Combination of a SGLT1 inhibitor and an enteroglucocin for the treatment

Abstract

Disclosed herein are methods of treating metabolic disorders, wherein the method administers a combination of a sodium / glucose co-transporter 1 (SGLT1) inhibitor and a glucagon-like peptide agonist 1 (GLP 1), a Gastrosuppressive Peptide-1 (GIP-1) analog, and / or d) a dual GLP-1-GIP-1 receptor agonist.

Description

Cross-references to related applications concerning combinations of SGLT1 inhibitors and glucagon for the treatment of metabolic diseases.

[0001] This application claims priority to U.S. Application No. 63 / 506,592, filed June 6, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0002] This invention relates to compositions and methods for treating metabolic diseases. Background Technology

[0003] The number of patients suffering from conditions involving abnormal lipid accumulation in the liver is increasing annually, including non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hypertrophic fatty liver, diabetic fatty liver, alcoholic fatty liver, toxic fatty liver, and common fatty liver. In particular, NASH is considered a significant problem due to its severe symptoms (see Non-Patent References 1 or 2 in '976). Furthermore, it is noted that abnormal lipid accumulation in the liver can lead to liver inflammation or fibrinolysis (cirrhosis) and progress to serious conditions such as liver cancer (see Non-Patent References 1 to 4 in '976), therefore, inhibiting this lipid accumulation is crucial.

[0004] It is generally believed that a combination of factors, including recent lifestyle changes, leads to abnormal liver energy metabolism, resulting in lipid accumulation in the liver. Therefore, treatment methods are not uniform. Currently, although dietary therapy, exercise therapy, and drug therapy are attempted as treatments for liver lipid accumulation, these methods are difficult to control or maintain consistently. Therefore, treatment outcomes are not always satisfactory. As mentioned above, a satisfactory method for treating liver lipid accumulation has not yet been established; therefore, there is a desire to develop more effective drugs for treating lipid accumulation.

[0005] Multiple pharmacological approaches can be used to treat hyperglycemia and subsequent type 2 diabetes mellitus (T2DM) (Hampp, C. et al. Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 2014, 37, 1367-1374). These can be categorized as follows, each acting through a different primary mechanism: (1) Insulin secretagogues, including sulfonylureas (such as glipizide, glimepiride, and glibenclamide); (2) meglitinides (such as nateglinide and repaglinide); (3) dipeptidyl peptidase-IV (DPP-IV) inhibitors (such as sitagliptin, vildagliptin, alogliptin, dugliptin, linagliptin, and saxagliptin); and (4) glucagon-like peptide-1 receptor (GLP-1R) agonists (such as liraglutide, abiglutide, exenatide, lixisenatide, dulaglutide, and smegliptin), which enhance insulin secretion by acting on pancreatic β-cells. Sulfonylureas and meglitinides have limited efficacy and tolerability, often leading to weight gain and hypoglycemia. DPP-IV inhibitors have limited efficacy. Commercially available GLP-1R agonists are peptide formulations administered subcutaneously. Liraglutide is also approved for the treatment of obesity.

[0006] Obesity is a prevalent chronic disease in modern society and is associated with a variety of medical problems, including hypertension, hypercholesterolemia, and coronary heart disease. It is also highly correlated with type 2 diabetes mellitus (T2DM) and insulin resistance, the latter often accompanied by hyperinsulinemia or hyperglycemia, or both. Furthermore, T2DM increases the risk of coronary artery disease by 2 to 4 times. Currently, the only highly effective treatment for eliminating obesity is bariatric surgery, but this method is costly and carries significant risks. Therefore, there is a clear need for more effective, less side-effect-prone, and conveniently administered drug interventions.

[0007] Although type 2 diabetes mellitus (T2DM) is primarily associated with hyperglycemia and insulin resistance, other diseases associated with T2DM include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and non-alcoholic fatty liver disease (NAFLD).

[0008] Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, a group of liver conditions including steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. NAFLD and NASH are considered primary fatty liver diseases because they account for the largest proportion of individuals with elevated liver lipids. The severity of NAFLD / NASH is based on the presence of lipids, inflammatory cell infiltration, hepatocellular ballooning degeneration, and the degree of fibrosis. Although not all individuals with steatosis will develop NASH, a significant proportion will.

[0009] Sodium-dependent glucose transporter 1 (SGLT1) is primarily expressed in the small intestine and is responsible for glucose absorption there. U.S. Patent Nos. 7,635,684 and 7,375,087 (which are incorporated herein by reference in their entirety) describe compounds that exhibit inhibitory activity against human SGLT1 in the small intestine for the prevention or treatment of diseases associated with hyperglycemia. U.S. Patent No. 9,200,025 (which is incorporated herein by reference in its entirety) describes selective inhibitors of SGLT1, as well as SGLT1 inhibitors with low systemic exposure that act locally in the intestine for the treatment or management of diseases and disorders, particularly cardiovascular and metabolic diseases and disorders.

[0010] GLP-1 is a 30-amino acid-long incretin hormone secreted by L cells in the gut in response to food intake. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, reduce glucagon secretion, inhibit gastric emptying, decrease appetite, and promote β-cell proliferation. In non-clinical studies, GLP-1 has promoted sustained β-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting β-cell regeneration (Meier et al. Biodrugs. 2003; 17(2): 93-102).

[0011] In healthy individuals, GLP-1 plays a crucial role in regulating postprandial blood glucose levels by stimulating the pancreas to secrete glucose-dependent insulin, leading to increased peripheral glucose uptake. GLP-1 also inhibits glucagon secretion, resulting in reduced hepatic glucose output. Furthermore, GLP-1 delays gastric emptying and slows small intestinal motility, thus delaying food absorption. In patients with TMD2, the normal postprandial GLP-1 elevation is absent or decreased (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).

