Polyhydroxy onium salt derivative as well as preparation method and application thereof

Abstract

The invention discloses a polyhydroxy onium salt derivative as well as a preparation method and application thereof, and the onium salt derivative with a brand new structure is designed on the basis of the structure of a natural product through principles of skeleton transition, bioisostere and the like. Compared with a natural product and a reported analogue, the onium salt compound has stronger alpha-glucosidase inhibitory activity and activity of reducing postprandial blood sugar in a mouse body, can be used as an onium salt type alpha-glucosidase inhibitor oral hypoglycemic drug, and is mainly prepared from D-arabinose as a raw material, the onium salt derivative molecule with alpha-glucosidase inhibitory activity is obtained through multi-step reaction, and the molecule has remarkable in-vivo blood sugar reducing activity.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a polyhydroxyonium salt derivative, its preparation method, and its application. Background Technology

[0002] The compound derived from the genus *Salacia* has an onium salt structure, as shown below. It exhibits hypoglycemic activity comparable to commercially available α-glucosidase inhibitors. Researchers are studying its structure-activity relationship in hopes of discovering a novel class of candidate hypoglycemic drugs.

[0003]

[0004] Using neoponkoranol as a lead compound, introducing benzene-based aldol structures at C-3' and C-5' of the polyhydroxy side chains to obtain two-site modified derivatives is an effective modification method. Introducing hydrophobic benzene methylene groups at the C-3' and C-5' hydroxyl groups is beneficial for increasing the sucrase inhibitory activity of this type of compound, and modification with strong electron-withdrawing groups attached to the ortho position of the benzene ring will enhance the compound's α-glucosidase inhibitory activity. References: Lu L, Chen JY, Tao WX, et al. Design and Synthesis of Sulfonium Derivatives: A Novel Class of α-Glucosidase Inhibitors with Potent In Vivo Antihyperglycemic Activities. J. Med. Chem., 2023, 66(5): 3484-3498. Reference Patent: CN201710649454.5. Introducing hydrophobic benzenemyl groups at C-3' and C-5' hydroxyl groups is beneficial for increasing the sucrase inhibitory activity of this type of compound. Furthermore, the connection of different substituents to the benzene ring affects the α-glucosidase inhibitory activity of the compound, indicating that the type and position of substituents have an important influence on the activity and hypoglycemic effect of the compound.

[0005]

[0006] By introducing benzylidene groups at C3' and C5' of the neoponkoranol side chain, the patent of the original compound was successfully broken, and good enzyme inhibitory activity was obtained. However, the acetal structure in this type of compound has poor stability to gastric acid, and since the site of action is located in the small intestine, it needs to pass through the acidic environment of the stomach to reach it. Although the decomposition products of compound 9 in the gastric acid environment have some enzyme inhibitory activity, their activity is poor, and the byproduct benzaldehyde may pose certain safety risks. Therefore, the acid resistance of the compound needs to be improved, and designing an acid-resistant, metabolically safer two-site modified derivative is particularly important. An acid-resistant two-site modified neoponkoranol derivative 10 was designed and synthesized to improve the disadvantage of the previous derivatives designed by the research group being relatively sensitive to acidic environments. The enzyme inhibitory activity of monosubstituted benzene ring onium salt derivatives is still at the μM level, and there is also a need to significantly improve the in vivo stability of monosubstituted benzene ring onium salt derivatives. Summary of the Invention

[0007] Objective of the invention: To address the problems existing in the prior art, this invention provides a novel class of onium salt derivatives that overcome the acid insensitivity of aldehyde derivatives modified at C3' and C5' dual sites. It synthesizes onium salt derivatives with disubstituted benzene rings and introduces selenium and nitrogen salt derivatives, thereby increasing the diversity of compounds and providing candidate compounds with better activity.

[0008] According to enzyme experiments, the compounds of the present invention have excellent α-glucosidase inhibitory activity and good gastric acid tolerance. Some small molecule inhibitors were selected for in vivo glucose-lowering activity tests in mice. The results showed that the candidate compounds also have stronger postprandial blood glucose-lowering activity than clinical drugs and natural products themselves.

[0009] The present invention also provides a method for preparing the aforementioned polyhydroxyonium salt derivatives and their pharmaceutical uses.

[0010] Technical solution: To achieve the above objectives, the present invention provides onium salt derivatives of substituted benzene rings as shown in general formulas (I) and (II).

[0011]

[0012] R1 and R2 are located in the ortho, meta, or para positions of the benzene ring;

[0013] R1 is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, hydroxyl, alkoxy, nitro, cyano, C1-C5 alkoxy, C1-C3 alkyl, amino, or substituted amino groups with six or fewer carbon atoms;

[0014] R2 is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, alkoxy, nitro, cyano, C1-C5 alkoxy, C1-C3 alkyl, amino, or substituted amino groups with six or fewer carbon atoms;

[0015] X is selected from S, Se, or NH;

[0016] Y is selected from chloride ion, bromide ion, trifluoroacetate ion, acetate ion, hydrogen sulfate ion, or dihydrogen phosphate ion.

[0017] Preferably, the polyhydroxyonium salt derivative or pharmaceutically acceptable salt is selected from any one of the following compounds:

[0018] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (11)

[0019] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (12)

[0020] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (13)

[0021] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (14)

[0022] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (15)

[0023] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (16)

[0024] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (17)

[0025] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (18)

[0026] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (19)

[0027] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (20)

[0028] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (21)

[0029] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (22)

[0030] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (23)

[0031] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (24)

[0032] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (25)

[0033] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (26)

[0034] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (27)

[0035] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (28)

[0036] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (29)

[0037] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (30)

[0038] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (31)

[0039] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (32)

[0040] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium (33)

[0041] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium (34)

[0042] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (35)

[0043] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (36)

[0044] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (37)

[0045] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (38)

[0046] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (39)

[0047] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (40)

[0048] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (41)

[0049] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (42)

[0050] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (43)

[0051] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (44)

[0052] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (45)

[0053] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (46)

[0054] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (47)

[0055] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (48)

[0056] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (49)

[0057] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (50)

[0058] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (51)

[0059] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (52)

[0060] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (53)

[0061] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (54)

[0062] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (55)

[0063] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (56)

[0064] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (57)

[0065] (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium (58)

[0066] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,3-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (59)

[0067] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,4-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium(60)

[0068] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,5-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (61)

[0069] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,6-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (62)

[0070] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,3-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (63)

[0071] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,4-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (64)

[0072] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,5-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (65)

[0073] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,6-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (66)

[0074] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,3-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (67)

[0075] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,4-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (68)

[0076] (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,5-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium (69)

[0077] This invention provides a method for preparing a polyhydroxyonium salt derivative or a pharmaceutically acceptable salt corresponding to general formula (I), comprising the following steps:

[0078] a) Using 1,2-O-isopropylidene-α-D-furanose as the starting material, it was reacted with sodium hydride and benzyl bromide to obtain benzyl-protected 1,2-O-isopropylidene-α-D-furanose.

[0079] b) Benzyl-protected 1,2-O-isopropylidene-α-D-furanose was reacted with 50% trifluoroacetic acid aqueous solution at room temperature for 4 hours to give 3,5,6-tri-O-benzylfuran-D-glucose.

[0080] c) The intermediate reacts with Wittig reagent and a base to generate 4,6,7-tris-O-benzyl-phenylheptenyl-3,5-diol intermediate;

[0081] d) The 4,6,7-tri-O-benzyl-phenylheptenyl-3,5-diol intermediate was subjected to an intramolecular cyclization reaction mediated by iodine reagent to generate the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate;

[0082] e) Remove the iodine atom from the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate to obtain the intermediate 2-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside;

[0083] f) Subsequently, the benzyl group of the 2-deoxy-4,6,7-tris-O-benzyl-1-C-phenylpyranoside intermediate was removed under concentrated hydrochloric acid to obtain the intermediate 2-deoxy-3,4,6,7-tetrahydroxy-1-C-phenylpyranoside.

[0084] g) Selectively attach a p-toluenesulfonyl group to the primary hydroxyl position of 2-deoxy-3,4,6,7-tetrahydroxy-1-C-phenylpyranoside, and then in an alkaline solution, the p-toluenesulfonyl group departs to generate the intermediate 3,4-dihydroxy-5-epoxyethyl-1-C-phenylpyranoside having an ethylene oxide structure.

[0085] h) Using acetonitrile as the reaction solution, the compound obtained in step g) is coupled with sucrose, selenoglycine, or glucosamine fragments in the presence of trifluoroacetic acid at -20°C to room temperature. The resulting compound is then treated with a chloride ion exchange resin to obtain the target compounds with different substitutions.

