Compositions and methods for treating gastroparesis

Abstract

This disclosure relates to compositions and methods for treating gastroparesis using an effective amount of an SGLT1 inhibitor compound of Formula I or II, or a pharmaceutically acceptable salt thereof. The invention also encompasses the use of these compounds in treating related gastrointestinal disorders such as irritable bowel syndrome (IBS), non-ulcer dyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duotienogastric reflux, gastroesophageal reflux disease (GERD), ileus inflammation, and heartburn. The SGLT1 inhibitor compounds act primarily in the intestinal lumen and can be administered in various oral dosage forms, including coated capsules, coated tablets, liquids, powders, and orally disintegrating tablets, with dosages ranging from about 0.1 mg / day to about 60 mg / day.

Description

COMPOSITIONS AND METHODS FOR TREATING GASTROPARESISCross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 605,203, filed on December 1, 2023; the disclosure of which is incorporated herein by reference.Field of Invention

[0002] The invention relates to compositions and methods for treating and ameliorating gastroparesis.Background

[0003] A key function of the stomach is to produce acid and facilitate the peptic digestion of food. In addition to this, the main motor functions of the stomach are accommodation, which allows the delivery and storage of food, followed by trituration (grinding of food into fragments) and emptying of solid food. Gastroparesis is a chronic disorder that is characterized by delayed emptying of the stomach after eating (gastric emptying), in the absence of any mechanical obstruction, particularly pyloric stenosis (1). Cardinal symptoms include early satiety after eating, postprandial fullness, nausea, vomiting, belching and bloating. The syndrome is caused by neuromuscular dysfunction that leads to delayed gastric emptying. To elaborate, the basic mechanisms that lead to gastroparesis involve derangements in extrinsic neural control (particularly vagal function), dysfunction of the intrinsic nerves and interstitial cells involved in local control of gastrointestinal muscle function, and the loss of function of smooth muscles.

[0004] Gastroparesis can be idiopathic, associated with diabetes mellitus, can occur after a medical intervention (iatrogenic or post-surgical), may be associated with neurological disorders or may occur after a viral or bacterial infection, such as Salmonella gastroenteritis (2) . Interestingly, Helicobacter pylori infection does not seem to influence gastric emptying or accommodation but may be associated with heightened sensitivity in patients with functional dyspepsia (a disorder associated with accelerated or delayed gastric emptying, impaired gastric accommodation and heightened sensitivity in the upper gastrointestinal tract) (3,4). Rarely, specific viral infections caused by herpes virus or Epstein-Barr virus may be associated with acute dysautonomia that results in a generalized motility disorder including gastroparesis (5). In addition, many other conditions such as Parkinson's disease, collagen vascular diseases (such as systemic sclerosis), chronic intestinal pseudo-obstruction, and other conditions can lead to gastroparesis or delayed gastric emptying. All of these causes ultimately induce gastroparesis through induction of neuromuscular dysfunction.

[0005] In recent years, suggestions have been made to change the definition of gastroparesis to "gastroparesis and related disorders", therefore recognizing the disorder as part of a broader spectrum of gastric neuromuscular dysfunction (6). There is symptom overlap between gastroparesis and postprandial distress syndrome, which is one of the recognized types of functional dyspepsia (7).Functional dyspepsia may be associated with accelerated or delayed gastric emptying, impaired gastric accommodation and heightened sensitivity in the upper gut (8,9).

[0006] With the availability of measurements of gastric volume with scintigraphy, single photon emission computed tomography (SPECT), or MRI, disorders of gastric accommodation, which result typically from functional dyspepsia or prior gastric surgery (such as fundoplication or vagal injury or vagotomy) can be differentiated from gastroparesis.

[0007] The determinants of postprandial glycemia include pre-prandial glycemic levels, meal composition, gastric emptying, insulin secretion, small intestinal glucose absorption, and hepatic and peripheral glucose metabolism. Furthermore, the relative contribution of each of these factors may vary over time during the postprandial state. Nevertheless, both the rate of gastric emptying and the secretion and action of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), exert a major influence (10). The latter limit postprandial glycemia through their insulinotropic and, in the case of GLP-1, glucagonostatic actions. They account for the "incretin effect"-an augmentation of insulin secretion following oral or enteral glucose exposure when compared with an isoglycemic intravenous glucose infusion, which is diminished in type 2 diabetes (11). GIP and GLP-1 are released from entero-endocrine cells located most densely in the proximal small intestine and distal small intestine / colon, respectively, following nutrient exposure.