[0012] Holst (Physiol.Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol.2012, 8, 728) described GLP-1 receptor agonists (e.g., GLP-1, liraglutide, and exenatide-4) as having three major pharmacological activities that improve glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing fasting and postprandial blood glucose (FPG and PPG): (i) increasing glucose-dependent insulin secretion (improving both phase I and phase II); (ii) glucagon-inhibiting activity under hyperglycemic conditions; and (iii) slowing gastric emptying rate, thereby reducing the absorption of meal-derived glucose. An easily implemented method for the prevention and / or treatment of cardiovascular metabolic and related diseases remains needed.

[0013] Glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory peptide) is one of two endogenous enterohepatic hormones. It is a 42-amino acid peptide hormone released from intestinal K cells after eating. GIP, along with other enterohepatic hormones (glucagon-like peptide-1 (GLP-1)), are hormones secreted by enteroendocrine cells and jointly mediate the enterohepatic effect, estimated to account for more than 70% of the total insulin response after oral glucose stimulation. Due to the enterohepatic effect, the GIP receptor has become a highly attractive drug target for the treatment of metabolic diseases such as obesity and diabetes using GIP receptor agonists. GIP itself has a short plasma half-life due to dipeptidyl peptidase-4 (DPP-IV)-mediated inactivation and poor physical stability due to its high tendency to form fibrils.

[0014] Dual GLP-1 and GIP-1 agonists: Ideal antidiabetic drugs should demonstrate proven efficacy in lowering elevated blood glucose levels, promoting weight loss, having a lower risk of hypoglycemia, and providing cardiovascular benefits. The idea of ​​simultaneously activating GIP and GLP-1 receptors appears attractive for treating type 2 diabetes mellitus (T2DM) because it may significantly enhance insulin secretion and improve insulin sensitivity. This is based on the fact that improved blood glucose restores sensitivity to GIP, and that peptide engineering can design hybrid ligands exhibiting dual agonist activity, as confirmed in experimental studies.

[0015] Tirzepatide, as the first dual receptor agonist of GIP and GLP-1, aligns with these principles. Its chemical formula is based on the GIP amino acid sequence, and its approximately 5-day half-life is suitable for once-weekly subcutaneous administration. Chemically, tirzepatide is a synthetic linear polypeptide based on the natural GIP sequence, containing 39 amino acids. This basic structure is accompanied by a 20-carbon fatty acid diacid moiety, which prolongs its half-life. Its mechanism of action is highly unbalanced, as it has a considerable affinity for the natural GIP receptor but a five-fold lower affinity for the natural GLP-1 receptor. Therefore, it is a dual receptor agonist, a product of the aforementioned peptide engineering techniques, created as a single agent active against more than one pharmacological target. Designed for once-weekly subcutaneous administration, early clinical studies of tirzepatide have demonstrated its excellent blood glucose-lowering and weight-loss effects in type 2 diabetes mellitus (T2DM). A Phase 1 proof-of-concept clinical trial was conducted in 53 patients with type 2 diabetes mellitus (T2DM), translating promising preclinical data into clinical reality. The compound demonstrated clinically meaningful improvements in glycemic control and weight, justifying further clinical evaluation for the treatment of T2DM and obesity. In a 26-week Phase 2b trial, approximately 30% of patients receiving the 15 mg dose achieved normal glycemic levels (HbA1C < 5.7%), and approximately 25% experienced a weight loss of ≥ 15%.

[0016] Compared to the GLP-1 agonist duraglutide, telpotetide reduced HbA1C by 1.6%, 2.0%, and 2.4% at 5 mg, 10 mg, and 15 mg doses, respectively, while the 1.5 mg dose of duraglutide reduced it by only 1.1%. Furthermore, 8% of patients receiving the 10 mg dose achieved normal glycemic levels (HbA1C < 5.7%), 30% of patients receiving the 15 mg dose achieved normal glycemic levels, compared to only 2% of subjects treated with duraglutide. Compared to duraglutide, the 5 mg and 10 mg doses of telpotetide provided superior glycemic and weight control with similar tolerability. These beneficial effects were confirmed in the SURPASS-1 study, the first randomized controlled phase 3 trial of telpotetide. The study participants had a mean diabetes duration of 4.7 years, a baseline A1C of 7.9%, and a baseline weight of 85.9 kg. Nearly 90% of all participants taking telpotetide achieved the target HbA1C >7%, and more than half of those taking the highest dose of the three doses also achieved HbA1C >5.7%, a level observable in non-diabetic individuals. No serious hypoglycemic events (<54 mg / dL) were observed. Regarding side effects, the most frequently reported were gastrointestinal-related reactions (diarrhea, nausea, vomiting, constipation), primarily occurring during dose escalation. Therefore, these results demonstrate a strong hypoglycemic effect close to the normal range, with a degree of weight loss previously not reported in patients with type 2 diabetes mellitus, and without increasing the clinical risk of significant hypoglycemia.

[0017] The recently published SURPASS-2 study compared the efficacy and safety of three doses of telposide with a 1 mg injectable dose of the GLP-1 agonist semaglutide in patients with type 2 diabetes mellitus (T2DM) who had not responded adequately to metformin monotherapy. This study was conducted in an open-label, 40-week phase 3 trial. Compared to semaglutide, all three doses of telposide achieved more significant reductions in A1C and weight loss. Furthermore, a composite endpoint was assessed, which included participants achieving an HbA1C level ≥6.5% and a weight loss of at least 10%. The proportion of patients achieving this composite endpoint was significantly higher in all three doses of telposide than in those receiving semaglutide, and the safety profile was satisfactory.