[0086] In step a), the reaction solvent is dichloromethane, ethyl acetate, tetrahydrofuran, or acetonitrile; the reaction time is 12-24 h, the feeding temperature is 0 °C, and the reaction temperature is room temperature. In step b), the reaction temperature is 0-60 °C, and the reaction time is 8-12 h. In step c), the Wittig reagent is benzyltriphenylphosphine bromide with disubstituted benzene rings, including 2,3-dichlorotriphenylphosphine bromide, 2,4-dichlorobenzyltriphenylphosphine bromide, 2,5-dichlorobenzyltriphenylphosphine bromide, 2,6-dichlorobenzyltriphenylphosphine bromide, 2,3-difluorotriphenylphosphine bromide, and 2,4-difluorobenzyltriphenylphosphine bromide. Phosphorus bromide or 2,5-difluorobenzyltriphenylphosphine bromide, 2,6-difluorobenzyltriphenylphosphine bromide, 2,3-dibromobenzyltriphenylphosphine bromide, 2,4-dibromobenzyltriphenylphosphine bromide, 2,5-dibromobenzyltriphenylphosphine bromide, 2,6-dibromobenzyltriphenylphosphine bromide, etc. containing different substituents, such as benzyltriphenylphosphine bromide; the iodine reagent in step d) is elemental iodine, N-iodosuccinimide, or 4,4'-xylyliodonium hexahydrate. The reaction is carried out at a temperature of -30℃ to 0℃ for 5-15 hours. In step e), the deiodination reagent is any one of NaBH4, LiAlH4, AIBN, Bu3SnH, Pd / C, and Et3N, and the solvent is tetrahydrofuran, toluene, or ethyl acetate. The reaction temperature is 0℃ to 100℃, and the reaction time is 1-12 hours. In step f), the solvent is concentrated hydrochloric acid:THF:anhydrous ethanol = 3:1:1, and the reaction temperature is 0℃ to 100℃ for 1-4 hours. In step g), the solvent is DCM, and the base is 1,8-diazabicycloundec-7-ene or anhydrous potassium carbonate. The reaction temperature is room temperature, and the reaction time is 4-6 hours. In step h), the reaction solvent is dichloromethane or acetonitrile, the reaction reagent is trifluoroacetic acid, and the reaction temperature is 20-40℃ for 12-48 hours.

[0087] The present invention also provides a method for preparing a polyhydroxyonium salt derivative or a pharmaceutically acceptable salt corresponding to general formula (II), which further includes the following steps:

[0088] a) Using 1,2-O-isopropylidene-α-D-furanose as the starting material, it was reacted with sodium hydride and benzyl bromide to obtain benzyl-protected 1,2-O-isopropylidene-α-D-furanose.

[0089] b) Benzyl-protected 1,2-O-isopropylidene-α-D-furanose was reacted with 50% trifluoroacetic acid aqueous solution at room temperature for 4 hours to give 3,5,6-tri-O-benzylfuran-D-glucose.

[0090] c) The intermediate reacts with Wittig reagent and a base to generate 4,6,7-tris-O-benzyl-phenylheptenyl-3,5-diol intermediate;

[0091] d) The 4,6,7-tri-O-benzyl-phenylheptenyl-3,5-diol intermediate was subjected to an intramolecular cyclization reaction mediated by iodine reagent to generate the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate;

[0092] e) Remove the iodine atom from the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate to obtain the intermediate 2-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside;

[0093] f) Under alkaline conditions, 2-deoxy-4,6,7-tris-O-benzyl-1-C-phenylpyranoside reacts with CS2 and MeI, and then the hydroxyl group is removed under Pd / C reducing hydrogenolysis to obtain the intermediate 2,3-deoxy-4,6,7-tris-O-benzyl-1-C-phenylpyranoside.

[0094] g) Subsequently, the benzyl group of the 2,3-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate was removed under concentrated hydrochloric acid to obtain the intermediate 2,3-deoxy-4,6,7-trihydroxy-1-C-phenylpyranoside.

[0095] h) The primary hydroxyl group of 2,3-deoxy-4,6,7-tris-O-benzyl-1-C-phenylpyranoside is selectively linked to a p-toluenesulfonyl group, which then departs in a K2CO3 solution of methanol to generate an intermediate 4-hydroxy-5-epoxyethyl-1-C-phenylfuranoside having an ethylene oxide structure.

[0096] i) Using acetonitrile as the reaction solution, the sulose fragment, selenosyl fragment, or glucosyl fragment, along with the compound obtained in step h), were coupled in a reaction catalyzed by trifluoroacetic acid at -20°C to room temperature. The resulting compounds were then treated with a chloride ion exchange resin to obtain target compounds with different substitutions. References for the synthesis methods of the sulose fragment (9a), selenosyl fragment (9b), and glucosyl fragment (9c): 1. Muraoka O, Yoshikai K, Takahashi H, et al. Synthesis and biological evaluation of deoxy salacinols, the role of polar substituents in the sidechain on the alpha-glucosidase inhibitory activity. Bioorg. Med. Chem., 2006, 14(2): 500-9.

[0097] 2,Mohan S,Pinto B.M.Zwitterionic glycosidase inhibitors:salacinol andrelated analogues.Carbohydr.Res..2007,342(12-13):1551-80.

[0098] 3,Choi H G,Park D S,Lee W K,et al.An efficient synthesis of 1,4-dideoxy-1,4-imino-d-and l-arabinitol and 1,4-dideoxy-1,4-imino-d-and l-xylitol from chiral aziridines

[0099] [J].Tetrahed-ron Letters.,2013,54(43).

[0100] In step a), the reaction solvent is dichloromethane, ethyl acetate, tetrahydrofuran, or acetonitrile; the reaction time is 12-24 h, the feeding temperature is 0 °C, and the reaction temperature is room temperature. In step b), the reaction temperature is 0-60 °C, and the reaction time is 8-12 h. In step c), the Wittig reagent is benzyltriphenylphosphine bromide with disubstituted benzene rings, including 2,3-dichlorotriphenylphosphine bromide, 2,4-dichlorobenzyltriphenylphosphine bromide, 2,5-dichlorobenzyltriphenylphosphine bromide, 2,6-dichlorobenzyltriphenylphosphine bromide, 2,3-difluorotriphenylphosphine bromide, 2,4-difluorobenzyltriphenylphosphine bromide, or 2,5-dichlorobenzyltriphenylphosphine bromide. 6-Difluorobenzyltriphenylphosphine bromide, 2,3-dibromotriphenylphosphine bromide, 2,4-dibromobenzyltriphenylphosphine bromide, 2,5-dibromobenzyltriphenylphosphine bromide, 2,6-dibromobenzyltriphenylphosphine bromide; the iodine reagent in step d) is elemental iodine, N-iodosuccinimide, or 4,4'-xylyliodonium hexafluorophosphate, the reaction temperature is -30℃ to 0℃, and the reaction time is 5-15 h; the deiodination reagent in step e) is NaBH4, LiAlH4, Al For step f), any one of BN, Bu3SnH, Pd / C, and Et3N is used, with tetrahydrofuran, toluene, or ethyl acetate as the solvent, at a reaction temperature of 0℃-100℃ and a reaction time of 1-12h. For step f), the base used is imidazole or sodium hydroxide, with anhydrous tetrahydrofuran or anhydrous acetonitrile as the solvent, at room temperature and a reaction time of 1-4h. For the Pd / C reduction hydrogenolysis reaction, the temperature is 60℃, with tetrahydrofuran, toluene, or ethyl acetate as the solvent, and a reaction time of 4-10h. In step g), the solvent used is concentrated hydrochloric acid: THF: anhydrous ethanol = 3:1:1, the reaction temperature is 0℃-100℃, and the reaction time is 1-4h; in step h), the solvent used is DCM, the base is 1,8-diazabicycloundec-7-ene and anhydrous potassium carbonate, the reaction temperature is room temperature, and the reaction time is 4-6h; in step i), the reaction solvent is dichloromethane or acetonitrile, the reaction reagent is trifluoroacetic acid, the reaction temperature is 20-40℃, and the reaction time is 12-48 hours.

[0101] The present invention relates to the use of polyhydroxyonium salt derivatives or pharmaceutically acceptable salts in the preparation of onium salt-type α-glucosidase inhibitors. Indications include glucose metabolism-related indications, such as diabetes mellitus and diabetes-related complications, impaired glucose tolerance (IGT), and pancreatic dysfunction-related diseases; lipid metabolism-related indications, such as hyperlipidemia, hypolipoproteinemia, and fatty liver disease; and metabolic syndromes, such as central obesity, obesity, and obesity-related complications.

[0102] The application of the polyhydroxyonium salt derivatives or pharmaceutically acceptable salts described in this invention in the preparation of hypoglycemic drugs.

[0103] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0104] 1. This invention designs novel onium salt derivatives based on the principle of bioelectron isosterism, and these compounds have good tolerance to gastric acid;

[0105] 2. The onium salt compounds involved in this invention have strong acid resistance and stronger α-glucosidase inhibitory activity, and can be used as onium salt-type α-glucosidase inhibitors. These molecules have hypoglycemic activity.

[0106] 3. The onium salt derivatives of the present invention replace the sulfur atoms in the sulfonium fragment with Se or NH. The partial Se substitution has stronger α-glucosidase inhibitory activity and better hypoglycemic activity than sulfonium salt compounds, while the NH substitution has slightly weaker α-glucosidase inhibitory activity and slightly weaker hypoglycemic activity than thioonium salt compounds.

[0107] The compounds of this invention are mainly derived from D-arabinitol, and through a multi-step reaction, strontium salt derivative molecules with α-glucosidase inhibitory activity are obtained. The compounds of this invention have simple structures, ingenious designs, inexpensive and readily available raw materials, safe and environmentally friendly synthesis processes, are easy to scale up for production, and are easy to prepare at low cost. Attached Figure Description

[0108] Figure 1 Method for preparing compound 13;

[0109] Figure 2 The preparation method of compound 37;

[0110] Figure 3 This describes the preparation method of compound 61.

[0111] Figure 4 Method for preparing compound 25;

[0112] Figure 5 The preparation method of compound 49;

[0113] Figure 6 The stability changes of compounds 13 and 9 in artificial gastric fluid are shown (red for compound 13, green for compound 9).

[0114] Figure 7 Blood glucose concentration-time plots after glucose loading of compounds 13 and 14 at 10 mg / kg (sucrose as substrate).

[0115] Figure 8 Blood glucose concentration-time plots after glucose loading of compounds 13 and 14 at 1 mg / kg (sucrose as substrate).

