg, 1.00 equivalent) and TES (157 mg) in acetonitrile (4 ml) and reacted for 30 min at a dropping temperature of -30°C. The reaction was monitored by LC-MS. After the reaction was complete, the reaction was quenched at room temperature with K2CO3 (aq) for 1 hour. The resulting mixture was extracted with ELISA (3 × 20 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a C18 silica gel column, acetonitrile-water mobile phase, a gradient of 40% to 85%, an elution time of 10 minutes, and a UV 254 nm detector. 6-[2-methoxy-5-[(2R,3S,4R,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxan-2-yl]phenoxy]-2,3-dihydro-1,4-benzodioxane (470 mg, yield 85.9%) was obtained as a grayish-white solid.

[0184] The reaction pathway is as follows:

[0185] [ka]

[0186] (4) 6-[2-methoxy-5-[(2R,3S,4R,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxy-2-yl]phenoxy]-2,3-dihydro-1,4-benzodioxane (500.00 mg, 1.00 equivalent) and 15% Pd / C were stirred overnight in methanol solution at 50°C under a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 silica gel column with acetonitrile-water mobile phase, a gradient of 10% to 50%, an elution time of 30 minutes, and a UV 254 nm detector. (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-oxyl)-4-methoxyphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (140 mg, yield 52.0%) was obtained as a grayish-white solid.

[0187] The reaction equation is as follows:

[0188] [ka]

[0189] LC-MS: (ES, m / z): [M-1] = 419; 1 H NMR: (400 MHz, Methanol-d4) δ 7.22 (dd, J= 8.4, 2.1 Hz, 1H), 7.13 - 7.03 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 6.44 - 6.36 (m, 2H), 4.24 - 4.16 (m, 4H), 4.07 (d, J = 9.4 Hz, 1H), 3.88 (dd, J = 12.0, 1.5 Hz, 1H), 3.80 (s, 3H), 3.76 - 3.65 (m, 1H), 3.51 - 3.32 (m, 5H).

[0190] Example 2: Preparation of Compound 2 (1) A solution of 6-bromo-2,3-dihydro-1,4-benzodioxane (4.40 g, 1.00 equivalent) and Mg (2.00 g, 5.00 equivalent) in THF (15 ml) was stirred under a nitrogen atmosphere at 50°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. 5-bromo-2-methylbenzaldehyde (3.00 g, 1.00 equivalent) was added dropwise to the above mixture, maintaining the reaction system temperature at 0°C, and the addition was completed within 10 minutes. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the reaction was quenched at 0°C with an ice water mixture. The resulting mixture was extracted with ELISA (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a C18 silica gel column, acetonitrile-water mobile phase, a gradient of 20% to 70%, for 5 minutes, and a UV 254 nm detector. (5-bromo-2-methylphenyl)(2,3-dihydro-1,4-benzodioxin-6-yl)methanol (4.8 g, yield 69.6%) was prepared as a grayish-white solid.

[0191] The reaction pathway is as follows:

[0192] [ka]

[0193] (2) (5-Bromo-2-methylphenyl)(2,3-dihydro-1,4-benzodioxin-6-yl)methanol (4.80 g, 1.00 equivalent) and TES (3.4 g, 2.0 equivalents) were added to acetonitrile (80 mL) to form a mixture. Under a nitrogen atmosphere and stirring conditions, BF3-Et2O was added dropwise to the above mixture at a dropping temperature of -30 °C. The resulting mixture was stirred at -30 °C for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. After completion of the reaction, the reaction was quenched with K2CO3 at -20 °C. The resulting mixture was extracted with EtOAc (3 × 70 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 silica gel column, with a mobile phase of MeOH-water, gradient 20% - 60%, for 25 minutes, and a detector at UV 254 nm. 6-[(5-Bromo-2-methylphenyl)methyl]-2,3-dihydro-1,4-benzodioxane (3.6 g, yield 78.0%) was prepared as an off-white solid.

[0194] The reaction route is as follows:

[0195]

Chemical formula

[0196] (3) Under stirring and nitrogen protection conditions, n-BuLi (1.2 eq) was added dropwise to a tetrahydrofuran mixture of 6-[(5-bromo-2-methylphenyl)methyl]-2,3-dihydro-1,4-benzodioxane (3.60 g, 1.20 equivalents) at a dropping temperature of -78 °C.

[0197] While stirring, under nitrogen protection conditions, t-BuMgCl (6.1 mL) was added dropwise over 30 minutes to a tetrahydrofuran (15 mL) mixture of (3aS,5S,6S,6aS)-2,2-dimethyl-5-(morpholine-4-carbonyl)-tetrahydrofuran[2,3-d][1,3]dioxol-6-ol (2.50 g, 1.00 equivalent) at a dropping temperature of 0 °C.

[0198] The solutions obtained above were mixed and stirred at -78°C for 30 minutes. The reaction was monitored by LC-MS. After the reaction was complete, NH4Cl (aq.) (5 mL) was added at room temperature to quench the reaction. The resulting mixture was extracted with RINKAN (3 × 50 mL) sorbate. The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 silica gel column, with acetonitrile-water mobile phase, a gradient of 15% to 60%, an elution time of 20 minutes, and a UV254 detector. (3aR,5S,6R,6aR)-5-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylbenzoyl]-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxin-6-ol (4.6 g, yield 95.0%) was prepared as a grayish-white solid.