[0018] In recent years, with the rapid increase in the number of diabetic patients, progress has been made in the research and development of various antidiabetic drugs. For example, alpha-glucosidase inhibitors, which delay the digestion and absorption of carbohydrates in the small intestine, have been used to improve postprandial hyperglycemia. Acarbose, an alpha-glucosidase inhibitor, has also been reported to have the effect of preventing or delaying the onset of diabetes when administered to patients with impaired glucose tolerance. However, since alpha-glucosidase inhibitors do not affect the rise in blood glucose caused by the intake of glucose monosaccharides, and with recent changes in the composition of sugars in the diet, it is hoped that agents with a broader range of carbohydrate absorption-inhibiting activities can be developed.

[0019] Meanwhile, SGLT1 (sodium-dependent glucose transporter 1) is known to exist in the small intestine, which controls carbohydrate absorption. Inadequate glucose and galactose absorption has also been reported in patients with dysfunction due to congenital abnormalities of human SGLT1 (References 6-8 in '684). Furthermore, SGLT1 has been confirmed to be involved in glucose and galactose absorption (References 9 and 10 in '684).

[0020] Furthermore, it has been confirmed that increased mRNA and protein levels of SGLT1, along with accelerated glucose absorption, are observed in OLETF rats and streptozotocin-induced diabetic rats (References 11 and 12, '684). Typically, carbohydrate digestion and absorption are increased in diabetic patients. For example, significantly increased mRNA and protein levels of SGLT1 have been observed in the human small intestine (Reference 13, '684). Therefore, blocking human SGLT1 activity inhibits the absorption of carbohydrates (such as glucose) in the small intestine, subsequently preventing an increase in blood glucose levels. In particular, delaying glucose absorption based on the aforementioned mechanism is considered effective in reducing calorie intake. Moreover, since increased SGLT1 in the small intestine is thought to contribute to increased carbohydrate absorption, there is a desire to rapidly develop agents with potent inhibitory activity against human SGLT1 for the prevention or treatment of obesity.

[0021] Recent clinical trial results suggest that inhibiting SGLT1 provides benefits exceeding those offered by inhibiting glucose reabsorption alone. See, for example, U.S. Patent Application Publication No. US-2011-0218159. Inhibition of SGLT1 is thought to increase glucagon-like peptide-1 (GLP-1) levels. See, for example, Moriya, R., et al., Am J Physiol Endocrinol Metab297: E1358‐E1365 (2009). Several well-known diabetes medications, including sitagliptin, vildagliptin, and saxagliptin, work by inhibiting dipeptidyl peptidase IV (DPP-4), the enzyme responsible for degrading GLP-1. Summary of the Invention

[0022] This invention generally relates to methods and compositions for treating metabolic diseases. Specifically, the invention relates to a) sodium / glucose cotransporter 1 (SGLT1) inhibitors, and b) glucagon-like peptide agonist 1 (GLP-1), and / or c) gastric inhibitory peptide-1 (GIP-1) analogs, and / or d) combinations of GLP-1-GIP-1 dual agonists and methods for treating metabolic diseases.

[0023] In one aspect, the present invention relates to an oral dosage form composition comprising an SGLT1 inhibitor compound that inhibits SGLT1 in the intestinal lumen.

[0024] In another aspect, the present invention relates to methods for treating metabolic diseases, comprising the step of administering to a subject in need an oral dosage form of a composition comprising an SGLT1 inhibitor compound that inhibits SGLT1 in the intestinal lumen in combination with a GLP-1 agonist, a GIP-1 analog, or a GLP-1-GIP1 dual agonist. In some methods of the present invention, the metabolic disease is associated with obesity, abnormal accumulation of lipids in the liver, and / or hyperglycemia.

[0025] In another aspect, the present invention relates to the ability of GLP-1 and GIP-1 to slow gastric emptying. This effect reduces the concentration of SGLT1 inhibitors required to produce the reduced glucose absorption effect.

[0026] In another aspect, the present invention relates to the ability of SGLT1 inhibitors to reduce or block postprandial increases in GLP-1 and GIP-1, indicating that the addition of either or both of them does not cause adverse events. Attached Figure Description

[0027] Figures 1A and 1B show the effect of mizagliflozin on the body weight of healthy rats over a 2-year period.

[0028] Figures 2A and 2B show the effects of mitazaggliflozin (also known as KGA-3235) on GLP-1 and GIP-1 levels in patients with hypoglycemia after bariatric surgery. Detailed Implementation

[0029] This invention generally relates to methods and compositions for treating metabolic diseases. Specifically, the invention relates to combinations of a) SGLT1 inhibitors, b) GLP-1 agonists, and / or c) GIP-1 analogs, and / or d) dual GLP-1-GIP-1 agonists, and methods of using these combinations to treat metabolic diseases.

[0030] The compositions according to the invention are oral dosage forms administered to subjects in need, comprising: A) an SGLT1 inhibitor that inhibits SGLT1 in the intestinal lumen of the subject, B) a GLP-1 agonist, and / or C) a GIP-1 analog, and / or D) a GLP-1-GIP-I dual agonist.