[0116] Figure 9Blood glucose concentration-time plots after glucose loading of compounds 13 and 14 at 1 mg / kg (maltose as substrate).

[0117] Figure 10 Effects of different treatment groups on fasting blood glucose in diabetic model mice

[0118] Figure 11 The effect of compound 13 on blood glucose levels in diabetic rats. (A) Oral sucrose tolerance test (OSTT) and (B) Area under the curve (AUC) of postprandial blood glucose changes; (C) Oral maltose tolerance test (OMTT) and (D) Area under the curve of diabetic mice treated on day 27.

[0119] Figure 12 The effect of compound 13 on blood glucose levels in diabetic rats. (A) Oral glucose tolerance test (OGTT); (B) Area under the curve (AUC) of postprandial blood glucose changes; (C) Insulin tolerance test (ITT); (D) Area under the curve (AUC) of diabetic mice on day 27 of treatment.

[0120] Figure 13 The effect of compound 13 on blood lipid levels. (A) Liver total cholesterol level, (B) Liver triglyceride level, (C) Serum total cholesterol level, and (D) Serum triglyceride level.

[0121] Figure 14 The effects of compound 13 on liver glycogen and glycated hemoglobin (HbA1c) levels in diabetic rats: (A) liver glycogen content; (B) glycated hemoglobin level.

[0122] Figure 15 The effect of compound 13 on organs (including liver fat accumulation) in diabetic mice. Scale bar = 100 micrometers.

[0123] Figure 16 The effect of compound 13 (using physiological saline as a solvent at doses of 20, 100, and 500 mg / kg) on ​​mouse body weight was investigated.

[0124] Figure 17 Biochemical analysis of compound 13 on ALT, AST, ALB, CRE, and BUN in mouse blood.

[0125] Figure 18 These are representative H and E staining images of major organs in ICR mice caused by compound 13. Detailed Implementation

[0126] The present invention will now be described in detail with reference to specific embodiments.

[0127] Example 1

[0128]

[0129] 20 g of isopropylidene-protected α-D-furanose was dissolved completely in 60 ml of DMF. Three equivalents of triphenylphosphine and 3.5 equivalents of sodium hydride were added to the reaction solution in five portions, 5 min apart, in an ice bath. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored by TLC. After the reaction was complete, the sodium hydride was quenched with 10 ml of ice water until no bubbles were generated. The reaction solution was extracted with ethyl acetate (40 ml × 3) until no product was found in the aqueous layer. The organic layers were combined and washed six times (60 ml × 6) with saturated sodium chloride solution to remove DMF. The filtrate was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain a pale yellow oily liquid.

[0130] Take the above-mentioned pale yellow oily liquid, add 50 ml of water and mix well, then add 50 ml of trifluoroacetic acid, and stir at room temperature for 6 hours. Monitor the reaction by TLC thin-layer chromatography. After the reaction is complete, weigh 40 g of sodium hydroxide solid and place it in a beaker containing ice. Pour the reaction solution into the beaker and stir rapidly. Add sodium bicarbonate powder in batches and adjust the pH to 6-7. Extract the reaction solution with ethyl acetate (60 ml × 3) until no product is found in the aqueous layer. Combine the organic layers and wash six times (60 ml × 6) with saturated sodium chloride solution to remove DMF. Dry the organic layer with anhydrous sodium sulfate. Remove the solvent by evaporation under reduced pressure, prepare the precipitate with 100-200 mesh silica gel, and precipitate by column chromatography with 200-300 mesh silica gel to obtain compound 71. The eluent is petroleum ether:ethyl acetate = 4:1-2:1. 1 H NMR (300MHz, CDCl3) δ7.44-7.30(m,15H),4.84(dd,J=13.6,11.4Hz,1H),4.70-4.42(m,7H),4.16-3.87(m,4H),3.79(ddd,J=16.1,10.7,5.3Hz,1H). 13 CNMR (75MHz, CDCl3) δ138.72,138.46,137.97,137.11,128.80,128.56,128.51, 128.46,128.33,127.96,127.93,127.89,127.83,127.76,127.73,127.69,103. 62,97.17,83.67,82.44,80.21,77.88,77.65,77.23,77.00,76.81,76.30,74.0 5,73.71,73.62,72.84,72.71,72.50,72.01,70.99,70.58.MS(ESI)450.1[M+H] + .

[0131] Example 2

[0132]

[0133] Weigh 3 g of compound 71 using the weight reduction method and add 20 ml of ethyl acetate to dissolve it completely. In a two-necked flask, weigh 3 equivalents of Wittig reagent (the corresponding Wittig reagent for each derivative) and 3 equivalents of anhydrous potassium carbonate, add 80 ml of ethyl acetate and mix thoroughly. React in an oil bath at 70°C for 30 minutes under argon protection. Add the ethyl acetate solution of compound 71 dropwise to the above reaction system using a syringe and react in an oil bath at 70°C for 8 hours. Monitor the reaction by TLC thin-layer chromatography. After the reaction is complete, remove the reaction solution and cool to room temperature. Filter the solution using a sintered glass funnel to remove insoluble matter. Wash the filtrate three times with saturated sodium chloride solution (60 ml × 3). Dry the filtrate with anhydrous sodium sulfate, evaporate under reduced pressure to remove the solvent, prepare silica gel slurry using 100-200 mesh, and precipitate by column chromatography using 200-300 mesh silica gel to obtain compound 72. The eluent was petroleum ether:ethyl acetate = 8:1. [a] D 20 = +15.9 (c = 1.0 in CHCl3); 1 H NMR (300MHz, Chloroform-d) δ7.29-7.17(m,17H),7.01-6.80(m,3H),6.72(d,J=16.1Hz,1H),6.21(dd,J=16.1,6.1Hz,1H),4.68(d,J=1 1.5Hz,1H),4.60(d,J=11.2Hz,1H),4.51-4.45(m,4H),4.38(d,J=11.5Hz,1H),3.87-3.77(m,3H),3.70-3.61(m,2H),2.93-2.84(m,2H). 13 C NMR (75MHz, CDCl3)δ

[0134] 160.4,157.2,138.1,138.0,137.9,132.8,128.6,128.5,128.1,128.1,127.9,127.9,123.2,117.0,116.9,116.7 ,116.6,115.5,115.4,115.2,115.1,113.7,113.3,79.9,78.0,75.0,74.0,73.6,71.9,69.4.MS(ESI)593.1[M+H] + .

[0135] Example 3

[0136]

[0137] The compound obtained in the previous step was dissolved in 15 ml of a 1:4 mixture of acetonitrile and dichloromethane and placed at 0–10°C. Three equivalents of iodine and five equivalents of anhydrous potassium carbonate were weighed and added to the reaction solution sequentially. The reaction was carried out for 3 hours. TLC was used for monitoring. After the reaction was complete, saturated sodium thiosulfate solution was added to quench the reaction. The reaction solution was extracted with ethyl acetate (40 ml × 3) until no product was found in the aqueous layer. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed by vacuum evaporation, and the solution was prepared by silica gel chromatography (100-200 mesh). Compound 73 was obtained by column chromatography on 200-300 mesh silica gel. The eluent was petroleum ether:ethyl acetate = 10:1. [a] D 20 = +28.9 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ7.45(t,J=6.0Hz,1H),7.21(q,J=6.2Hz,20H),7.04(d,J= 7.0Hz,1H),5.68(dd,J=10.9,4.1Hz,1H),4.88(d,J=11.0Hz,1H),4.72(dd,J=11.3,4.0H z,1H),4.38(dddd,J=27.8,17.0,13.4,7.0Hz,10H),3.97(d,J=4.1Hz,1H),3.88(dd,J= 9.6,5.0Hz,1H),3.65-3.56(m,1H),3.38(dt,J=10.4,4.7Hz,1H),2.96(d,J=4.7Hz,1H). 13 C NMR (75MHz, CDCl3)δ

[0138] 141.1,140.7,138.6,138.3,137.8,133.3,132.1,129.4,128.5,128.4,128.3,127.9,127.6,127.6,127.5,127.4,127. 3,127.0,127.0,83.8,82.8,80.7,77.6,77.2,76.7,76.2,74.6,73.3,72.5,72.3,70.8,65.1,24.9.MS(ESI)719.1[M+H] + .

[0139] Example 4

[0140]

[0141] The compound obtained in the previous step was dissolved in 10 ml of anhydrous tetrahydrofuran, and 3 equivalents of tributyltin hydride and 0.2 equivalents of AIBN were added. The air in the reaction apparatus was replaced with argon, and the reaction was carried out in an oil bath at 60°C. The reaction was monitored by TLC (thin-layer chromatography). After the reaction, the reaction solution was evaporated to dryness, and the solution was purified by silica gel chromatography (100-200 mesh) followed by column chromatography (200-300 mesh). The eluent was petroleum ether:ethyl acetate = 8:1. [a] D 20 = +26.9 (c = 1.0 in CHCl3); 1 H NMR (300MHz, Chloroform-d)δ

[0142] 7.36-7.15(m,18H),5.33(d,J=11.1Hz,1H),4.73(dd,J=11.6,3.1Hz,1H),4.50-4.31(m,6H),4. 20-4.15(m,2H),3.86(t,J=4.6Hz,2H),3.69(d,J=10.8Hz,1H),3.55-3.46(m,1H),2.45(s,1H). 13 C NMR (75MHz, CDCl3) δ139.4,138.6,138.5,138.2,133.0,132.7,130.5,129.8,128.6,128.4,128.4,128. 0,127.8,127.6,127.5,76.2,75.8,74.0,73.6,73.4,72.9,72.1,70.5,69.5,38.4.MS(ESI)719.1[M+H] + .