[0199] The reaction pathway is as follows:

[0200] [ka]

[0201] (4) Under nitrogen protection and stirring conditions, (3aR,5S,6R,6aR)-5-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylbenzoyl]-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxol-6-ol (4.60 g, 1.00 equivalent) and CeCl3·7H2O (5.20 g, 1.30 equivalent) were mixed in methanol (20 mL) with NaBH4 (0.50 g, 1.20 equivalent) and reacted at -30°C for 30 min. The reaction was monitored by LC-MS. After the reaction was complete, the reaction was quenched by adding HCl (2N) at -30°C. The resulting mixture was extracted with ELISA (3 × 40 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a C18 silica gel column, acetonitrile-water mobile phase, a gradient of 10% to 50%, an elution time of 10 minutes, and a UV 254 nm detector. (3aR,5R,6S,6aR)-5-[[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl](hydroxy)methyl]-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxin-6-ol (2.6 g, yield 56.2%) was obtained as a grayish-white solid.

[0202] The reaction pathway is as follows:

[0203] [ka]

[0204] (5) (3aR,5R,6S,6aR)-5-[[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl](hydroxy)methyl]-2,2-dimethyl-tetrahydrofuran[2,3-d][1,3]dioxol-6-ol (2.60 g, 1.00 equivalent) and AcOH (20 mL) were reacted in H2O (20 mL) at 100 °C for 4 hours with stirring. The reaction was monitored by LC-MS. After the reaction was complete, the reaction system was concentrated under reduced pressure, and the resulting concentrate was extracted with SiO (3 × 100 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 silica gel column, with acetonitrile-water mobile phase, a gradient of 10% to 40%, an elution time of 15 minutes, and a UV 254 nm detector. (2S,3S,4R,5R)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]oxane-2,3,4,5-tetraol (2.25 g, yield 95.0%) was obtained as a grayish-white solid.

[0205] The reaction pathway is as follows:

[0206] [ka]

[0207] (6) Under stirring conditions, TEA (3.52 g, 6.00 equivalent) and DMAP (8.00 mg, 0.01 equivalent) were added to a solution of (2S,3S,4R,5R)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]oxane-2,3,4,5-tetraol (2.25 g, 1.00 equivalent) and Ac2O (3.55 g) in acetonitrile (20 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction was monitored by LC-MS. After the reaction was complete, the resulting mixture was extracted with SiO2 (3 × 50 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 silica gel column, with methanol-water mobile phase, a gradient of 40% to 70%, an elution time of 10 minutes, and a UV254 nm detector. 3,4,5-tri(acetoxy)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]oxan-2-yl acetate (2.08 g, purity 64.5%) was obtained as a grayish-white solid.

[0208] The reaction pathway is as follows:

[0209] [ka]

[0210] (7) Under stirring conditions, CH3I (1.20 g, 3.00 equivalent) was added to a mixed solution of 1,4-dioxane, consisting of 4,5-bis(acetoxy)-2-(carbamoylthio)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]oxan-3-yl acetate (1.55 g, 1.00 equivalent) and DIPEA (1.80 g, 5.00 equivalent), and the mixture was reacted at room temperature for 24 hours. The reaction was monitored by LC-MS. After the reaction was complete, the reaction was quenched with an ice water mixture at room temperature. The resulting mixture was extracted with SiO2 (3 × 50 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a C18 silica gel column, acetonitrile-water mobile phase, gradient 50%~70%, elution time 20 minutes, and UV254 nm detector. 4,5-bis(acetoxy)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]-2-(methylthio)oxy-3-ylacetate (1.09 g, yield 71.8%) was obtained as a grayish-white solid.

[0211] The reaction pathway is as follows:

[0212] [ka]

[0213] (8) Under stirring conditions, 4,5-bis(acetoxy)-6-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]-2-(methylthio)oxy-3-ylacetate (1.09 g, 2.00 mmol) was added to a mixed solution of THF (4 mL), MeOH (8 mL), and water (8 mL), and the mixture was reacted at room temperature for 1 hour. The mixture was then acidified with saturated NaHSO4 (aq.) to a pH of 2. The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic phase was concentrated by distillation under reduced pressure. The residue was purified by reverse-phase flash chromatography using a C18 silica gel column, acetonitrile-water mobile phase, gradient 10%~50%, elution time 15 minutes, and UV 254 nm detector. 2-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylphenyl]-6-(methylthio)oxane-3,4,5-triol (520.1 mg, yield 44.6%) was obtained as a grayish-white solid.

[0214] The reaction pathway is as follows:

[0215] [ka]

[0216] LC-MS: (ES, m / z):[M+23] =441. 1 H NMR:(400 MHz, DMSO-d6) δ 7.09 (s, 3H), 6.77 - 6.70 (m, 1H), 6.62 - 6.56 (m, 2H), 5.19 (d, J = 5.5 Hz, 1H), 5.08 (d, J = 4.5 Hz, 1H), 4.84 (d, J = 5.5 Hz, 1H), 4.33 (d, J = 9.4 Hz, 1H), 4.05 (d, J = 9.1 Hz, 1H), 3.81 (s, 2H), 3.32 (d, J = 1.8 Hz, 1H), 3.31 - 3.13 (m, 2H), 2.17 (s, 3H), 2.05 (d, J = 14.1 Hz, 3H).