[0031] The oral dosage form of the SGLT1 inhibitor of the present invention comprises an SGLT1 inhibitor compound of formula I or formula II and a pharmaceutically acceptable salt thereof; wherein, the compound of formula I is: Formula I; where R1 represents H, or optionally substituted C. 1-6 Alkyl; one of Q and T represents a group: or The other one indicates C. 1-6 Alkyl, halogenated (C 1-6 Alkyl), C 1-6 Alkoxy-substituted (C 1-6 alkyl) or C 3-7 Cycloalkyl; R2 represents hydrogen atom, halogen atom, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, Halogenated (C 1-6 Alkyl), halogenated (C) 1-6 alkoxy), C 1-6 Alkoxy-substituted (C 1-6 alkoxy), C 3-7 Cycloalkyl-substituted (C 2-6 alkoxy) or —A—R A Where A represents a single bond, oxygen atom, methylene, ethylene, -OCH2- or -CH2O-; R A Indicate C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, or heteroaryl, wherein the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups, halogenated (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), carboxyl, C 2-7 The group consisting of alkoxycarbonyl, cyano, and nitro groups, wherein the heteroaryl group may have substituents selected from halogen atoms and C. 1-6 The group consists of alkyl groups; X represents a single bond, oxygen atom, or sulfur atom; Y represents a C that can be substituted with a hydroxyl group. 1-6 Alkylene, or C 2-6 alkenylene; Z represents -RB -COR C -SO2R C -CON(R) D )R E -SO2NHR F or -C(═NR) G )N(R H )R I ;R C Indicates aryl, heteroaryl, or C 1-6 Alkyl group; the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, C atoms, etc. 1-6 alkylsulfonylamino, C 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C. 1-6 The group consisting of alkyl groups; the C 1-6 Alkyl groups may have 1 to 5 identical or different groups selected from the following substituent group (i); R4, R B R D R E and R F Whether they are the same or different, they each represent a hydrogen atom, aryl, heteroaryl, or C atom. 1-6 Alkyl group; the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, C atoms, etc. 1-6 alkylsulfonylamino, C 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C. 1-6 The group consisting of alkyl groups; the C 1-6 Alkyl groups may have 1 to 5 identical or different groups selected from the following substituent group (i); or, R4 and R B All combine with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents, wherein the substituents are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; or, R D and R E All combine with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6Cyclic amino groups may have substituents, wherein the substituents are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; R G R H and R I Whether they are the same or different, they represent hydrogen atom, cyano group, carbamoyl group, and C, respectively. 2-7 Acyl group, C 2-7 alkoxycarbonyl, aryl (C 2-7 alkoxycarbonyl), nitro, C 1-6 alkylsulfonyl, sulfonamide, carbamimidoyl group, or C 1-6 Alkyl, the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i); or, R G and R H Combine to form ethylene; or R H and R I All combine with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6 Cycloamino groups may have substituents, which are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consists of alkyl groups; R3, R5, and R6 may be the same or different, each representing a hydrogen atom, a halogen atom, and a carbon atom. 1-6 Alkyl or C 1-6 alkoxy groups; and substituent group (i) consists of: hydroxyl group; C 1-6 Alkoxy; C 1-6 Alkylthio; amino; mono- or di(C) 1-6 Alkyl)amino; mono- or di[hydroxy(C 1-6 [alkyl]amino; urea; sulfonamide; mono- or di(C) 1-6 Alkyl)urea; mono- or di(C) 1-6 alkyl)sulfonamide group; C 2-7 Acylamino; C 1-6 alkylsulfonylamino; C 1-6 Alkyl sulfonyl; carboxyl; C 2-7 Alkoxycarbonyl; -CON(R) J )R K , where RJ and R K Whether they are the same or different, they each represent a hydrogen atom or a carbon atom. 1-6 Alkyl, the C 1-6 Alkyl groups may have one to three identical or different substituents, wherein the substituents are selected from hydroxyl, amino, mono- or di-(C) groups. 1-6 Alkyl)amino, mono- or di-hydroxy(C) 1-6 [alkyl]amino, urea, mono- or di(C) 1-6 Alkyl) urea, C 2-7 Acylamino, C 1-6 The group consisting of alkylsulfonylamino and carbamoyl groups, or R J and R K It combines with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6 The cyclic amino group has substituents, said substituents being selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; aryl groups (C 1-6 alkoxy), the aryl (C 1-6 The alkoxy ring may have 1 to 3 identical or different substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; aryl (C 1-6 alkylthio), the aryl (C 1-6 The alkylthio group may have 1 to 3 identical or different substituents on its ring, wherein the substituents are selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; C 3-7 cycloalkyl; C 2-6 Heterocyclic alkyl; aryl, wherein the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C-type substituents. 1-6 alkylsulfonylamino, C 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; heteroaryl groups, which may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 The group consisting of alkyl groups; C 2-6 Cyclic amino, the C 2-6 Cycloamino groups may have substituents, which are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; and C 1-4 Aromatic cyclic amino, the C 1-4 Aromatic cyclic amino groups can have C 1-6 Alkyl groups are used as substituents; wherein, the compounds of formula II are: Formula II; wherein R7 is hydrogen or an optionally substituted C 1-10 Alkyl, C 1-5 Cycloalkyl or 5-membered heterocycle, wherein the optional substitution is by one or more R 7A Replace; each R 7A C is independently an amino, ester, amide, thiol, carboxylic acid, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 Cycloalkyl or 5-membered heterocycle, wherein the optional substitution is by one or more R 7B Replace; each R 7B Independently for C 1-4 Alkyl, halogen, or hydroxyl; n is 0, 1, or 2; each R8 is independently F or OR. 8A , where each R 8A Independently hydrogen, C 1-4 Alkyl or acyl; each R9 is independently halogenated, hydroxyl, or optionally substituted C. 1-10 Alkyl or C 1-10 alkoxy, wherein the optional substitution is by one or more R 9A Replace; each R 9A C is independently an amino, ester, amide, thiol, carboxylic acid, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 Cycloalkyl or 5-membered heterocycle, wherein the optional substitution is by one or more R 9B Replace; each R 9B Independently for C 1-4 Alkyl, amino, cyano, halogen, or hydroxyl; p is 0, 1, or 2; each R 10 Independently for R 10A -N(R) 10A (R10B), -OR 10A -SR 10A -S(O)R 10A or -S(O)2R 10A ;R 10A C is an optional replacement 4-20 Alkyl or 4-20 heteroalkyl, wherein the optional substitution is by one or more R 10C Instead, it is optionally connected to another R. 10ASome are provided as dimers or trimers; R 10B For hydrogen or R 10A ; Each R 10C Independently, it is an amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxyl, imide, imino, isothiocyanate, nitrile, nitroso, nitrosyl, nitoxy, oxo, sulfanyl, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thionyl, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3; wherein X1, X2, and X3 are each independently substituted C with optional substitution. 1-4 Alkyl, C 1-6 Cycloalkyl, 5- or 6-membered heterocyclic or aryl, wherein the optional substitution is by one or more R 10D Substitution; L1 and L2 are each independently optional C. 1-6 Alkyl or 1-10 heteroalkyl, wherein the optional substitution is by one or more R 10E Replace; each R 10D Independently for R 10E Or optionally by one or more R 10E Replacement C 1-6 Alkyl; each R 10E The group is independently amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxy, imide, imino, isothiocyanate, nitrile, nitro, nitroso, nitoxy, oxo, thio, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thionyl, or urea; m is 1, 2, or 3; wherein the main pharmacological site of action of the SGLT1 inhibitor compound is in the intestinal lumen of the subject.