[0143] Example 5

[0144]

[0145] The compound obtained in the previous step was dissolved in 22 ml of a mixed solvent (tetrahydrofuran: anhydrous ethanol: concentrated hydrochloric acid = 1:1:3), and reacted in an oil bath at 100 °C for 3 hours. The reaction was monitored by TLC thin-layer chromatography. After the reaction was completed, the pH of the reaction solution was adjusted to 7 with a sodium methoxide methanol solution, and the residue was removed by diatomaceous earth filtration. The solvent was removed by vacuum evaporation, and the solution was prepared by silica gel chromatography (100-200 mesh). The solution was then subjected to silica gel column chromatography (200-300 mesh). The eluent was ethyl acetate:methanol = 10:1. 1H NMR(300MHz,Chloroform-d)δ7.43-7.25(m,18H),5.17-5.11(m,1H),4.93(d,J=11.6Hz,1H),4.72-4.55(m,6H),4.2 4(d,J=9.6Hz,2H),4.13(dd,J=10.8,4.3Hz,1H),3.99(dd,J=17.4,8.8Hz,2H),3.80-3.68(m,2H),2.03-1.93(m,2H). 13 C NMR (75MHz, CDCl3) δ146.1,142.1,138.8,138.5,133.1,130.3,128.5,128.4,128.3,127.9,127. 7,127.6,127.5,76.5,74.1,73.7,73.3,72.7,72.2,70.5,69.3,65.0,34.3.MS(ESI)593.2[M+H] + .

[0146] Example 6

[0147]

[0148] Compound 75 (0.4 mmol) was dissolved in 10 mL of tetrahydrofuran, and 2 equivalents of triethylamine, 0.1 equivalents of dibutyltin oxide, and 1.2 equivalents of p-toluenesulfonyl chloride were added sequentially. The reaction was carried out at room temperature for 4–8 hours, and the reaction was monitored by TLC. After the reaction was completed, the tetrahydrofuran was evaporated to dryness, and the mixture was extracted with EA (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The compound obtained in the previous step was dissolved in 3 mL of dichloromethane, and 2 equivalents of DBU were added. The reaction was carried out at room temperature for 1 hour (not exceeding 25 °C). The reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into cold water. The mixture was extracted with dichloromethane (30 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The mixture was prepared by silica gel chromatography (100–200 mesh), and compound 77 was obtained by column chromatography on 200–300 mesh silica gel. The eluent was ethyl acetate:petroleum ether = 1:2. [a] D 20 = +46.4 (c = 1.0 in CH3OH); 1H NMR (300MHz, Methanol-d4) δ7.70(d,J=2.7Hz,1H),7.31(d,J=8.5Hz,1H),7.23(dd,J=8.5,2.6Hz,1H),5.13(dd,J=10.9,3. 0Hz, 1H), 4.01 (q, J = 3.1Hz, 1H), 3.92 (d, J = 4.9Hz, 2H), 3.80 (dd, J = 12.8, 3.0Hz, 2H), 3.65-3.63 (m, 1H), 1.95-1.79 (m, 2H). 13 C NMR(75MHz,MeOD)δ143.9,134.2,131.4,130.6,129.4,128.8,76.1,72.1,71.4,68.9,67.4,64.7,35.0.MS(ESI)305.1[M+H] + .

[0149] Example 7

[0150]

[0151] Compound 74 (0.4 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. Two equivalents of sodium hydroxide were added, and the mixture was stirred for 30 minutes. Then, 2.5 equivalents of CS2 and 2.5 equivalents of MeI were added, and the mixture was stirred at room temperature. After the reaction was complete, the mixture was extracted with EA (40 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting solution was dissolved in 10 mL of anhydrous tetrahydrofuran, and Pd / C was added. The air in the reaction apparatus was replaced with hydrogen, and the reaction was carried out in an oil bath at 70 °C. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, and the solution was purified to 100-200 mesh silica gel. The purified solution was then subjected to column chromatography on 200-300 mesh silica gel to obtain 81. The eluent was petroleum ether:ethyl acetate = 8:1. 1 H NMR(300MHz,Chloroform-d)δ7.55-7.46(m,1H),7.41-7.28(m,7H),7.29(ddd,J=5.8,3.9,1.8Hz,1H),5.00-4.89(m,0H),4. 59(s,1H),4.60-4.50(m,1H),4.55-4.42(m,1H),4.09-3.89(m,2H),3.65-3.41(m,1H),2.13-1.98(m,1H),1.98-1.66(m,1H). 13C NMR(75MHz,Methanol-d4)δ138.7,138.2,138.0,137.9,132.1,130.4,130.1,128.9,128.4,128.4,128.3,128.3,128.3,1 28.3,128.2,128.2,128.1,128.1,127.8,78.1,76.9,76.9,74.2,73.7,72.4,71.9,69.2,30.3,28.9.MS(ESI)577.18[M+H] + .

[0152] Example 8

[0153]

[0154] The compound obtained in the previous step was dissolved in 22 ml of a mixed solvent (tetrahydrofuran: anhydrous ethanol: concentrated hydrochloric acid = 1:1:3), and reacted in an oil bath at 100 °C for 3 hours. The reaction was monitored by TLC thin-layer chromatography. After the reaction was completed, the pH of the reaction solution was adjusted to 7 with a sodium methoxide methanol solution, and the residue was removed by diatomaceous earth filtration. The solvent was removed by vacuum evaporation, and the solution was prepared by silica gel chromatography (100-20 mesh) followed by column chromatography on 200-300 mesh silica gel. The eluent was ethyl acetate:methanol = 10:1. 1 H NMR (300MHz, Chl oroform-d)δ7.49-7.35(m,3H),4.93(tdd,J=7.1,2.5,0.7Hz,1H),4.72-4.61(m,1H),4.48(t,J=7.7Hz,1H),3.93-3.69(m,4H),3.50(ddd, J=12.3,7.7,6.9Hz,1H),3.39(ddd,J=12.4,7.8,7.0Hz,1H),2.18-1.94(m,2H),1.86(dq,J=12.3,7.0Hz,1H),1.69(dq,J=12.3,7.1Hz,1H). 13 CNMR(75MHz,Methanol-d4)δ140.3,132.7,132.7,130.2,130.1,129.9,129.2,129.1,80.5,75.4,72.0,70.6,63.9,30.7,29.2.MS(ESI)307.04[M+H] + .

[0155] Example 9

[0156]

[0157] Compound 82 (0.4 mmol) was dissolved in 10 mL of tetrahydrofuran, and 2 equivalents of triethylamine, 0.1 equivalents of dibutyltin oxide, and 1.2 equivalents of p-toluenesulfonyl chloride were added sequentially. The reaction was carried out at room temperature for 4–8 hours, and the reaction was monitored by TLC. After the reaction was completed, the tetrahydrofuran was evaporated to dryness, and the mixture was extracted with EA (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The compound obtained in the previous step was dissolved in 3 mL of dichloromethane, and 2 equivalents of DBU were added. The reaction was carried out at room temperature for 1 hour (not exceeding 25 °C). The reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into cold water. The mixture was extracted with dichloromethane (30 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The mixture was prepared by silica gel chromatography (100–200 mesh), and compound 84 was obtained by column chromatography on 200–300 mesh silica gel. The eluent was ethyl acetate:petroleum ether = 1:2. [a] D 20 = +46.4 (c = 1.0 in CH3OH); 1 H NMR(300MHz,Chloroform-d)δ7.46(d,J=7.7Hz,1H),7.40(ddd,J=4.3,3.6,1.4Hz,2H),4.93(tdd,J=7.1,2.5,0.7Hz,1H),4.10-3.87(m,3H),3.55(dd, J=12.3,7.0Hz,1H),3.40(dd,J=12.3,6.8Hz,1H),3.27(q,J=6.9Hz,1H),2. 18-1.95(m,2H),1.86(dq,J=12.4,7.0Hz,1H),1.67(dq,J=12.3,7.0Hz,1H). 13 C NMR(75MHz,Methanol-d4)δ139.9,132.7,130.1,130.0,129.9,129.1,78.5,75.6,70.3,52.8,46.2,30.6,29.2.MS(ESI)289.1[M+H] + .

[0158] Example 10

[0159]

[0160] Under argon protection, trifluoroacetic acid (0.36 mmol), compound 77 (0.4 mmol), and sucrase 78 (0.36 mmol) were added to 4.0 mL of anhydrous acetonitrile. The mixture was stirred at -20°C for 10 min, then cooled to room temperature and stirred for another 8 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methanol, and a strongly basic anion exchange resin (Cl...) was added. -Type, 2.0 g, Brand: Bide) ion exchange reagent; the reaction mixture was stirred at room temperature for 4 hours, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain a pale yellow oily liquid 11 (0.18 mmol, 46%). [α] D 25 = +15.6 (c = 0.165, MeOH). 1 H NMR (300MHz, Methanol-d4) δ7.44-7.35(m,2H),7.22(t,J=7.8Hz,1H),4.70-4.51(m,1H),4.47-4.28(m,3H),4.23(d,J=3.5Hz,1H),4.11(ddt ,J=15.6,8.3,3.2Hz,3H),4.03-3.89(m,4H),3.87-3.78(m,2H),3.71(dq,J=12.5,7.3,6.4Hz,1H),3.10(dt,J=8.3,3.7Hz,2H),2.02(s,1H). 13 C NMR(75MHz,MeOD)δ140.6,133.8,133.2,131.2,129.7,128.6,83.7,81.5,79.5,78.3,77.6,7 3.8,66.9,61.0,52.8,51.7,49.9,49.6,49.3,49.0,48.7,48.4,48.1,34.8.HRMS(ESI)calcd for[M] + 455.0015, found 455.0016.