[0217] Example 3: Preparation of Compound 3 (1) Under stirring conditions, Cu(AcO)2 (4.82 g, 26.512 mmol, 1.1 equivalent) and pyridine (5.72 g, 72.307 mmol, 1.1 equivalent) were added to a mixed solution of 4-ethoxyphenylboronic acid (5.20 g, 31.329 mmol, 1.30 equivalent) and 5-bromo-2-chlorophenol (5.00 g, 24.102 mmol, 1.00 equivalent) in dichloromethane (100 mL), and the mixture was reacted at room temperature for 2 days. The reaction was quenched with water (100 mL). The resulting mixture was extracted with siRNA (3 × 200 mL). The combined organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE to obtain 4-bromo-1-chloro-2-(4-ethoxyphenoxy)benzene (1.2 g, yield 15.20%) as a grayish-white solid.

[0218] The reaction equation is as follows:

[0219] [ka]

[0220] (2) Under a nitrogen atmosphere and stirring conditions, n-BuLi (2.20 mL, 5.500 mmol, 2.00 equivalent) was added dropwise to a solution of 4-bromo-1-chloro-2-(4-ethoxyphenoxy)benzene (900.00 mg, 2.747 mmol, 1.00 equivalent) in THF (15.00 mL) at a dropping temperature of -78°C. After 1 hour, a solution of (3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]oxan-2-one (3.70 g, 6.868 mmol, 2.50 equivalent) in THF (5.00 mL) was added dropwise to the above mixture at -78°C. The reaction was continued with stirring at -78°C for 1 hour. The reaction was raised to room temperature and the reaction was quenched by adding saturated NH4Cl (aq.). The resulting mixture was extracted with toluene (3 x 200 mL). The combined organic phase was washed with saturated brine (3 x 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography on a C18 silica gel column under FA-water mobile phase conditions. (2R,3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]-2-[4-chloro-3-(4-ethoxyphenoxy)phenyl]oxan-2-ol (1.2 g, yield 55.48%) was obtained as a grayish-white solid.

[0221] The reaction pathway is as follows:

[0222] [ka]

[0223] (3) A solution of (2R,3R,4S,5R,6R)-3,4,5-tri(benzyloxy)-6-[(benzyloxy)methyl]-2-[4-chloro-3-(4-ethoxyphenoxy)phenyl]oxan-2-ol (1.25 g, 1.588 mmol, 1.00 equivalent) in acetonitrile (20 mL) was placed in a flask, the flask was evacuated, and nitrogen purging was performed three times. The reaction system was then cooled to -30°C, and after a few minutes, triethylsilane (0.69 g, 4.763 mmol, 3.00 equivalent) and BF3-Et2O (0.34 g, 2.381 mmol, 1.50 equivalent) were added at -30°C, the reaction system was stirred at -30°C for 1 hour, and then the temperature was allowed to rise naturally to room temperature. The reaction was quenched with K2CO3 (5 mL), and the mixture was extracted with EA (2 x 200 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using a C18 silica gel column, FA-water mobile phase, and a UV 254 nm detector. (2R,3R,4R,5S,6R)-3,4,5-tri(benzyloxy)-2-[(benzyloxy)methyl]-6-[4-chloro-3-(4-ethoxyphenoxy)phenyl]oxane (1.2 g, yield 97.99%) was obtained as a colorless oil.

[0224] The reaction pathway is as follows:

[0225] [ka]

[0226] (4) At room temperature and under stirring conditions, Pd / C (150.00 mg, 1.410 mmol, 2.17 equivalents) was added to a solution of (2R,3R,4R,5S,6R)-3,4,5-tri(benzyloxy)-2-[(benzyloxy)methyl]-6-[4-chloro-3-(4-ethoxyphenoxy)phenyl]oxane (500.00 mg, 0.648 mmol, 1.00 equivalent) in MeOH (50 mL). Under a hydrogen atmosphere, the mixture was stirred overnight at room temperature and a pressure of 5 atm. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid-phase chromatography using an XBridge Prep OBD C18 chromatographic column (19 × 250 mm, 5 μm), mobile phase A: water (0.05% NH3H2O), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient: 25B~40B, elution time: 12 min, UV detector: 254 nm, under RT1 conditions of 11.02. (2R,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxyphenoxy)phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (92 mg, yield 34.03%) was obtained as a grayish-white solid.

[0227] The reaction pathway is as follows:

[0228] [ka]

[0229] LC-MS 3: (ES, m / z): [M-1]=409 H-NMR 3: 1H NMR (400 MHz, Methanol-d4) δ 7.42 (d, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.2, 1.9 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.89 (s, 4H), 4.11 - 3.95 (m, 3H), 3.85 (d, J = 11.9 Hz, 1H), 3.71 - 3.54 (m, 1H), 3.56 - 3.34 (m, 3H), 3.21 (t, J = 9.0 Hz, 1H), 1.38 (t, J = 7.0 Hz, 3H).

[0230] Furthermore, the following compounds were produced using a similar method in this invention. The structural formulas and mass spectrometry data of these compounds are shown in the table below.

[0231] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0232] To evaluate the pharmacological effects of the glycoside derivatives according to the present invention, the following studies on biological activity were conducted.