[0032] Preferably, the SGLT1 inhibitor compounds of formula I and formula II are selected from the group consisting of: , , , and .

[0033] Another example of an SGLT1 inhibitor compound is KGA-2891: .

[0034] Preferably, the SGLT1 inhibitor compound is selected from LX2671 and midazaggliflozin. More preferably, the SGLT1 inhibitor is midazaggliflozin. Midazaggliflozin, namely 3-(3-{4-[3-(β-D-glucopyranoyl)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide, can be converted into a pharmaceutically acceptable salt according to methods known in the art. Examples of such salts include: acid addition salts formed with mineral acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; acid addition salts formed with organic acids, such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, etc.; salts formed with inorganic bases, such as sodium salts, potassium salts, etc.; and salts formed with organic bases, such as N-methyl-D-glucosamine, N,N'-dibenzylethylenediamine, 2-aminoethanol, tris(hydroxymethyl)aminomethane, arginine, lysine, etc.

[0035] Preferably, the pharmaceutical salt of mizaggliflozin is selected from mizaggliflozin monosaccharide and the dehydrated mizaggliflozin hemifumarate. The mizaggliflozin hemifumarate dihydrate of U.S. Patent No. 8,354,382 is shown below: .

[0036] The mirtazolidin monosaccharide in U.S. Patent No. 8,399,418 is shown below: .

[0037] Subjects with metabolic disorders typically exhibit abnormal physiological responses to ingested food after meals. In particular, insufficient insulin secretion is associated with the development of metabolic disorders such as type 2 diabetes. This weakened insulin response is caused by the absence of the "enteroglucagon effect," resulting in reduced gut-dependent secretion of intestinal glucagons (e.g., hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)). Therefore, modulating signaling pathways in the gastrointestinal tract presents a promising approach for treating metabolic disorders such as type 2 diabetes, obesity, and related comorbidities.

[0038] The invention described herein relates to a combination therapy for treating metabolic disorders (e.g., type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)) in individuals receiving gastrointestinal implant therapy. In one aspect, the invention is characterized by a method for treating metabolic disorders (e.g., type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)) in individuals receiving gastrointestinal implant therapy, wherein the method comprises administering a dose of one or more metabolic agents to the individual for a period of time to treat the metabolic disorder (e.g., type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)).

[0039] In some embodiments, an SGLT1 inhibitor is combined with an enterokinin modulator. In some embodiments, the enterokinin modulator may be a glucagon-like peptide-1 (GLP-1) receptor agonist. The GLP-1 receptor agonist may be liraglutide, exenatide, lixinatide, duraglutide, or abiglutide. Liraglutide may be administered in doses from 0.006 mg to 3 mg. Exenatide may be administered in doses from 0.05 μg to 10 μg. Lixinatide may be administered in doses from 0.1 μg to 20 μg. Duraglutide may be administered in doses from 0.0075 mg to 1.5 mg. Abiglutide may be administered in doses from 0.3 mg to 50 mg. In any of the foregoing embodiments, GLP-1 receptor agonist therapy is administered concurrently with the SGLT1 inhibitor, or separately within 24 hours.

[0040] In some embodiments, one or more metabolites may be administered via the enteral route, while the SGLT1 inhibitor may be administered orally. Alternatively, one or more metabolites may be administered via a parenteral route, while the SGLT1 inhibitor may be administered orally.

[0041] In some embodiments, one or more metabolizing agents may be administered once or more months, while the SGLT1 inhibitor is administered daily. In some embodiments, one or more metabolizing agents may be administered once or more weeks, while the SGLT1 inhibitor is administered daily. In some embodiments, one or more metabolizing agents may be administered once or more daily, and the SGLT1 inhibitor is also administered once or more daily.