[0161] Example 11

[0162]

[0163] Under argon protection, trifluoroacetic acid (0.36 mmol), compound 77 (0.4 mmol), and selenosaccharide 79 (0.36 mmol) were added to 4.0 mL of anhydrous acetonitrile. The mixture was stirred at -20°C for 10 min, then cooled to room temperature and stirred for another 8 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methanol and a strongly basic anion exchange resin (Cl...) was added. - Type, 2.0 g, Brand: Bide) ion exchange reagent; the reaction mixture was stirred at room temperature for 4 hours, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain a pale yellow oily liquid 28 (0.18 mmol, 46%). [α] D 25 = +15.7 (c = 0.165, MeOH). 1HNMR(300MHz,Methanol-d4)δ7.41(d,J=7.9Hz,2H),7.25(d,J=7.9Hz,1H),4. 71(s,1H),4.50-4.37(m,2H),4.31(d,J=6.0Hz,1H),4.23(s,1H),4.12(d,J=11 .1Hz,2H),3.98(s,2H),3.91(s,1H),3.80(d,J=8.9Hz,1H),3.75-3.64(m,1H), 3.57(d,J=11.9Hz,1H),3.36-3.29(m,2H),3.12(d,J=6.6Hz,2H),2.03(s,1H). 13 C NMR(75MHz,MeOD)δ139.3,135.1,132.6,129.9,128.5,127.3,83.0,80.2,79.1,78.8,76.9,7 6.4,72.6,65.4,59.7,48.9,48.5,48.2,47.9,47.6,47.3,47.1,46.8,33.5.HRMS(ESI)calcd for[M] + 503.0015, found 503.0018.

[0164] Example 12

[0165]

[0166] Under argon protection, trifluoroacetic acid (0.36 mmol), compound 77 (0.4 mmol), and glucosamine 80 (0.36 mmol) were added to 4.0 mL of anhydrous acetonitrile. The mixture was stirred at -20°C for 10 min, then cooled to room temperature and stirred for another 8 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methanol, and a strongly basic anion exchange resin (Cl...) was added. - Type, 2.0g, Brand: Bide) Ion exchange reagent; the reaction mixture was stirred at room temperature for 4 hours, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain a pale yellow oily liquid 44 (46%). [α] D 25 = +15.7 (c = 0.165, MeOH). 1H NMR(500MHz,Chloroform-d)δ8.33(tq,J=8.8,7.6Hz,1H),7.33-7.26(m,2H),7.06(ddt,J=5.5,3.5,1. 0Hz,1H),5.01(d,J=7.7Hz,1H),4.97(d,J=7.4Hz,1H),4.90(d,J=8.9Hz,1H),4.45-4.34(m,3H),4.33(d ,J=7.3Hz,1H),4.31-4.24(m,1H),4.27-4.21(m,1H),4.24-4.18(m,1H),4.21-4.11(m,2H),3.99(t,J=7 .0Hz,1H),3.82-3.70(m,2H),3.30-3.17(m,5H),3.21-3.10(m,2H),3.05(ddd,J=12.3,7.0,0.9Hz,1H). 13 C NMR (125MHz, Common NMR Solvents)δ135.6,132.2,131.9,129.2,129.2,128.8,128.8,83.3,83.1,77.0,75.0,73.6,71.2,70.8,68.1,60.6,57.6,55.5,36.5.HRMS(ESI)calcd for[M] + 438.1015, found 438.1018.

[0167] Example 13

[0168]

[0169] Under argon protection, trifluoroacetic acid (0.36 mmol), compound 84 (0.4 mmol), and sucrase 78 (0.36 mmol) were added to 4.0 mL of anhydrous acetonitrile. The mixture was stirred at -20°C for 10 min, then cooled to room temperature and stirred for another 8 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methanol, and a strongly basic anion exchange resin (Cl...) was added. - Type, 2.0 g, Brand: Bide) ion exchange reagent; the reaction mixture was stirred at room temperature for 4 hours, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain a pale yellow oily liquid 11 (0.18 mmol, 46%). [α] D 25 = -15.6 (c = 0.165, MeOH). 1H NMR(300MHz, Methanol-d4)δ7.37-7.26(m,1H),7.26(dd,J=7.5,1.9Hz,1H),7.08(ddt,J=7 .1,1.9,1.0Hz,1H),4.85(d,J=8.8Hz,1H),4.74-4.58(m,2H),4.47-4.33(m,3H),4.27(pd, J=6.9,0.8Hz,1H),3.95(t,J=6.9Hz,1H),3.91-3.72(m,3H),3.76-3.60(m,3H),3.66-3.47 (m,1H),3.51-3.33(m,3H),2.96(qdd,J=12.4,7.0,1.0Hz,2H),2.18(td,J=7.0,1.4Hz,2H). 13 C NMR(75MHz,Methanol-d4)δ136.8,132.2,131.7,129.3,128.9,83.7,78.4,74.3,74.2,73.7,72.3,69.6,59.6,58.6,46.6,46.0,40.8,40.4.HRMS(ESI)calcd for[M] + 439.0715, found 439.0716.

[0170] Example 14

[0171]

[0172] Under argon protection, trifluoroacetic acid (0.36 mmol), compound 77 (0.4 mmol), and selenosaccharide 79 (0.36 mmol) were added to 4.0 mL of anhydrous acetonitrile. The mixture was stirred at -20°C for 10 min, then cooled to room temperature and stirred for another 8 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methanol and a strongly basic anion exchange resin (Cl...) was added. - Type, 2.0 g, Brand: Bide) ion exchange reagent; the reaction mixture was stirred at room temperature for 4 hours, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain a pale yellow oily liquid 4 (0.18 mmol, 46%). [α] D 25 = -15.7 (c = 0.165, MeOH). 1HNMR(300MHz, Methanol-d4)δ7.37-7.27(m,1H),7.26(dd,J=7.5,1.9Hz,1H),7.08(ddt,J=7.1,1.9, 1.0Hz,1H),4.71(d,J=8.8Hz,1H),4.51(d,J=7.3Hz,1H),4.46-4.30(m,2H),4.34-4.19(m,3H),3.98( t,J=7.0Hz,1H),3.85-3.50(m,5H),2.96(qdd,J=12.4,7.0,1.0Hz,2H),2.58(qd,J=6.9,0.9Hz,1H),2 .55-2.45(m,1H),2.49-2.39(m,1H),2.21(td,J=7.0,0.6Hz,2H),1.79(ddd,J=12.4,6.9,4.9Hz,2H). 13 C NMR(75MHz,Methanol-d4)δ136.7,132.0,131.4,128.9,85.3,78.8,78.8,76.4,76.3,74.0,72.4,72.1,61.7,56.5,44.0,42.0,40.9,40.3.HRMS(ESI)calcd for[M] + 487.0215, found 487.0200.

[0173] Example 15: Enzyme Activity Assay of a Class I Onium Salt-Type α-Glucosidase Inhibitor

[0174] α-Glucosidases are a large class of enzymes in the glycosidic hydrolase family, whose main function is to hydrolyze glucosidic bonds, releasing glucose as the product. They include maltase and sucrase. This invention selects sucrose and maltose as substrates and determines the IC50 of compounds on maltase and sucrase. 50 .

[0175] Previously, our research group designed and synthesized a series of monosubstituted thioonium salts A on the benzene ring and determined their biological activity (patent CN202111267189).

[0176]

[0177] Table 1 IC50 of compound A 50 (μM)

[0178]

[0179]

[0180] In this invention, 1 mg of the compound in Table 2 was weighed as the test derivative and prepared into a 1 mM solution using a 0.1 mol / L phosphate buffer solution with a pH of 6.8. This solution was then serially diluted to 1 × 10⁻⁶. -1 mM, 1*10 -2 mM, 1*10 -3 mM, 1*10 -4 mM, 1*10 - 5 mM, 1*10 -6 A mM solution was prepared as a sample. IIIe was 1,4-dideoxy-1,4-[(R)-(5-deoxy-1,3-O-(2-nitrobenzylmethyl-D-arabinitol-5-yl)thioylide]-D-arabinitol chloride. Reference: Lu L, Chen JY, Tao WX, et al. Design and Synthesis of Sulfonium Derivatives: A Novel Class of α-Glucosidase Inhibitors with Potent In Vivo Antihyperglycemic Activities. J. Med. Chem., 2023, 6(5): 3484-3498.

[0181] Ten SD rats (5 males, 140g-160g; 5 females, 120g-140g, purchased from Qinglongshan Breeding Base) were taken and fed for one week to allow them to adapt to the new environment. They were fasted (with continuous water supply) for 12 hours to empty their small intestine. The rats were euthanized by cervical vertebrae dislocation, and the abdominal cavity was opened to separate the small intestine. The contents of the small intestine were rinsed clean with ice-cold physiological saline. The rinsed small intestine was placed on an ice plate and longitudinally cut open. The small intestinal mucosa was gently scraped off with a glass slide, and the resulting tissue was ground using a tissue homogenizer until no obvious tissue remained. 30mL of the homogenized tissue was collected and placed in a centrifuge tube. The tube was centrifuged at 4000 rpm for 15 minutes at below 4°C. The supernatant (8mL) was collected as the enzyme stock solution. Long-term storage requires -20°C.