[0008] Each macronutrient has the capacity to stimulate GLP-1 and GIP release, although the mechanisms underlying secretion differ, and fat and carbohydrate may be more potent stimuli than protein (12). Carbohydrates, for example, stimulate incretin secretion through several interrelated mechanisms that are likely to include the sodium-glucose cotransporter-1 (SGLT-1) and intestinal "sweet taste" receptors (12). While GIP may be the most important incretin hormone in health, its capacity to stimulate insulin is markedly diminished in type 2 diabetes (12).

[0009] As well as being a determinant of glycemia, gastric emptying is itself modulated by acute changes in the blood glucose concentration (13, 14). While there is a lack of consensus in relation to the magnitude of the effect of acute hyperglycemia and the potential influence of chronic elevation of blood glucose, it is clear that marked acute hyperglycemia (i.e., blood glucose level; 15 mmol / L) delays gastric emptying substantially in both health and type 1 diabetes when compared with euglycemia (5 mmol / L). Emptying is slowed even at physiological degrees of hyperglycemia (8 mmol / L) (14) and is accelerated during insulin-induced hypoglycemia.

[0010] It is clear GLP-1 reduces gastric emptying (15-17) and GLP-1 agonists, such as semaglutide, also reduces gastric emptying (18). By contrast, in healthy subjects, exogenous GIP in pharmacological doses does not slow gastric emptying (19) and may accelerate it modestly (20).

[0011] Patients with idiopathic gastroparesis exhibit abnormal GIP levels associated with impaired insulin sensitivity during oral glucose load, suggesting a role of GIP in gastroparesis. Specifically fastingGIP concentration was significantly higher in the patient group (56.1 ± 5.8 pg / mL vs 29.9 ± 7.7 pg / mL, P=0.012). Postglucose load GIP concentrations were also significantly elevated in patients with gastroparesis, whereas GLP-1 concentrations during fasting and post-glucose load conditions were not different to those of healthy controls. Moreover, glucose tolerance during glucose load was abnormal in patients, combining hyperglycemic insulin resistance and hyperinsulinism patterns, while fasting values for glycemia, insulin sensitivity, and insulin concentrations were normal (21). So we conclude that patients with idiopathic gastroparesis exhibit abnormal GIP levels associated with impaired insulin sensitivity during oral glucose load. Further studies are needed to establish the involvement of these defects in the pathophysiology of gastroparesis.

[0012] Mizagliflozin has been shown to reduce postprandial circulating GIP in healthy volunteers, patients with T2DM and patients diagnosed with PBH. Mizagliflozin has also been shown to reduce postprandial hyperglycemia in healthy volunteers, patients with T2DM and patients diagnosed with PBH.

[0013] Furthermore, by inhibiting SGLT1 and reducing the absorption of glucose in the small intestine, mizagliflozin hydrates the Gl track and has been shown to be effective in increasing transit time and relieving chronic idiopathic constipation. Additionally, inhibition of SGLT1 would block the fooddependent increase in GIP.

[0014] Subtypes of SGLT include SGLT1, which is primarily expressed in the small intestine, and SGLT2, which is expressed in the renal proximal tubule. These are responsible for absorption of glucose in the small intestine and reabsorption of glucose in the proximal tubule. U.S. Patent No. 7,635,684, herein incorporated by reference in its entirety, describes compounds that show an inhibitory activity in human SGLT1 at the small intestine. U.S. Patent No. 9,200,025, herein incorporated by reference in its entirety, describes potent inhibitors of SGLT1, with particular inhibitors selective inhibitors for SGLT1, and particular inhibitors having low systemic exposure, and act locally in the gut. The disclosure of U.S. Patent No. 11,596,644 describes studies that demonstrate mizagliflozin's selectivity for SGLT1 over SGLT2 as assessed by cellular uptake of radiolabeled methyl-a -D-glucopyranoside (a-MG) in vitro.