[0233] Examples of biological activity: Test Example 1 - In vitro SGLT2 inhibitory activity

[0234] By establishing an SGLT2 overexpression cell model, we investigated the effects of compounds on SGLT2-mediated glucose uptake using the fluorescent glucose (2-[N-(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-2-deoxy-D-glucose, 2-deoxy-1-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose, 1-NBDG) tracer method, and discovered candidate compounds with SGLT2 inhibitory activity.

[0235] 1. Materials and Methods (1) Material Human-derived SGLT2 overexpressing cell lines (CHO-SGLT2) constructed from Chinese hamster ovary cells (CHO) were cultured in 1640 medium (Gibco) and 10% imported fetal bovine serum (Gibco, 10270), subcultured in a 1:3 ratio, and the culture medium was changed three times a week. Fluorescence detection cell culture plates and other culture flasks were purchased from Corning. Dapagliflozin was used as a positive control, and the test compounds were compounds 2 and 3. These compounds were weighed in appropriate amounts, 100 mM stock solutions were prepared with DMSO, and stored in the dark at 4°C.

[0236] (2) Main reagents Preparation of choline buffer: 140 mM choline chloride, 5 mM KCl, 2.5 mM CaCl2, 1 mM mgSO4, 1 mM KH2PO4, 10 mM HEPES, and Tris base were used to adjust the pH to 7.4. The solution was filtered through a 0.22 μm membrane.

[0237] Sodium salt incubation solution (Na + Preparation of Sodium buffer: 140 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, 1 mM mgSO4, 1 mM KH2PO4, 10 mM HEPES, and Tris base were used to adjust the pH to 7.4.

[0238] Preparation of neutral hydrolysate: 1% Nonidet P-40, 1% sodium deoxycholate, 40 mM KCl, 20 mM Tris base, pH = 7.4.

[0239] (3)Equipment Biotek Synergy2 Multifunctional Microplate Reader

[0240] (4) Detection of NBDG uptake into cells: Prior to detecting 1-NBDG uptake, CHO-SGLT2 cells were digested and seeded at 40,000 cells / well in a 96-well cell culture plate. After culturing the cells for 48 hours, the culture medium was aspirated and discarded. 100 μl of choline buffer was added to each well, and the cells were starved at 37°C for 30 minutes. The choline buffer was discarded, and 100 μl of a newly prepared sodium salt incubation solution containing 100 μM 1-NBDG and the test compound was added. DMSO was used as the negative control for the test compound, and the sodium salt incubation solution without 1-NBDG was used as the blank control. After culturing for 1 hour, the incubation solution was aspirated, the cells were washed three times with choline buffer, 50 μl of neutral decomposition solution was added to each well, and the cells were decomposed on ice for 10 minutes. The fluorescence values ​​of each well were detected using a multifunctional microplate reader with Em=485 / 20nm and Ex=528 / 20nm.

[0241] (5) Calculation methods and statistical methods The experiment was repeated at least three times for each fixed concentration of compound, and the data was expressed as mean ± SEM. 1-NBDG intracellular uptake = fluorescence value 1-NBDG - Fluorescence value Blank The following was calculated: SGLT2 glucose uptake inhibition rate (%) = (uptake amount) control - Intake amount compound ) / Amount taken in control I calculated ×100%. I used Graphpad Prism software to create a concentration-inhibition curve and IC 50 The value was calculated.

[0242] 2.Results For each compound, several concentration gradients were established by diluting the stock solution 10 / 20 times according to preliminary experimental results (see Table 1). The effect of each compound on cellular 1-NBDG uptake at various concentrations is shown as the SGLT2 inhibition rate by each compound at specific concentrations (Table 1). Concentration-inhibition rate curves for each compound (Figure 4) were created, and the relative maximum activity (Max%) of each compound and the IC50 of the SGLT2 inhibition of each compound were calculated, with the maximum inhibitory activity of the positive control dapagliflozin set to 100%. 50 The values ​​were calculated (Table 2).

[0243] [Table 2]

[0244] [Table 3-1]

[0245] From the above results, it was found that the compound according to the present invention has good SGLT2 inhibitory activity.

[0246] Test Example 2: Evaluation of the in vivo activity of the compound according to the present invention (effect on blood glucose levels after oral glucose loading in normal mice)

[0247] 1. Materials and Methods (1)Animals ICR mice (male, 18-20g) purchased from Beijing Weitong Lihua Experimental Technology Co., Ltd. were adaptively reared for 4 days and then randomly divided into four groups of 8 mice each: a normal control group, a positive control group, and two test compound groups.

[0248] (2) Setting of compounds and dosages Using compound 2 according to the present invention as an example, animal experiments were conducted at two doses, 2 mg / kg and 4 mg / kg, with the dose of dapagliflozin, a positive control drug, set to 2 mg / kg. The stock solution was diluted to an appropriate concentration with redistilled water.

[0249] (3) Experimental plan Mice were fasted overnight. The normal control group received intragastric administration of 0.5% DMSO in redistilled water (Note: the stock solution was prepared with DMSO), the positive control group received intragastric administration of dapagliflozin 2 mg / kg, and the two test compound groups received intragastric administration of compound 2 at 2 mg / kg and 4 mg / kg, respectively. One hour later, blood was collected at 0 minutes (fasting), and then each group of mice was administered glucose (2.0 g / kg) solution intragastricly. Blood was collected 30, 60, and 120 minutes after glucose administration, and blood glucose levels were measured using the glucose oxidase-peroxidase method, and the area under the blood glucose curve was calculated.