[0182] Using sucrose (72 mM) as the substrate and voglibose as the positive control (concentration 3 μM, based on the IC50 value in the literature)... 50(To determine the concentration), the enzyme stock solution was diluted with physiological saline at 1 / 2, 1 / 4, 1 / 8, and 1 / 16 times, respectively. 25 μl of each enzyme concentration, 25 μl of voglibose solution, and 50 μl of substrate were mixed and incubated at 37°C for 30 minutes. After incubation, the 96-well plate was immediately immersed in boiling water to quench the enzymatic reaction. The absorbance of each well was then measured using the glucose oxidase-peroxidase method. The inhibition rate of the positive control at different enzyme concentrations was calculated, and the enzyme concentration with an inhibition rate of approximately 50% was selected as the concentration of the α-glucosidase solution for subsequent experiments, i.e., diluted to 1 / 4 of its original concentration. The enzyme stock solution was then diluted to this concentration. Take 25 μL of the above α-glucosidase solution, and after determining the protein solution using the Coomassie blue method, mix 50 μL of substrate (0.74 mM sucrose and 0.74 mM maltose), 25 μL of α-glucosidase solution, and 25 μL of the above samples with different gradients. Incubate at 37 °C for 30 min, quench the enzyme-catalyzed reaction with boiling water, and determine the amount of glucose produced using the glucose oxidase-peroxidase method. Calculate the IC50 of the compound using the SPSS probit regression model. 50 Some compounds have IC50 values ​​for maltase and sucrase. 50 As shown in Table 2.

[0183] Table 2 shows the IC50 values ​​of some target products. 50 (μM)

[0184]

[0185]

[0186]

[0187] Among them, 1-5 are sulfonium salts of this type disclosed in existing literature, 6 is clinical voglibose, and 7 is clinical acarbose, the activity of which was determined under the same conditions as the derivative of the present invention.

[0188] As shown in Table 2, most of the compounds prepared in this invention exhibit good inhibitory activity against sucrase and maltase, showing a significant increase in activity compared to monosubstituted compounds. This demonstrates the hypoglycemic activity of these small molecule compounds. Some Se-substituted compounds exhibit stronger α-glucosidase inhibitory activity and superior hypoglycemic activity than sulfonium salts, while NH-substituted compounds show slightly weaker α-glucosidase inhibitory activity and slightly weaker hypoglycemic activity than thioonium salts. Compounds 13, 14, 35, and 47 show significantly stronger enzyme inhibitory activity than clinically used α-glucosidase inhibitors such as acarbose and voglibose, and can be used for the prevention and treatment of diabetes, representing a potential candidate hypoglycemic drug molecule.

[0189] Example 16 Study on the gastric acid tolerance of onium salt derivatives

[0190] By simulating the changes of the drug in gastrointestinal fluid after oral administration, the effect of simulated gastric juice pH on the stability of compound 13 and biacetal compound 9 was investigated using high-performance liquid chromatography (HPLC). The chromatographic conditions for content determination were determined through simulation experiments, and the chromatographic conditions are shown in Table 3.

[0191] Table 3 Chromatographic conditions

[0192]

[0193] Standard solutions of 13 and 9 with a concentration of 5 mM were prepared using pure water. These solutions were then serially diluted to obtain standard solutions with concentrations of 1.7 mM, 0.87 mM, 0.43 mM, 0.21 mM, and 0.10 mM, respectively. Peak areas were determined by HPLC, and concentration standard curves were plotted using GraphPad-prism. Regression equations for the two compounds were then calculated.

[0194] Samples 13 and 9 were prepared with a concentration of 5 mg / mL using pure water. 105 μL of the sample pure water solution was placed in 1 mL of simulated gastric fluid (final product concentration 0.475 mg / mL) and heated in a 37°C water bath. Five parallel preparations were made for each sample, and the pH was adjusted to 7 with 0.5 mol / L sodium hydroxide pure water solution at 15, 30, 60, 90, and 120 minutes. The mixture was then centrifuged at 13000 g for 10 minutes at 4°C. The solution was filtered through a 0.2 μM microporous membrane to obtain the test solution. The peak area was recorded, and the remaining content of the sample at different time points was calculated according to the standard curve formula. Figure 6 As shown.

[0195] Compound 13 showed no significant change in content over time in artificial gastric fluid, decomposing 1% after 2 hours, with a 99% retention rate. Compound 9, however, showed a significant change in content over time in artificial gastric fluid: 4% decomposition at 15 minutes, 25% at 30 minutes, 50% at 60 minutes, and 70% at 120 minutes. Therefore, compound 9's retention rate of 50% after 1 hour in the highly acidic gastric environment significantly impacts therapeutic efficacy. Compared to compound 9 containing a biacetal structure, the compound protected by this patent exhibits superior acid resistance.

[0196] Example 17 Oral Sucrose Tolerance Test

[0197] Normal male ICR mice (30-35g) were fasted for 12 hours, and their body weight and fasting blood glucose were measured. They were then divided into 8 groups of 8 mice each, based on their body weight and blood glucose levels:

[0198] Blank control group: 6ml of 0.17g / ml sucrose + 2ml of double-distilled water;

[0199] Positive control group: 6 ml of 0.17 g / ml sucrose + 2 ml of 4 mg / ml acarbose;

[0200] Group 13 (10 mg / kg): 6 ml of 0.17 g / ml sucrose + 2 ml of 13 (2 mg / ml sucrose);

[0201] Group 14 (10 mg / kg): 6 ml of 0.17 g / ml sucrose + 2 ml of 2 mg / ml sucrose;

[0202] Group 13 (1 mg / kg): 6 ml of 0.17 g / ml sucrose + 2 ml of 0.2 mg / ml sucrose;

[0203] Group 14 (1 mg / kg): 6 ml of 0.17 g / ml sucrose + 2 ml of 0.2 mg / ml sucrose;

[0204] 35 10mg / kg group: 0.17g / ml sucrose 6ml + 2mg / ml 35 2ml;

[0205] 47 10mg / kg group: 0.17g / ml sucrose 6ml + 2mg / ml 47 2ml;

[0206] 35 1mg / kg group: 0.17g / ml sucrose 6ml + 0.2mg / ml 35 2ml;

[0207] 47 1mg / kg group: 0.17g / ml sucrose 6ml + 0.2mg / ml 47 2ml;

[0208] Mice in each group were orally administered the above-mentioned mixture of sucrose and different concentrations of drugs. Blood glucose levels were measured at 15, 30, 60, 90, and 120 minutes after administration. Figure 7 , Figure 8 As shown in Tables 4 and 5, the blood glucose decrease levels and the area under the curve after glucose load at 15, 30, and 60 minutes were calculated.

[0209] Table 4. Blood glucose reduction level and area under the curve after glucose load (1.0 mg / kg, sucrose as substrate)

[0210]

[0211]

[0212] Table 5. Blood glucose reduction level and area under the curve after glucose load (10.0 mg / kg, sucrose as substrate)

[0213]

[0214] In a sucrose tolerance test, comparing the hypoglycemic effects of the four compounds with those of the positive control drug acarbose revealed that all four compounds effectively reduced postprandial blood glucose levels in normal mice. The 10.0 mg / kg concentration of the compound exhibited a stronger hypoglycemic effect than 20.0 mg / kg acarbose, while the 1.0 mg / kg concentration had a similar effect to 20.0 mg / kg acarbose. Compounds 35 and 36 showed good in vitro enzyme-inhibiting activity and also demonstrated good hypoglycemic effects in vivo. Compounds 35 and 36, with different skeletons, showed comparable activity, with compound 13 exhibiting stronger in vivo hypoglycemic activity than other compounds.

[0215] Example 18 Oral Maltose Tolerance Test

[0216] Normal male ICR mice (30-35g) were fasted overnight, and their body weight and fasting blood glucose were measured. They were then divided into 8 groups of 8 mice each, based on their body weight and blood glucose levels:

[0217] Blank control group: 6ml maltose (0.17g / ml) + 2ml double-distilled water;

[0218] Positive control group: 6 ml of 0.17 g / ml maltose + 2 ml of 4 mg / ml acarbose;

[0219] Group 13 (1 mg / kg): 6 ml of 0.17 g / ml maltose + 2 ml of 0.2 mg / ml maltose;

[0220] Group 14 (1 mg / kg): 6 ml of 0.17 g / ml maltose + 2 ml of 0.2 mg / ml maltose;

[0221] 35 1mg / kg group: 0.17g / ml maltose 6ml + 0.2mg / ml 35 2ml;

[0222] 47 1mg / kg group: 0.17g / ml maltose 6ml + 0.2mg / ml 47 2ml;

[0223] Mice in each group were orally administered a mixture of maltose and different drug concentrations. Blood glucose levels were measured at 15, 30, 60, 90, and 120 minutes after administration. Figure 9 As shown in Table 6, the blood glucose decrease levels at 15, 30, and 60 minutes and the area under the curve after glucose load were calculated.

[0224] Table 6. Blood glucose reduction level and area under the curve after glucose load (1.0 mg / kg, maltose as substrate)

[0225]

[0226]

[0227] In the maltose tolerance test, by comparing the hypoglycemic effects of the above four compounds at 1.0 mg / kg with the hypoglycemic effect of the positive control drug voglibose, it was found that all four compounds at a concentration of 1.0 mg / kg could effectively reduce the postprandial blood glucose level in normal mice.