[0015] Mizagliflozin, 3-(3-{4-[3-(P-D-glucopyranosyloxy)-5-isopropyl-lH-pyrazol-4-ylmethyl- ]-3- methylphenoxy}propylamino)-2,2-dimethylpropionamide, is a SGLT1 inhibitor created by Kissei Pharmaceutical Co., Ltd. No SGLT1 inhibitors have been approved to date. Mizagliflozin suppresses the secretion of gastrointestinal inhibitory peptide 1 (G I P-1), a known insulin secretagogue, from the digestive tract by selectively inhibiting SGLT1. Gastrointestinal symptoms are not readily likely if the amount of glucose that remains without being absorbed is small.

[0016] Since an increase of SGLT1 activity in the small intestine is thought to contribute to increased insulin secretagogue production, fast development of agents, which have a potent inhibitory activity in human SGLT1, has been desired for the prevention or treatment of diabetes. See, e.g., U.S. Patent No. 8,324,176. Crystalline compounds of mizagliflozin have been described for use of prevention ortreatment of a disease associated with hyperglycemia such as diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications or obesity, and a disease associated with the increase in blood galactose level such as galactosemia. U.S. Patent No. 8,399,418 describes the monosebacate salt of mizagliflozin, and U.S. Patent No. 8,354,382 describes the hemifumarate dehydrate salt of mizagliflozin. US Patent No. 11,596,644 describes the use of mizagliflozin to treat post-bariatric hypoglycemia.Summary of the Invention

[0017] Methods and compositions according to the principles and illustrative embodiments of the invention are used for the treatment of gastroparesis in subjects in need thereof.