[0250] (4) Statistical methods Data were expressed as mean ± SD. One-way ANOVA was used for comparisons between multiple groups, and Dunnett's t-test was used for comparisons between two groups. Statistical graphs were created using Graphpad Prism software.

[0251] The results are shown in Tables 5 and 3. Table 5 shows graphs illustrating the effect of compound 2 on the blood glucose curve and area under the blood glucose curve after oral glucose loading in normal ICR mice. ***p<0.001, vs. Nor group.

[0252] [Table 4]

[0253] Compared to the normal control group (Nor), the positive control drug dapagliflozin not only lowered fasting blood glucose (P<0.001), but also significantly lowered blood glucose levels at each time point after glucose loading (P<0.001) and reduced the area under the blood glucose curve (AUC) by 35.2% (P<0.001). Test compound 2, administered at two doses of 2 mg / kg and 4 mg / kg, lowered fasting blood glucose (P<0.001), significantly lowered blood glucose levels at each time point after glucose loading by 37.4% (P<0.001), and also significantly reduced the area under the blood glucose curve (AUC) by 42.9% (P<0.001), proving superior to the positive control drug dapagliflozin.

[0254] Study Example 3: Research on the pharmacokinetic effects of the compound according to the present invention in an in vivo anti-aloxane diabetic mouse model.

[0255] 1. Materials and Methods (1)Animals Aloxan-induced diabetic mice were used. Normal ICR mice (male, 22-24g) were randomly divided into a normal group, a model group (con), a positive control group, and four groups of test compounds at different doses (n=11). Mice that were not injected with aloxan were designated as the normal control group (n=10).

[0256] (2) Setting of test compound and dosage Four dosage levels were established for compound 2 according to the present invention, which serves as an example: 0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg. The dosage of the positive control drug, dapagliflozin, was set to 2.0 mg / kg.

[0257] (3) Experimental plan The drugs were administered to mice via intragastric injection. The positive control group received dapagliflozin (2.0 mg / kg), while the test groups received compound 2 at different doses (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg).

[0258] Single-dose administration: After fasting mice for 3 hours, fasting blood (0 min) was collected. Then, each group of mice was administered the drug intragastricly, and 1 hour later, a glucose (2.0 mg / kg) solution was administered intragastricly to each group. Blood was collected 30, 60, 120, and 180 minutes after glucose administration, and blood glucose levels were measured using the glucose oxidase-peroxidase method, and the area under the blood glucose curve was calculated.

[0259] On the sixth day of continuous administration, the mice were not fasted, and blood glucose levels were measured by taking blood samples before administration (0:00), 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration.

[0260] On the ninth day of continuous administration, mice were fasted for one hour before each drug was administered intragastricly. An oral glucose tolerance test (OGTT) was then performed one hour after administration.

[0261] On the 16th day of continuous administration, mice were not fasted, and urine was collected one hour after each administration to measure urinary glucose concentration.

[0262] On the 22nd day of continuous administration, mice were fasted for one hour before each drug was administered intragastricly. Blood samples were taken one hour after administration to measure fasting blood glucose levels.

[0263] On the 28th day of continuous administration, mice were not fasted, and blood samples were taken one hour after each administration to measure random blood glucose levels.

[0264] On the 32nd day of continuous administration, the mice were not fasted, and blood was collected to measure glycated hemoglobin (HbA1c).

[0265] (4) Statistical methods The data were represented using mean ± SEM (n=10-11). One-way ANOVA was used for comparisons between multiple groups, and Dunnett's test was used for comparisons between two groups. Statistical graphs were created using Graphpad Prism software.

[0266] 2.Results (1) A single dose of compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) significantly reduced glucose levels and area under the glucose curve (AUC) after glucose loading in alloxan-treated diabetic mice. Under the same dosage conditions, the potency of the effect was superior to that of the positive control drug.

[0267] (2) Continuous administration of compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) for 6 days significantly reduced non-fasting blood glucose levels in alloxan-diabetic mice (p<0.001 or p<0.01), decreased area under the blood glucose curve (AUC), and improved oral glucose load. Dapagliflozin (2.0 mg / kg) showed a significant weakening of its hypoglycemic effect after 8 hours, and no significant effect after 24 hours, while compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) showed good hypoglycemic activity from 8 hours to 24 hours. Compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) had a significantly longer duration of action compared to dapagliflozin (2.0 mg / kg), the positive control drug (p<0.05, p<0.01, or p<0.001).

[0268] (3) Multiple consecutive administrations of compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) significantly reduced fasting blood glucose levels in alloxan-diabetic mice on days 9 and 22 (p<0.001). Compound 2 (1.0 mg / kg and 2.0 mg / kg) reduced blood glucose levels more significantly than the positive control drug dapagliflozin (2.0 mg / kg) (p<0.01), and its effect was significantly stronger than that of the positive control drug.