[0228] Example 19: Study on hypoglycemic and lipid-lowering effects in model mice

[0229] Model mouse construction: Eighty male C57 mice were acclimatized for one week. Ten mice were randomly selected as the control group based on body weight, while the remaining 70 mice were fed a high-fat diet and fasted overnight (with free access to water) for STZ modeling (intraperitoneal injection of STZ 40 mg / kg). One week after modeling, mice were considered successfully modeled if their fasting blood glucose level was ≥11.1 mmol / L after tail clipping. The modeled mice were then randomly divided into four groups (n=14 per group) based on their blood glucose levels: STZ model control group, positive control group (acarbose 50 mg / kg), low-dose (3 mg / kg) compound 13 group, medium-dose (10 mg / kg) compound 13 group, and high-dose (30 mg / kg) compound 13 group. The same volume of normal diet control and STZ model control group was administered via gavage. Fasting blood glucose levels were measured weekly at fixed times for four weeks. During this period, all mice had free access to food and water, and their body weight, food intake, and fasting blood glucose levels were recorded weekly. In the final week, oral glucose tolerance tests (2 g / kg), oral maltose tolerance tests (2 g / kg), oral sucrose tolerance tests (2 g / kg), and insulin tolerance tests (0.5 U) were conducted at 2 g / kg. After drug administration, mice were anesthetized, and blood was collected from the aorta. The collected blood was centrifuged at 3500 rpm for 10 min at low temperature to obtain serum, which was then aliquoted into cryovials. A portion of the blood was also collected and centrifuged at 3500 rpm for 10 min at low temperature to obtain hemoglobin precipitate. After blood collection, the mice were euthanized by cervical dislocation, and the abdominal cavity was opened to dissect the liver and pancreas. Blood stains on the tissues were washed away with physiological saline, and excess surface moisture was blotted with filter paper. The tissues were weighed, and a portion was cut and placed in a sample tube containing 4% paraformaldehyde for fixation, while the other portion was placed in cryovials for preservation.

[0230] Fasting blood glucose levels were determined in diabetic and normal mice using tail vein blood collection. Mice were fasted overnight for 12 hours before measurement, but were allowed free access to water. Results are as follows: Figure 10As shown, blood glucose levels decreased over time in all treatment groups except the control group and the model group, with the most significant decrease occurring in week four. At week four, the blood glucose levels in the high-dose (30 mg / kg) compound 13 group were significantly different from those in other groups.

[0231] The results of oral glucose (2 g / kg), oral maltose (2 g / kg), oral sucrose (2 g / kg), and insulin (0.5 U) tolerance tests in mice under different treatment groups are shown in [the table below]. Figure 11 and Figure 12 After gavage administration of glucose solution, the blood glucose levels of mice in different treatment groups reached their peak at 15 minutes. With increasing time, the blood glucose levels in all groups decreased, but the blood glucose levels in the model group remained essentially unchanged. After gavage administration of sucrose and maltose, the blood glucose levels of mice in different treatment groups reached their peak at 30 minutes. With increasing time, the blood glucose levels in all groups decreased. In diabetic mice, the high-dose (30 mg / kg) compound 13 group showed lower blood glucose levels at all time points than other groups. Compound 13 significantly improved glucose metabolism and insulin sensitivity in diabetic mice.

[0232] Diabetic mice exhibit a significant reduction in liver glycogen, likely due to insulin deficiency and impaired liver glycogen synthesis. Figure 13 As shown, compound 13 can prevent the decline of liver glycogen. During 28 days of treatment, the high-dose (30 mg / kg) group showed the most significant improvement, with an improvement rate of 54.39%. In diabetic patients, excess glucose in the blood reacts with hemoglobin to form HbA1c, whose concentration is a longitudinal parameter representing the average blood glucose level over the past 2-3 months, unaffected by temporary fluctuations in blood glucose concentration, and is an important indicator for the clinical diagnosis of diabetes. After 28 days of oral administration of the compounds, both the compound 13 group and the acarbose group showed a decreasing trend in HbA1c levels, with the high-dose (30 mg / kg) compound 13 group showing a significant effect. These two compounds are more effective than acarbose.

[0233] Diabetic patients with glucose metabolism disorders often also have lipid metabolism disorders. Compared with normal mice, diabetic mice have higher levels of total cholesterol (TC) and triglycerides (TG) in their serum and liver. Figure 14As shown, in the liver, TC was reduced by 22.7%, 25.5%, and 39.8% in the 13-3mpk, 13-10mpk, and 13-30mpk groups, respectively, while TG was inhibited by 24.7%, 29.2%, and 38.4%, respectively. Acarbose did not significantly inhibit TC and TG. Surprisingly, the improvement in lipid metabolism was more pronounced in serum. Highly produced TC in serum was inhibited by 36.3%, 37.0%, and 42.7% in the 13-3mpk, 13-10mpk, and 13-30mpk groups, respectively, while it was inhibited by 30.0% in the acarbose-50mpk group. The inhibition rates of TG production in serum were 39.6%, 45.0%, and 45.1%, respectively. These results indicate that 13 has the ability to improve lipid metabolism in diabetes.

[0234] To evaluate the potential therapeutic efficacy and safety of compound 13 on the liver of diabetic mice, clinical biomarkers were analyzed. For example... Figure 15 As shown, hepatocytes in normal mice were arranged in an orderly manner with a clear structure, while the model group exhibited obvious pathological changes, including hepatocyte swelling, vacuolation, and inflammatory cell infiltration. With increasing intake of compound 13, the liver tissue structure of type 2 diabetic mice gradually became clearer, and the number and size of fat vacuoles decreased. These results indicate that compound 13 treatment can alleviate liver damage induced by type 2 diabetes in a dose-dependent manner.

[0235] Example 20: Study on Subacute Toxicity

[0236] To further evaluate the in vivo safety profile of compound 13, we conducted a 14-day subacute toxicity study in ICR mice at doses of 20, 100, and 500 mg / kg. During the study, mice received oral administration of compound 13 daily via gavage. Mice body weight was monitored daily throughout the study period. Figure 16 As shown, no abnormal behavior was observed. On day 14, the mice were euthanized and subjected to necropsy and tissue collection.

[0237] Biochemical analysis of liver and kidney biomarkers (including liver function indicators (AST, ALT, ALB) and kidney function parameters (creatinine [CRE], blood urea nitrogen [BUN])). Results are as follows. Figure 17 As shown, compared with the solvent control group, the compound 13 treatment group did not exhibit significant hepatotoxicity or nephrotoxicity at any dose level. The organ-to-body weight ratios showed no statistically significant differences among the different treatment groups. Histopathological evaluation by hematoxylin-eosin (HE) staining, as shown... Figure 18As shown, no significant tissue damage or pathological changes were observed in the major organs of mice treated with compound 13 at any dose level. These results collectively demonstrate that compound 13 maintains acceptable safety at doses up to 500 mg / kg without any indication of dose-dependent toxicity. Overall, these results support the favorable preclinical safety profile of compound 13, which maintains normal physiological parameters and organ integrity under subacute exposure conditions. This safety profile, coupled with its previously demonstrated antidiabetic efficacy, suggests that compound 13 is suitable for further preclinical development and clinical trials. The absence of significant toxicity at doses well above therapeutic concentrations (30 mg / kg) provides a robust safety profile for this potential novel therapeutic candidate, making it a promising new option for diabetes treatment.

[0238] In vitro and in vivo hypoglycemic experiments revealed that increasing the number of electron-withdrawing groups and introducing stronger electron-withdrawing groups were beneficial to the inhibitory activity of the compound against α-glucosidase. Changes in the position of substituents and alterations to the skeletal structure also had some impact on activity. Compound 13 exhibited stronger in vivo hypoglycemic activity than other compounds. In diabetic mouse models, compound 13 also demonstrated excellent in vivo hypoglycemic activity, significantly improving glucose metabolism and insulin sensitivity in diabetic mice, and also improving lipid metabolism in diabetes, alleviating liver damage caused by type 2 diabetes. It exhibited good preclinical safety profiles, maintaining normal physiological parameters and organ integrity under subacute exposure conditions. This suggests that compound 13 has a good postprandial hypoglycemic effect and could be a potential candidate drug for treating diabetes and preventing diabetic complications.

Claims

1. Polyhydroxysulfonium salt derivatives as shown in general formulas (I) and (II), R1 and R2 are not independent and are located in the ortho, meta, or para positions of the benzene ring; R1 is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, hydroxyl, alkoxy, nitro, cyano, C1-C5 alkoxy, C1-C3 alkyl, amino, or substituted amino groups with six or fewer carbon atoms; R2 is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, hydroxyl, alkoxy, nitro, cyano, C1-C5 alkoxy, C1-C3 alkyl, amino, or substituted amino groups with six or fewer carbon atoms; X is selected from S, Se, or NH; Y is selected from monovalent anions such as chloride ion, bromide ion, trifluoroacetate ion, acetate ion, hydrogen sulfate ion, or dihydrogen phosphate ion.

2. The polyhydroxysulfonium salt derivative according to claim 1, characterized in that, The polyhydroxyonium salt derivative or pharmaceutically acceptable salt is selected from any one of the following compounds: (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,3-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,4-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,5-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,4S,6R)-6-(2,6-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dichlorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-difluorophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,3-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,4-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,5-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3S,4S)-1-((S)-2-((2S,3R,6R)-6-(2,6-dibromophenyl)-3-hydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-selenophen-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,3-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,4-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,5-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,6-dichlorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,3-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,4-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,5-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,6-difluorophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,3-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,4-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,5-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium; (1S,2R,3R,4R)-1-((R)-2-((2R,3R,4S,6R)-6-(2,6-dibromophenyl)-3,4-dihydroxytetrahydro-2H-pyran-2-yl)-2-hydroxyethyl)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine-1-onium.