[0018] According to one aspect of the invention, a method of treating gastroparesis in a subject, includes orally administering an effective amount of an 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, to the subject, wherein the compound of Formula I is:Formula I; whereinRi represents H, or an optionally substituted CI G alkyl group; one of Q and T represents a group:while the other represents a C; 6alkyl group, a halo(Ci.g alkyl) group, a CM alkoxy-substituted (CM alkyl) group or a C3.7 cycloalkyl group;R2represents a hydrogen atom,, a halogen atom., a hydroxy group, a Cwalkyl group, a CM alkoxy group, a C3.6alkylthio group, a halo(C-;.6alkyl) group, a halo(Ci-5alkoxy} group, a CM alkoxy-substituted (CM alkoxy) group, a C37 cycloaikyl-substituted (Cj s alkoxy) group or A RAin which A represents a single bond, an oxygen atom, a methylene group, an ethylene group, — OCHj— or —Cl-hO—; and RArepresents a C3.7 cycloa Iky! group, a C2.« heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a CM alkyl group, a CM alkoxy group, 3 CM alkenyloxy group, a haloJCi-s alkyl) group, 3 hydroxy(CM alkyl) group, a carboxy group, a C?.? alkoxycarbonyl group, a cyano group and a nitro group, or a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom and « CM alkyl group;X represents a single bond, an oxygen atom or a sulfur atom;Y represents a CM alkylene group which may be substituted by a hydroxy group or a CM alkenylene group:Z represents — RB, — CORc, — SO2RC, — CON(Rc)RE, — SO2NHRFor — C(=NRG)N(RH)R'; RCrepresents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a CM, alkylsulfonylamino group, a CM alkyl group and a CM alkoxy group, a heteroaryl group which may have a substituent selected from thegroup consisting of a haiogen atom, an amino group and a Ci-e alkyl group, or a Ci-e alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i);R4, RB, RD, REand RFare the same or different, and each represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-g alkylsulfonylamino group, a Ci-6 alkyl group and a Ci-s alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a Ci-6alkyl group, or a Ci-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of R4and RBbind together with the neighboring nitrogen atom to form a C2.6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-6alkyl group, an oxo group, a carbamoyl(Ci-6 alkyl) group, a hydroxy(Ci-6 alkyl) group and a Ci-e alkylsulfonylaminosubstituted (Ci-6 alkyl) group, or both of RDand REbind together with the neighboring nitrogen atom to form a C2.5cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-6alkyl group, an oxo group, a carbamoyl(Ci.6alkyl) group, a hydroxy(Ci-6alkyl) group and a Ci-6alkylsulfonylamino-substituted (Ci-6alkyl) group; RG, RHand R1are the same or different, and each represents a hydrogen atom, a cyano group, a carbamoyl group, a C2.7acyl group, a C2-7 alkoxycarbonyl group, an a ryl (C2.? alkoxycarbonyl) group, a nitro group, a Ci-e alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a Ci-e alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of RGand RHbind to form an ethylene group, or both of RHand R1bind together with the neighboring nitrogen atom to form a C2-e cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-e alkyl group, an oxo group, a carbamoyl(Ci-6 alkyl) group, a hydroxy(Ci-e alkyl) group and a Ci-6 alkylsulfonylamino-substituted (Ci-e alkyl) group;Rs, Rs and Rg are the same or different,, and each represents a hydrogen atom, a halogen atom, a Ci- s alkyl group or a Ci6alkoxy group; and substituent group (I) consists of a hydroxy group, a Cj.s alkoxy group, a Ci-s alkylthio group, an amino group, a mono or dii'Ci.g alkyl)amino group, a mono or di[hydroxy(C-:.6alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(Ci6a Ikyllu reido group, a mono or di(Ci-6alkyl)sulfamide group, a C2.7 acylamino group, a Ci.g alkylsulfonylamino group, a Cj g alkylsuifonyl group, a carboxy group, a Cj.7 alkoxycarbonyl group, — CON(R’)RKin which R‘ and Rl;are the same or different, and each represents a hydrogen atom or a Ci-6alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(Cisalkyl)amino group, a mono or di[hydroxy{C;,-G alkyljjamino group, an ureido group, a mono or di(C\.r, aikyijureido group, a C?.? acyiamino group, a Ci-5alkylsulfonylamino group and a carbamoyl group, or both of RJ and Rl< bind together with the neighboring nitrogen atom to form a C2g cyclic amino groupwhich may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Cj-6 a iky! group, an exo group, a carbamoylfC^, alkyl) group, a hydroxyalkyl) group and a CWiaikyisuifonylamino-substituted (Ci-6alkyl) group, an aryl(Ci.salkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Crs alkyl group and a Ci-e alkoxy group on the ring, an a ryl(C-;.r> alkylthio) group 'which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Cj,5alkyl group and a Cis alkoxy group on the ring, a C3 7cycloalkyl group, a Ca-s heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-t aikyisuifonyiamino group, a Cj6alkyl group and a Ci.&alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a Ci s alkyl group, a C3.6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-talkyl group, an oxo group, a carba moyl(C3-6 alkyl) group, a hydroxylCi s alkyl ) group and a Ci.« alkylsulfonylamino-substituted (Ci-e alkyl) group, and a Ci.< aromatic cyclic amino group which may have a Ci e alkyl group as a substituent; andFormula I I; whereinR,- is hydrogen or optionally substituted G-io-alkyl, Ci-s-cycloaikyi, or 5-membered heterocycle, which optional substitution is with one or more P.7A; each R7Ais Independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted Ci4-alkoxy, Cis-cycloaikyl, or 5- membered heterocycle, which optional substitution is with one or more R7B; each R7E!is independently Cj^-alkyl, halo, or hydroxyl; n is 0, 1, or 2; each R? is independently F or OR3A, wherein each R3Ais independently hydrogen, Ci.4-alkyl, or acyl; each R9is independently halo, hydroxyl, or optionally substituted Ci io-ulkyl or Ci io-alkoxy, which optional substitution is with one or more R9A; each R9Ais independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted Ci^-alkoxy, C:.5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R9B; each R9Bis independently C),4-alkyl, amino, cyano,, halo, or hydroxyl: p is 0, 1, or 2; each Rio is independently RIOA, . N(RIOA)(R1OB),- ••■■ORIOA, •■■• SRIOA, . S(0)RIOA, or . S(0 )2RIOA; RIOA is optionally substituted C^o-alkyl or 4-20-membered heteroalkyl, which: optional substitution is with one or more Rioc, and which is optionally attached to another Riaftmoiety to provide a dimer or trimer; RJOIS is hydrogen or RI0A; each Rioc is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, thiourea, urea, or X];Xi-i5-X?, or Xi-Li-X3-Lz-X3, wherein each of Xi, X.> and X3is independently optionally substituted Ci^-alkyl, Ci.6-cydoalkyl, 5- or 6-membered heterocycle, or aryl, which optional substitution is with one or more RiOn, and each of Li and L,;is independently optionally substituted Ci5-aikyi or 1-10-membered heteroalkyl, which optional substitution is with one or more of Rioc; each RJOD is independently RJOs or Ct-c-alkyl optionally substituted with one or more of Rx0E; each RJI3i: is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, or urea; and m is 1, 2 or 3; wherein the SGLT1 inhibitor compound has a primary site of pharmacological action in the intestinal lumen of the subject.