[0269] (4) Continuous administration of compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) for 28 days significantly reduced random blood glucose levels in alloxan-diabetic mice (p<0.001). Compound 2 (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) reduced blood glucose levels more significantly than the positive control drug dapagliflozin (2.0 mg / kg) (p<0.05, p<0.01). Continuous administration of compound 2 (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) for 32 days significantly reduced the levels of glycated blood glucose proteins in alloxan-diabetic mice. Compound 2 (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) significantly reduced glycated hemoglobin on day 32 (p<0.05) compared to the positive control drug dapagliflozin (2.0 mg / kg), demonstrating a significantly stronger effect than the positive control drug.

[0270] (5) Continuous administration of compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) for 16 days significantly increased the urinary glucose concentration in alloxan-treated diabetic mice, and its potency was superior to that of the positive control drug.

[0271] The test results are shown in Tables 4 to 7 below.

[0272] [Table 5]

[0273] [Table 6]

[0274] [Table 7]

[0275] [Table 8]

[0276] Furthermore, continuous administration of compound 2 (0.25 mg / kg, 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) according to the present invention for 22 days showed no significant effect on the body weight, food intake, or drinking water of alloxan-diabetic mice, demonstrating its good safety.

[0277] Test Example 4: Pharmacological effects of the compound according to the present invention on spontaneously developing type 2 diabetes db / db mice

[0278] 1. Materials and Methods (1)Animals Spontaneously diabetic type 2 diabetes db / db mice and their normal control mice db / m mice (male, 5-6 weeks old), as well as db / db mice, were randomly divided into six groups: a model group (con), a positive control group, and three dose groups (n=10) of the test compound, based on random blood glucose levels, fasting blood glucose, 40-minute blood glucose reduction rate, blood triglycerides, blood total cholesterol, and body weight.

[0279] (2) Setting of compounds and dosages For the test, compound 2 according to the present invention was used as an example, and three dosages were set: 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg. The positive control drug was dapagliflozin, administered at a dose of 2.0 mg / kg.

[0280] (3) Experimental plan The drugs were administered to mice via intragastric injection. The positive control group received dapagliflozin (2.0 mg / kg), while the two groups of three compounds received compound 2 at concentrations of 0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg, respectively.

[0281] Mice were fasted for 2 hours, and blood was collected at 0:00 (fasting). Subsequently, each group of mice was administered intragastricly, and blood was collected 1, 2, 4, 6, 8, and 24 hours after administration. Blood glucose levels were measured using the glucose oxidase-peroxidase method, and the area under the blood glucose curve was calculated. Simultaneously, urine was collected 2 and 4 hours after administration, and urinary glucose concentration was measured.

[0282] On the 15th day of continuous administration, blood was collected from the mice before fasting to measure random blood glucose levels. After fasting and administering the compound, blood was collected two hours later to measure fasting blood glucose levels.

[0283] On the 22nd day of continuous administration, mice were fasted and given the compound. Blood samples were taken 2 hours later to measure blood glucose levels, blood triglycerides, and total cholesterol.

[0284] On day 28 of continuous administration, the mice were not fasted, and blood samples were taken from each mouse to measure random blood glucose levels and glycated hemoglobin (HbA1c).

[0285] (4) Statistical methods The data were represented using mean ± SEM (n=10). One-way ANOVA was used for comparisons between multiple groups, and Dunnett's test was used for comparisons between two groups. Statistical graphs were created using Graphpad Prism software.

[0286] 2.Results (1) A single dose of compound 2 (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) according to the present invention significantly reduced fasting blood glucose levels at 1, 2, 4, 6, 8, and 24 hours after administration in spontaneously developing type 2 diabetes db / db mice (p<0.001 or p<0.01) and significantly reduced the area under the blood glucose curve (AUC). Compound 2 (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) was significantly more potent than the positive control drug dapagliflozin (2.0 mg / kg) (p<0.01 or p<0.001). A single dose of compound 2 (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) was able to lower blood glucose levels in spontaneously type 2 diabetic db / db diabetic mice for up to 24 hours, which was significantly longer than that of the positive control drug dapagliflozin (2.0 mg / kg).

[0287] (2) After a single administration of compound 2 according to the present invention (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg), the urinary glucose concentration in db / db mice increased 2 hours after administration, but did not increase 4 hours after administration. Compound 2 was found to have the same effect as the positive control drug dapagliflozin.

[0288] (3) Multiple consecutive administrations of compound 2 (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) according to the present invention significantly reduced fasting blood glucose and random blood glucose levels in spontaneously developing type 2 diabetes db / db mice at different doses. Under the same dose conditions, compound 2 (2.0 mg / kg) was significantly more potent than the positive control drug dapagliflozin (2.0 mg / kg) (p<0.001, p<0.01, or p<0.05).

[0289] (4) On day 22 of continuous administration of compound 2 according to the present invention (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg), the blood triglyceride (TG) levels of spontaneously type 2 diabetic db / db diabetic mice were significantly reduced at different doses, without affecting blood cholesterol levels. No difference was found between compound 2 according to the present invention and the positive control drug dapagliflozin.

[0290] (5) Continuous administration of compound 2 according to the present invention (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) for 28 days significantly reduced the glycated blood glucose protein levels in spontaneously type 2 diabetic db / db diabetic mice at different doses. Under the same dose conditions, compound 2 according to the present invention (2.0 mg / kg) was found to have a stronger effect than the positive control drug dapagliflozin (2.0 mg / kg).

[0291] (6) Continuous administration of compound 2 according to the present invention (0.5 mg / kg, 1.0 mg / kg, and 2.0 mg / kg) had no significant effect on body weight, food intake, or drinking water in spontaneously developing type 2 diabetes db / db mice.