3. A method for preparing a polyhydroxyonium salt derivative corresponding to general formula (I) as described in claim 1 or 2, characterized in that, Includes the following steps: 3.1) Using 1,2-O-isopropylidene-α-D-furanose as the starting material, it was reacted with sodium hydride and benzyl bromide to obtain benzyl-protected 1,2-O-isopropylidene-α-D-furanose. 3.2) Benzyl-protected 1,2-O-isopropylidene-α-D-furanose was reacted with aqueous fluoroacetic acid at room temperature to give 3,5,6-tri-O-benzylfuran-D-glucose; 3.3) 3,5,6-tris-O-benzylfuran-D-glucose was reacted with substituted Wittig reagents and bases to generate 4,6,7-tris-O-benzyl-phenylheptenyl-3,5-diol intermediates; 3.4) The 4,6,7-tri-O-benzyl-phenylheptenyl-3,5-diol intermediate was subjected to an intramolecular cyclization reaction mediated by iodine reagent to generate the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate; 3.5) Remove the iodine atom from the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate to obtain the intermediate 2-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside; 3.6) Subsequently, the benzyl group of the 2-deoxy-4,6,7-tris-O-benzyl-1-C-phenylpyranoside intermediate was removed under concentrated hydrochloric acid to obtain the intermediate 2-deoxy-3,4,6,7-tetrahydroxy-1-C-phenylpyranoside. 3.7) Selectively attaching a p-toluenesulfonyl group to the primary hydroxyl position of 2-deoxy-3,4,6,7-tetrahydroxy-1-C-phenylpyranoside, followed by the removal of the p-toluenesulfonyl group in an alkaline solution, to generate an intermediate 3,4-dihydroxy-5-epoxyethyl-1-C-phenylpyranoside having an ethylene oxide structure. 3.8) Using acetonitrile as the reaction solution, the compound obtained in step 3.7) is coupled with the sucrose fragment, selenoglucan fragment or glucosamine fragment in the presence of trifluoroacetic acid at -20°C to room temperature. The resulting compound is then treated with a chloride ion exchange resin to obtain the target compound with different substitutions.

4. A method for preparing a polyhydroxyonium salt derivative corresponding to general formula (II) as described in claim 1 or 2, characterized in that, Includes the following steps: 4.1) Starting with 1,2-O-isopropylidene-α-D-furanose, it was reacted with sodium hydride and benzyl bromide to obtain benzyl-protected 1,2-O-isopropylidene-α-D-furanose. 4.2) Benzyl-protected 1,2-O-isopropylidene-α-D-furanose was reacted with 50% trifluoroacetic acid aqueous solution at room temperature for 4 hours to give 3,5,6-tri-O-benzylfuran-D-glucose; 4.3) 3,5,6-tris-O-benzylfuran-D-glucose was reacted with Wittig reagent and a base to generate 4,6,7-tris-O-benzyl-phenylheptenyl-3,5-diol intermediate; 4.4) The 4,6,7-tri-O-benzyl-phenylheptenyl-3,5-diol intermediate was subjected to an intramolecular cyclization reaction mediated by iodine reagent to generate the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate; 4.5) Remove the iodine atom from the 2-I-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate to obtain the intermediate 2-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside; 4.6) Under alkaline conditions, 2-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside reacts with CS2 and MeI, and then the hydroxyl group is removed under Pd / C reducing hydrogenolysis to obtain the intermediate 2,3-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside. 4.7) Subsequently, the benzyl group of the 2,3-deoxy-4,6,7-tri-O-benzyl-1-C-phenylpyranoside intermediate was removed under concentrated hydrochloric acid to obtain the intermediate 2,3-deoxy-4,6,7-trihydroxy-1-C-phenylpyranoside. 4.8) A p-toluenesulfonyl group is selectively attached to the primary hydroxyl position of 2,3-deoxy-4,6,7-trihydroxy-1-C-phenylpyranoside, and then the p-toluenesulfonyl group is removed in a K2CO3 solution of methanol to generate an intermediate 4-hydroxy-5-epoxyethyl-1-C-phenylpyranoside having an ethylene oxide structure. 4.9) Using acetonitrile as the reaction solution, the compound obtained in step 4.8) is coupled with the sucrose fragment, selenoglucan fragment or glucosamine fragment in the presence of trifluoroacetic acid at -20°C to room temperature. The compound is then treated with a chloride ion exchange resin to obtain the target compound with different substitutions.

5. The method for preparing polyhydroxyonium salt derivatives according to claim 3 or 4, characterized in that, The reaction solvent in steps 3.1) and 4.1) is dichloromethane, ethyl acetate, tetrahydrofuran or acetonitrile; the reaction time is 12-24 h, the feeding temperature is 0 °C, and the reaction temperature is room temperature. The reaction temperature in steps 3.2) and 4.2) is 0-60 °C, and the reaction time is 8-12 h.

6. The method for preparing polyhydroxyonium salt derivatives according to claim 3 or 4, characterized in that, The Wittig reagent in steps 3.3) and 4.3) is a benzyltriphenylphosphine bromide with disubstituted benzene ring, including 2,3-dichlorotriphenylphosphine bromide, 2,4-dichlorobenzyltriphenylphosphine bromide, 2,5-dichlorobenzyltriphenylphosphine bromide, 2,6-dichlorobenzyltriphenylphosphine bromide, 2,3-difluorotriphenylphosphine bromide, 2,4-difluorobenzyltriphenylphosphine bromide, or 2,5-difluorobenzyltriphenylphosphine bromide, 2,6-difluorobenzyltriphenylphosphine bromide, 2,3-dibromotriphenylphosphine bromide, 2,4-dibromobenzyltriphenylphosphine bromide, 2,5-dibromobenzyltriphenylphosphine bromide, 2,6-dibromobenzyltriphenylphosphine bromide, etc., as described in claim 1, containing different substituents.

7. The method for preparing polyhydroxyonium salt derivatives according to claim 3 or 4, characterized in that, The iodine reagent in steps 3.4) and 4.4) is elemental iodine, N-iodosuccinimide or 4,4'-dimethyliodonium hexafluorophosphate, the reaction temperature is -30℃ to 0℃, and the reaction time is 5-15h.

8. The method for preparing polyhydroxyonium salt derivatives according to claim 3 or 4, characterized in that, In steps 3.5) and 4.5), the reagent for deiodination is any one of NaBH4, LiAlH4, AIBN, Bu3SnH, Pd / C and Et3N, the solvent is tetrahydrofuran, toluene or ethyl acetate, the reaction temperature is 0℃-100℃, and the reaction time is 1-12h.

9. The method for preparing the polyhydroxysulfonium salt derivative according to claim 3, characterized in that, The solvent used in step 3.6 is concentrated hydrochloric acid: THF: anhydrous ethanol = 3:1:1, the reaction temperature is 0℃-100℃, and the reaction time is 1-4h.

10. The method for preparing polyhydroxyonium salt derivatives according to claim 3, characterized in that, In step 3.7, the solvent used is DCM, the base is 1,8-diazabicycloundec-7-ene and anhydrous potassium carbonate, the reaction temperature is room temperature, and the reaction time is 4-6 hours.

11. The method for preparing polyhydroxyonium salt derivatives according to claim 3, characterized in that, The reaction solvent in step 3.8) is dichloromethane or acetonitrile, the reaction reagent is trifluoroacetic acid, acetic acid or calcium trifluoroacetate, the reaction temperature is 20-40℃, and the reaction time is 12-48 hours.

12. The method for preparing polyhydroxysulfonium salt derivatives or ononium salt derivatives according to claim 4, characterized in that, In step 4.6), the base used is imidazole or sodium hydrogen, the reaction solvent is anhydrous tetrahydrofuran or anhydrous acetonitrile, the reaction temperature is room temperature, and the reaction time is 1-4 h. The Pd / C reduction hydrogenolysis reaction temperature is 60 °C, the solvent used is tetrahydrofuran, toluene or ethyl acetate, and the reaction time is 4-10 h.

13. The method for preparing polyhydroxysulfonium salt derivatives or ononium salt derivatives according to claim 4, characterized in that, In step 4.7), the solvent used is concentrated hydrochloric acid: THF: anhydrous ethanol = 3:1:1, the reaction temperature is 0℃-100℃, and the reaction time is 1-4h.

14. The method for preparing polyhydroxyonium salt derivatives according to claim 4, characterized in that, In step 4.8), the solvent used is DCM, the base is 1,8-diazabicycloundec-7-ene and anhydrous potassium carbonate, the reaction temperature is room temperature, and the reaction time is 4-6 hours.

15. The method for preparing polyhydroxyonium salt derivatives according to claim 4, characterized in that, The reaction solvent in step 4.9) is dichloromethane or acetonitrile, the reaction reagent is trifluoroacetic acid, the reaction temperature is 20-40℃, and the reaction time is 12-48 hours.

16. The use of a polyhydroxyonium salt derivative or a pharmaceutically acceptable salt as described in claim 1 in the preparation of strontium salt-type α-glucosidase inhibitors.

17. The use of a polyhydroxyonium salt derivative or a pharmaceutically acceptable salt as described in claim 1 in the preparation of a hypoglycemic drug.

18. The use of a polyhydroxyonium salt derivative or a pharmaceutically acceptable salt as described in claim 1 in the preparation of a drug for a metabolic indication, wherein the metabolic indication includes glucose metabolism-related indications, lipid metabolism-related indications, and metabolic syndrome; The glucose metabolism-related indications include diabetes and diabetes-related complications, impaired glucose tolerance, and diseases related to pancreatic dysfunction; the lipid metabolism-related indications include hyperlipidemia, low-density lipoproteinemia, and fatty liver disease; the metabolic syndromes include central obesity, obesity, and obesity-related complications.

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