[0019] The method treats gastroparesis along with, but not limited to gastrointestinal disorders include for example, irritable bowel syndrome (IBS), non-ulcer dyspepsia, chronic intestinal pseudoobstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, gastroesophageal reflux disease (GERD), ileus inflammation (e.g., post-operative ileus), heartburn (high acidity in the Gl tract).

[0020] The method of the invention may administer various SGLT1 inhibitor compounds, including, but not limited to:

[0021] According to the invention, an SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, may be administered at a dosage amount of, but not limited to, about 0.1 mg / day to about 60 mg / day.

[0022] In yet another aspect of the invention, an SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered before a meal.Brief Description of the Drawings

[0023] FIG. 1 depicts GLP-1 and GIP levels measured in post-bariatric hypoglycemia patients after administration of a single oral dose of 2.5 mg, 5.0 mg, and 10 mg of mizagliflozin.Detailed Description

[0024] The invention relates to methods and compositions for the treatment of treats gastroparesis. In particular, methods of the invention relate to treating a subject with gastroparesis, comprising the step of orally administering a SGLT1 inhibitor compound of Formula I or II, or a pharmaceutically acceptable salt thereof, to said subject, wherein the compound of Formula I is:whereinRi represents H, or an optionally substituted Ci-6alkyl group; one of Q. and T represents a group:while the other represents a Ci-6 alkyl group, a halo(Ci-6 alkyl) group, a Ci-6 alkoxy-substituted (Ci-e alkyl) group or a C3-7 cycloalkyl group;R2represents a hydrogen atom, a halogen atom, a hydroxy group, a Ci.salkyl group, a Ci.salkoxy group, a Ci-e alkylthio group, a halo(Ci.salkyl) group, a halo(Ci.salkoxy) group, a Ci.Galkoxy-substituted (C1-6 alkoxy) group, a C3.7 cycloalkyl-substituted (C2.6alkoxy) group or — A— RAin which A represents a single bond, an oxygen atom, a methylene group, an ethylene group, — OCH2— or — CH2O— ; and RArepresents a C3.7 cycloalkyl group, a C2.Gheterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-6alkyl group, a Ci-6alkoxy group, a C2.6alkenyloxy group, a halo(Ci-6alkyl) group, a hydroxy(Ci-Galkyl) group, a carboxy group, a C2.7alkoxycarbonyl group, a cyano group and a nitro group, or a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom and a Ci-6 alkyl group;X represents a single bond, an oxygen atom or a sulfur atom;Y represents a Ci-6alkylene group which may be substituted by a hydroxy group or a C2.5alkenylene group;Z represents — RB, — CORc, — SO2RC, — CON(RD)RE, — SO2NHRFor — C(=N RG)N( RH)R'; RCrepresents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-s alkylsulfonylamino group, a Ci-e alkyl group and a Ci-Galkoxy group, a heteroaryl group which may have a substituent selected fromthe group consisting of a halogen atom, an amino group and a Ci-6alkyl group, or a Ci-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i); R4, RB, RD, REand RFare the same or different, and each represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-6 alkylsulfonylamino group, a Ci-6 alkyl group and a Ci-e alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a Ci-6alkyl group, or a Ci-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group ( i ), or both of R4and RBbind together with the neighboring nitrogen atom to form a C2.6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-5alkyl group, an oxo group, a carbamoyl(Ci-6 alkyl) group, a hydroxy(Ci-6 alkyl) group and a Ci-g alkylsulfonylamino-substituted (Ci-6 alkyl) group, or both of RDand REbind together with the neighboring nitrogen atom to form a C2.6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci.salkyl group, an oxo group, a carbamoyl(Ci-Galkyl) group, a hydroxy(Ci.salkyl) group and a Ci-6alkylsulfonylamino-substituted (Ci-6alkyl) group; RG, RHand R1are the same or different, and each represents a hydrogen atom, a cyano group, a carbamoyl group, a C2.7acyl group, a C2.7alkoxycarbonyl group, an aryl(C2.7alkoxycarbonyl) group, a nitro group, a Ci-e alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a Ci-e alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of