[0042] As used herein, the terms "effective amount" or "therapeutic effective amount" are used interchangeably and refer to the amount of a pharmaceutical agent (e.g., a metabolite or microbiome modifier) ​​that allows it to partially or completely treat or prevent type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD), as described herein. Therefore, an effective amount of the agent can induce a decrease in blood glucose levels and / or weight loss. The effective amount will depend on a variety of factors, including biological activity, age, weight, sex, general health condition, severity of the condition being treated, and appropriate pharmacokinetic characteristics. Therapeutic effective amounts of the compositions of the present invention can be administered via a suitable route in a single dose or multiple doses. Furthermore, the dosage of the composition can be increased or decreased proportionally as needed for the treatment or prevention of an emergency.

[0043] As used herein, the term "intestinal glucagon" refers to compounds that directly or indirectly stimulate insulin release, inhibit glucagon release, and slow gastric emptying. For example, when plasma glucose levels rise relative to normal after a meal, intestinal glucagon stimulates an increase in the amount of insulin released by the pancreas, thereby lowering blood glucose levels. Specific examples of intestinal glucagons include gastric inhibitory peptides (i.e., glucose-dependent insulinotropic peptides, or GIPs) and glucagon-like peptide-1 (GLP-1), as well as their analogues and derivatives.

[0044] As used herein, the term “GLP-1 receptor agonist” or “GLP-1 agonist” refers to a substance (such as a polypeptide or small molecule) that activates a GLP-1 receptor (such as the human GLP-1 receptor). Examples include polypeptides that activate the human GLP-1 receptor (e.g., natural GLP-1 peptide hormones GLP-1(7-37), GLP-1(7-36)amide, oxyntomodulin, exendin-3, exendin-4, glucagon, gastric inhibitory peptide (GIP), and their functional peptide analogs and derivatives) and compounds with similar functions (e.g., exendin, liraglutide, lixisenatide, abiglutide, duraglutide, tasglutide, and smegglutide). As used herein, the term "dipeptidyl peptidase-4 inhibitor" refers to compounds that exhibit inhibitory activity against dipeptidyl peptidase IV (DPP-4), thereby acting as enhancers of intestinal hypoglycemic agents, including compounds such as sitagliptin, vildagliptin, saxagliptin, linagliptin, giglitazone, anagliptin, ticagliptin, alogliptin, treagliptin, dugliptin, eugliptin, berberine, and lupeol. Other metabolizing agents that may be used as part of this invention include metformin, sodium-glucose cotransporter 2 (SGLT-2) inhibitors (such as empagliflozin, canagliflozin, or dapagliflozin), sulfonylureas (such as glimepiride, glibenclamide, glipizide, glibenclamide, tolazoline, or tolbutamide), thiazolidinediones, and insulin.

[0045] GIP (glucose-dependent insulinotropic peptide) is a polypeptide composed of 42 amino acids. GIP(1-42) has physiological activity (active GIP). In a preferred embodiment of the invention, the SGLT1 inhibitor is micazagliptin sebacate, and the GIP receptor antagonist is GIP[3-30]NH2. Optionally, the method is combined with administration of a GLP-1 compound (smegglutinin).

[0046] In some methods of this invention, metabolic diseases are those associated with abnormal accumulation of lipids in the liver, and / or those associated with hyperglycemia. The term "disease associated with abnormal accumulation of lipids in the liver" refers to diseases with abnormal accumulation of lipids, including triglycerides, in the liver; diseases with an abnormal increase in the proportion of lipid content relative to healthy liver cells and liver weight; and diseases with an abnormal increase in liver size. It also includes progressive diseases with further increases in lipid accumulation. Furthermore, it includes diseases that develop into other diseases due to lipid accumulation, and diseases accompanied by inflammation. Specifically, in addition to common fatty liver, examples include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertrophic fatty liver, alcoholic fatty liver disease, toxic fatty liver, diabetic fatty liver, and acute fatty liver of pregnancy.

[0047] The term "diseases associated with hyperglycemia" includes diseases such as diabetes, impaired glucose tolerance, impaired fasting glucose, diabetic complications, obesity, hyperinsulinemia, hyperinsulinemic hypoglycemia, reactive hypoglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, and gout.

[0048] In some methods of the present invention, the metabolic disease is diabetes, or metabolic syndrome, or dumping syndrome, or hypoglycemia after bariatric surgery and / or non-alcoholic steatohepatitis and / or non-alcoholic fatty liver disease. According to the methods of the present invention, other metabolic diseases include insulin resistance, primary biliary cholangitis, primary sclerosing cholangitis, gallbladder disease, dyslipidemia, high cholesterol, high triglyceride levels, high blood pressure, hypertension, coronary artery disease, heart disease, stroke, thrombotic stroke, deep vein thrombosis (DVT), metabolic disorders, hypoalpha-lipoproteinemia, familial mixed hyperlipidemia, syndrome X, or insulin resistance syndrome X.

[0049] Example Example 1: Combination therapy of mizaggliflozin and remogliflozinNormal rats were treated with a combination of KGT-1681 and KGA-3235. KGT-1681 was suspended in 0.1% methylcellulose (MC), and KGA-3235 was dissolved in distilled water (DW). Nine-week-old rats were randomly assigned to four groups and treated as instructed: vehicle group (0.1% MC + DW); KGT group (KGT-1681 (3 mg / kg, 5 mL / kg) plus DW); KGA group (0.1% MC plus KGA-3235 (0.03 mg / kg, 5 mL / kg); and a combo group (KGT-1681 plus KGA-3235 (3 mg / kg and 0.03 mg / kg, respectively)). After a 16-hour fast, rats were orally administered the drugs and glucose solution (400 g / L, 5 mL / kg). At each sampling point, blood was collected from the tail vein and placed in heparinized and aprotinin-treated tubes. Plasma glucose concentration was determined using the Glucose CII-test Wako (Wako Pure Chemicals, Osaka, Japan). Plasma insulin was determined using an enzyme-linked immunosorbent assay kit (Morinaga Institute of Biological Science, Inc., Yokohama, Japan). The area under the curve (AUC) of plasma glucose and insulin was calculated from plasma glucose and insulin concentrations during the OGTT (Table 1).