[0292] The results are shown in Tables 8-11 below.

[0293] [Table 9]

[0294] [Table 10]

[0295] [Table 11]

[0296] [Table 12]

[0297] From the above results, it was found that compound 2 according to the present invention has particularly advantageous effects on spontaneously developing type 2 diabetes mice, including a superior duration of blood glucose reduction compared to the positive control drug dapagliflozin, stronger fasting blood glucose lowering efficacy and random blood glucose lowering efficacy compared to the positive control drug, and stronger glycated blood glucose protein level reduction effect compared to the positive control drug. The above results demonstrate that the compound according to the present invention has excellent pharmacokinetic effects and good safety.

[0298] Test Example 5: Safety study of the compound according to the present invention The following acute toxicity studies were conducted on the compounds according to the present invention in mice.

[0299] 1. Purpose of the examination Compound 2 according to the present invention was used as an example and compared to the strength of the acute toxic reaction caused by oral administration of dapagliflozin to mice.

[0300] 2. Dosage setting Mice were administered both compound 2 and dapagliflozin intragastricly at a dose of 3000 mg / kg, and the differences in acute toxicity between compound 2 and dapagliflozin were compared.

[0301] 3. Frequency and method of detecting indicators 3.1 General observation of condition and mortality After administration, the animals were observed once daily for 7 consecutive days near their cages, particularly within 4 hours of administration, and their toxic reaction symptoms and time of death were recorded.

[0302] 3.2 Test Groups The mice were randomly divided into three groups of 10 mice each, based on body weight: a blank control group, a dapagliflozin group, and two compound groups. Each group consisted of 10 mice, half male and half female. The animals were fasted for 17 hours the day before administration, but water was not prohibited. Each test group received the corresponding test product intragastricly, while the blank control group received an equal dose of the solvent intragastricly once.

[0303] 4. Experimental Results When the test solutions were administered intragastricly to mice at equal doses of 3000 mg / kg to both the compound 2 group and the dapagliflozin group, the compound 2 group showed significantly lower toxicity than the dapagliflozin group. Furthermore, there was a large sex difference in animal mortality between the two groups; all deaths occurred in males, while no females died.

[0304] [Table 13]