[0050] Table 1

[0051] KGT-1681 and KGA-3235 inhibited the increase in plasma glucose after glucose loading. Furthermore, the combination therapy showed a stronger inhibitory effect on plasma glucose levels compared to either drug alone (Figure 1A). The AUC0-1h of plasma glucose is shown in Figure 1B. Two-way ANOVA showed that KGT-1681 and KGA-3235 had significant main effects on the AUC0-1h of plasma glucose (F(1,20)=15.66, P=0.0008; F(1,20)=16.23, P=0.0007, respectively). KGT-1681 and KGA-3235 reduced plasma insulin levels (Figure 2A), consistent with the decrease in plasma glucose levels. The AUC0-1h of plasma insulin is shown in Figure 2B.

Claims

1. A method for treating a metabolic disorder in a subject in need, the method comprising administering to the subject a sodium / glucose cotransporter 1 (SGLT1) inhibitor compound of formula I or II, or an effective amount of a pharmaceutically acceptable salt of an SGLT1 inhibitor compound of formula I or II, and a glucagon-like peptide agonist 1 (GLP1), a gastric inhibitory peptide-1 (GIP-1) analog, and / or d) a combination of GLP-1-GIP-1 dual agonists; wherein, The compound of formula I is: Formula I; where R1 represents H, or optionally substituted C. 1-6 Alkyl; one of Q and T represents a group: or The other one indicates C. 1-6 Alkyl, halogenated (C 1-6 Alkyl), C 1-6 Alkoxy-substituted (C 1-6 alkyl) or C 3-7 Cycloalkyl; R2 represents hydrogen atom, halogen atom, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, Halogenated (C 1-6 Alkyl), halogenated (C) 1-6 alkoxy), C 1-6 Alkoxy-substituted (C 1-6 alkoxy), C 3-7 Cycloalkyl-substituted (C 2-6 alkoxy) or -AR A Where A represents a single bond, oxygen atom, methylene, ethylene, -OCH2- or -CH2O-; R A Indicate C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, or heteroaryl; the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups, halogenated (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), carboxyl, C 2-7 The group consisting of alkoxycarbonyl, cyano, and nitro; the heteroaryl group may have substituents selected from halogen atoms and C. 1-6 The group consists of alkyl groups; X represents a single bond, oxygen atom, or sulfur atom; Y represents a C that can be substituted with a hydroxyl group. 1-6 Alkylene or C 2-6 Ideonyl substitution; Z represents -R B -COR C -SO2R C -CON(R) D )R E -SO2NHR F or -C(═NR) G )N(R H )R I ;R C Indicates aryl, heteroaryl, or C 1-6 Alkyl group; the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, C atoms, etc. 1-6 alkylsulfonylamino, C 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C. 1-6 The group consisting of alkyl groups; the C 1-6 Alkyl groups may have 1 to 5 identical or different groups selected from the following substituent group (i); R4, R B R D R E and R F Whether they are the same or different, they each represent a hydrogen atom, aryl, heteroaryl, or C atom. 1-6 Alkyl group; the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, C atoms, etc. 1-6 alkylsulfonylamino, C 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C. 1-6 The group consisting of alkyl groups; the C 1-6 Alkyl groups may have 1 to 5 identical or different groups selected from the following substituent group (i); or, R4 and R B All combine with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents, wherein the substituents are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; or, R D and R E All combine with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents, wherein the substituents are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; R G R H and R I Whether they are the same or different, they represent hydrogen atom, cyano group, carbamoyl group, and C, respectively. 2-7 Acyl group, C 2-7 alkoxycarbonyl, aryl (C 2-7 alkoxycarbonyl), nitro, C 1-6 alkylsulfonyl, sulfonamide, amidine or C 1-6 Alkyl, the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i); or, R G and R H Combine to form ethylene; or R H and R I All combine with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6 Cycloamino groups may have substituents, which are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consists of alkyl groups; R3, R5, and R6 may be the same or different, each representing a hydrogen atom, a halogen atom, and a carbon atom. 1-6 Alkyl or C 1-6 alkoxy groups; and substituent group (i) consists of the following: hydroxyl group; C 1-6 Alkoxy; C 1-6 Alkylthio; amino; mono- or di(C) 1-6 Alkyl)amino; mono- or di[hydroxy(C 1-6 [alkyl]amino; urea; sulfonamide; mono- or di(C) 1-6 Alkyl)urea; mono- or di(C) 1-6 alkyl)sulfonamide group; C 2-7 Acylamino; C 1-6 alkylsulfonylamino; C 1-6 Alkyl sulfonyl; carboxyl; C 2-7 Alkoxycarbonyl; -CON(R) J )R K , where R J and R K Whether they are the same or different, they each represent a hydrogen atom or a carbon atom. 1-6 Alkyl, the C 1-6 Alkyl groups may have one to three identical or different substituents, wherein the substituents are selected from hydroxyl, amino, mono- or di-(C) groups. 1-6 Alkyl)amino, mono- or di-hydroxy(C) 1-6 [alkyl]amino, urea, mono- or di(C) 1-6 Alkyl) urea, C 2-7 Acylamino, C 1-6 The group consisting of alkylsulfonylamino and carbamoyl groups, or R J and R K It combines with adjacent nitrogen atoms to form C 2-6 Cyclic amino, the C 2-6 The cyclic amino group has substituents, said substituents being selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; aryl groups (C 1-6 alkoxy), the aryl (C 1-6 The alkoxy ring may have 1 to 3 identical or different substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; aryl (C 1-6 alkylthio), the aryl (C 1-6 The alkylthio group may have 1 to 3 identical or different substituents on its ring, wherein the substituents are selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; C 3-7 cycloalkyl; C 2-6 Heterocyclic alkyl; aryl, wherein the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C-type substituents. 1-6 alkylsulfonylamino, C 1-6 Alkyl and C 1-6 The group consisting of alkoxy groups; heteroaryl groups, which may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 The group consisting of alkyl groups; C 2-6 Cyclic amino, the C 2-6 Cycloamino groups may have substituents, which are selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonylamino substituted (C 1-6 The group consisting of alkyl groups; and C 1-4 Aromatic cyclic amino, the C 1-4 Aromatic cyclic amino groups can have C 1-6 Alkyl groups are used as substituents; wherein, the compounds of formula II are: Formula II; wherein R7 is hydrogen or an optionally substituted C 1-10 Alkyl, C 1-5 Cycloalkyl or 5-membered heterocycle, wherein the optional substitution is by one or more R 7A Replace; each R 7A C is independently an amino, ester, amide, thiol, carboxylic acid, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 Cycloalkyl or 5-membered heterocycle, wherein the optional substitution is by one or more R 7B Replace; each R 7B Independently for C 1-4 Alkyl, halogen, or hydroxyl; n is 0, 1, or 2; each R8 is independently F or OR. 8A , where each R 8A Independently hydrogen, C 1-4 Alkyl or acyl; each R9 is independently halogenated, hydroxyl, or optionally substituted C. 1-10 Alkyl or C 1-10 alkoxy, wherein the optional substitution is by one or more R 9A Replace; each R 9A C is independently an amino, ester, amide, thiol, carboxylic acid, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 Cycloalkyl or 5-membered heterocycle, wherein the optional substitution is by one or more R 9B Replace; each R 9B Independently for C 1-4 Alkyl, amino, cyano, halogen, or hydroxyl; p is 0, 1, or 2; each R 10 Independently for R 10A -N(R) 10A (R10B), -OR 10A -SR 10A -S(O)R 10A or -S(O)2R 10A ;R 10A C is an optional replacement 4-20 Alkyl or 4-20 heteroalkyl, wherein the optional substitution is by one or more R 10C Instead, it is optionally connected to another R. 10A Some are provided as dimers or trimers; R 10B For hydrogen or R 10A ; Each R 10C Independently, it is an amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxyl, imide, imino, isothiocyanate, nitrile, nitro, nitroso, nitoxy, oxo, thio, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thionyl, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3; wherein X1, X2, and X3 are each independently substituted C with optional substitution. 1-4 Alkyl, C 1-6 Cycloalkyl, 5- or 6-membered heterocyclic or aryl, wherein the optional substitution is by one or more R 10D Substitution; L1 and L2 are each independently optional C. 1-6 Alkyl or 1-10 heteroalkyl, wherein the optional substitution is by one or more R 10E Replace; each R 10D Independently for R 10E Or optionally by one or more R 10E Replacement C 1-6 Alkyl; each R 10E The group is independently amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxy, imide, imino, isothiocyanate, nitrile, nitro, nitroso, nitoxy, oxo, thio, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thionyl, or urea; m is 1, 2, or 3; wherein the primary pharmacological site of action of the SGLT1 inhibitor compound is in the intestinal lumen of the subject.