[0305] The above description of embodiments is intended solely for understanding the method and gist of the present invention. Those skilled in the art should note that several improvements and modifications can be made to the present invention without departing from its principles, and these improvements and modifications are also within the scope of protection of the claims of the present invention. This specification includes the disclosure of the following inventions. [Item 1] A glycoside derivative which is a compound represented by the following formula I or a pharmaceutically acceptable salt thereof. [ka] (In the formula, A is an oxygen atom, -(CH 2 ) m - or -NH-, where m is 1, 2, or 3. B is an oxygen atom or a sulfur atom, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 These are independently hydrogen, hydroxyl group, carboxyl group, halogen, -CN, alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH 2 -aryl group, -OCH 2 -heteroaryl group, -O-heterocyclyl group, -OCH 2 -heterocyclyl group, ester group, -NR 11 R 11a , as well as N, O, S, SO and / or SO 2 Selected from the group consisting of 3-14 member heterocyclyl groups containing 1-4 heteroatoms, Alternatively, the aforementioned R 1 and R 2 Together, they form a heterocyclyl group, cycloalkyl group, aryl group, or heteroaryl group condensed on the benzene ring, and / or the R 3 and R 4 Together, they form a cyclopentyl group or oxacyclopentyl group condensed on the benzene ring. R 7 、R 8 、R 9 、R 10 These are independently selected from the group consisting of hydrogen, hydroxyl group, alkyl group, alkoxy group and alkylthio group, The aforementioned R 11 、R 11a These are independently selected from the group consisting of hydrogen atoms and alkyl groups, Here, the alkyl group, alkoxy group, alkoxyalkoxy group, cycloalkyl group, aryl group, heteroaryl group, -O-aryl group, -O-heteroaryl group, -OCH 2 -aryl group, -OCH 2 -heteroaryl group, -O-heterocyclyl group, -OCH 2 -heterocyclyl group, ester group, -NR 11 R 11a The heterocyclyl group and alkylthio group may be further substituted with one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, alkyl groups, alkoxy groups, and nitro groups. [Item 2] Above R 1 、R 2 、R 3 、R 4 、R 5 、R 6 These are independently hydrogen, hydroxyl group, carboxyl group, halogen, -CN, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C16 alkoxyalkoxy group, C3-C6 cycloalkyl group, C6-C12 aryl group, C2-C12 heteroaryl group, -O-C6-C12 aryl group, -O-C2-C12 heteroaryl group, and -OCH 2 -C6~C12 aryl group, -OCH 2 -C2~C12 heteroaryl group, -O-C2~C6 heterocycline group, -OCH 2 -C2-C6 heterocyclyl group, C1-C6 ester group, -NR 11 R 11a , as well as N, O, S, SO and / or SO 2 Selected from the group consisting of 3-14 member heterocyclyl groups containing 1-4 heteroatoms, Alternatively, the aforementioned R 1 and R 2 These are condensed together around a benzene ring, forming N, O, S, SO and / or SO 2 A 3-14 member heteroatom containing 1-4 heteroatoms selected from Forms a cyclyl group, a C3-C6 cycloalkyl group, a C6-C12 aryl group, or a C2-C12 heteroaryl group, The aforementioned R 7 、R 8 、R 9 、R 10 These are independently selected from the group consisting of hydrogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group. The aforementioned R 11 、R 11a The glycoside derivative according to claim 1, characterized in that is independently selected from the group consisting of a hydrogen atom and a C1-C6 alkyl group. [Item 3] The above A is an oxygen atom or -CH 2 -and, The aforementioned B is an oxygen atom, The aforementioned R 1 、R 2 、R 3 、R 4 、R 5 、R 6 These are independently hydrogen, hydroxyl group, carboxyl group, fluorine, chlorine, bromine, -CN, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methoxymethoxy group, ethoxymethoxy group, ethoxyethoxy group, n-propyloxy group Poxymethoxy group, isopropoxymethoxy group, n-propoxyethoxy group, isopropoxyethoxy group, cyclopropyl group, methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyrrolyl group, thienyl group, furanyl group, oxazolyl group, thiazolyl group, imidazolyl group, triazolyl group, phenoxy group, pyridyloxy group, pyrimidinyloxy group, pyrrolyloxy group, furanyloxy group, thienyloxy group, oxazolyloxy group, benzyloxy group, -OCH 2 -pyridyl group, -OCH 2 -pyrimidinyl group, -OCH 2 -pyrrolyl group, -OCH 2 -thienyl group, -OCH 2 -Furanyl group, -OCH 2 -Oxazolyl group, -OCH 2 -thiazolyl group, -OCH 2 -Imidazolyl group, -OCH 2 -A glycoside derivative according to claim 1 or 2, characterized in that it is selected from the group consisting of a triazolyl group, a methyl ester group, an ethyl ester group, an isopropyl ester group, a sulfonic acid ester group, an amino group, a hexahydropyridyl group, a hexahydropyradinyl group, a morpholinyl group, a tetrahydropyrrolyl group, and a tetrahydrooxazolyl group (one or more hydrogen atoms of these groups may be further substituted by one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, carboxyl groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and nitro groups). [Item 4] Above R 1 and R 2 The glycoside derivative according to any one of claims 1 to 3, characterized in that the groups together form a cyclohexyl group, phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyrrolyl group, thienyl group, furanyl group, oxazolyl group, thiazolyl group, imidazolyl group, triazolyl group, hexahydropyridyl group, hexahydropyradinyl group, morpholinyl group, tetrahydropyrrolyl group, tetrahydrooxazolyl group, or dioxane condensed on a benzene ring. [Item 5] Above R 7 、R 8 、R 9 、R 10 The glycoside derivative according to any one of claims 1 to 4, characterized in that is independently selected from the group consisting of hydrogen, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, hydroxymethyl group, hydroxyethyl group, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t-butylthio group, n-pentylthio group, isopentylthio group, or n-hexylthio group. [Item 6] A glycoside derivative according to any one of claims 1 to 5, which is a compound represented by the following formula II or a pharmaceutically acceptable salt thereof.

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Claims

1. A glycoside derivative which is a compound represented by the following formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 In the formula, A is -(CH 2)-, B is an oxygen atom, R1 and R2 together form a 5-6 membered heterocyclyl group condensed on a benzene ring, and the 5-6 membered heterocyclyl group is a 5-6 membered heterocyclyl group containing one or two oxygen atoms. R3 is selected from the group consisting of CH3(CH2)n-, where n is 0. R4 is hydrogen, R5 and R6 are hydrogen. R7, R8 and R9 are hydroxyl groups. R10 is a glycoside derivative selected from the group consisting of a methoxy group and a methylthio group.

2. The glycoside derivative according to claim 1, having a structure selected from the group consisting of the following: 【Chemistry 2】

3. A method for producing a glycoside derivative according to claim 1 or 2, comprising producing a compound represented by formula I-a below from a compound represented by formula VII below via a sulfurization reaction and a deprotection reaction. 【Transformation 3】 (In the formula, A is -(CH ２ )m - and m is 1, B is an oxygen atom, The aforementioned R １ and R ２ Together, they form a 5- to 6-membered heterocyclyl group condensed on a benzene ring, containing one or two oxygen atoms. R3 is selected from the group consisting of CH3(CH2)n-, where n is 0. R4 is hydrogen, R5 and R6 are hydrogen. R １０ It is a methylthio group, R １２ (These are alkyl groups, trimethylsilyl groups, benzyl groups, formyl groups, acetyl groups, tetrahydropyranyl groups, methoxymethyl groups, or t-butyldimethylsilyl groups.)

4. A pharmaceutical composition comprising a glycoside derivative according to claim 1 or 2 or a glycoside derivative produced by the manufacturing method according to claim 3, and a pharmaceutically acceptable carrier, excipient, diluent, auxiliary agent, medium, or combination thereof.

5. Use of a glycoside derivative according to claim 1 or 2, or a glycoside derivative produced by the manufacturing method according to claim 3, or a pharmaceutical composition according to claim 4, in the manufacture of a pharmaceutical product for preventing, treating, or alleviating diabetes and its complications.

6. The use according to claim 5, characterized in that the diabetes is type II diabetes or type I diabetes, and the complication is a cardiovascular disease caused by type II or type I diabetes.

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