2. The method for treating metabolic disorders according to claim 1, wherein, The dosage of the SGLT1 inhibitor is from 0.25 mg to 20 mg.

3. The method for treating metabolic disorders according to any one of claims 1-2, wherein, The SGLT1 inhibitor compounds are selected from the group consisting of: ， ， ， ， and 。 4. The method for treating metabolic disorders according to any one of claims 1-3, wherein, The SGLT1 inhibitor compound is selected from mezaggliflozin or LX2761.

5. The method for treating metabolic disorders according to claim 4, wherein, The SGLT1 inhibitor compound is midazaggliflozin.

6. The method for treating metabolic disorders according to claim 4, wherein, The SGLT1 inhibitor compound is LX2761.

7. The method for treating metabolic disorders according to claim 1, wherein, The pharmaceutical salts of the SGLT1 inhibitor compounds are selected from the monosaccharide and hemifumarate dehydrates of the compounds.

8. The method according to claim 1, wherein, The metabolic diseases mentioned are those associated with abnormal accumulation of lipids in the liver and / or those associated with hyperglycemia.

9. The method according to claim 1, wherein, The metabolic diseases mentioned are diabetes mellitus, metabolic syndrome, dumping syndrome, post-barbital hypoglycemia, non-alcoholic steatohepatitis, and / or non-alcoholic fatty liver disease.

10. The method according to claim 9, wherein, The metabolic diseases selected are those consisting of diabetes mellitus, elevated fasting blood glucose, insulin resistance, impaired glucose tolerance, primary biliary cholangitis, primary sclerosing cholangitis, gallbladder disease, dyslipidemia, gout, high cholesterol, high triglycerides, high blood pressure, hypertension, coronary artery disease, heart disease, stroke, thrombotic stroke, deep vein thrombosis (DVT), metabolic disorders, hypoalpha-lipoproteinemia, familial mixed hyperlipidemia, syndrome X, or insulin resistance syndrome X.

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