RGand RHbind to form an ethylene group, or both of RHand R1bind together with the neighboring nitrogen atom to form a C2.Gcyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-6 alkyl group, an oxo group, a carbamoyl(Ci-6 alkyl) group, a hydroxy(Ci-6 alkyl) group and a Ci- e alkylsulfonylamino-substituted (Ci-s alkyl) group;Ra, Rs and Re are the same or different, and each represents a hydrogen atom, a halogen atom, a Ci-e alkyl group or a Ci-6alkoxy group; and substituent group (i) consists of a hydroxy group, a Ci-5alkoxy group, a Ci-6alkylthio group, an amino group, a mono or di(Ci-salkyl)amino group, a mono or di[hydroxy(Ci-salkyl)]amino group, an ureido group, a sulfamide group, a mono or di(Ci-6a lkyl)u reido group, a mono or di(Ci-5alkyl)sulfamide group, a C2.7acylamino group, a Ci-e alkylsulfonylamino group, a Ci-e alkylsulfonyl group, a carboxy group, a C2.7alkoxycarbonyl group, — CON(RJ)RKin which RJand RKare the same or different, and each represents a hydrogen atom or a Ci-6alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or d i (Ci_6alkyl)amino group, a mono or di[hydroxy(Ci-salkyl)]amino group, an ureido group, a mono or di(Ci-salkyl)ureido group, a C2.7acylamino group, a Ci-6alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind together with the neighboring nitrogen atom to form a C2.s cyclic amino groupwhich may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-6 alkyl group, an oxo group, a carbamoyl(Ci.6alkyl) group, a hydroxy(Ci.6alkyl) group and a Ci.salkylsulfonylamino-substituted (Ci-6alkyl) group, an a ryl(Ci-6alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-6 alkyl group and a Ci-6 alkoxy group on the ring, an aryl(Ci-6 alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-6alkyl group and a Ci-6alkoxy group on the ring, a C3-7 cycloalkyl group, a C2.sheterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-6 alkylsulfonylamino group, a Ci-6alkyl group and a Ci-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a Ci-6 alkyl group, a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-6alkyl group, an oxo group, a carbamoyl(Ci-6alkyl) group, a hydroxy(Ci-6alkyl) group and a Ci-6alkylsulfonylamino-substituted (Ci.Galkyl) group, and a C1.4 aromatic cyclic amino group which may have a Ci-Galkyl group as a substituent; and wherein the compound of Formula II is:whereinR7 is hydrogen or optionally substituted Ci-10-a Ikyl, Ci-s-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7A; each R7A is independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted Ci-4-alkoxy, Ci-s-cycloalkyl, or 5- membered heterocycle, which optional substitution is with one or more R7B; each R7Bis independently Ci-4-alkyl, halo, or hydroxyl; n is 0, 1, or 2; each Rs is independently F or ORSA, wherein each RSA is independently hydrogen, Ci-4-alkyl, or acyl; each Rg is independently halo, hydroxyl, or optionally substituted Ci-io-a Ikyl or Ci-io-alkoxy, which optional substitution is with one or more R9A; each R9Ais independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted Ci.4-alkoxy, Ci.g-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R9B; each R9Bis independently Ci-4-alkyl, amino, cyano, halo, or hydroxyl; p is 0, 1, or 2; each Rio is independently RIOA, — N(RIOA)(R10B), — ORIOA, — SRIOA, — S(0)RIOA, or — S(0)2RIOA; RIOA is optionally substituted C^o-alkyl or 4-20-membered heteroalkyl, which optional substitution is with one or more Rioc, and which is optionally attached to another RIOA moiety to provide a dimer or trimer; RIOBis hydrogen or RIOA; each Rioc is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, thiourea, urea, or Xi, Xi-Li-X2, or Xi-Li-X2-L2-X3, wherein each of Xi, X2and X3is independently optionally substituted Ci-4-alkyl, Ci-5-cycloalkyl, 5- or 6-membered heterocycle, or aryl, which optional substitution is with one or more Rioc, and each of Li and L2is independently optionally substituted Ci.6-a Ikyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of RIOE; each RIOD is independently RIOE or Ci-6-al kyl optionally substituted with one or more of RIOE; each RIOE is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, or urea; and m is 1, 2 or 3; and wherein the SGLT1 inhibitor compound inhibits SGLT1 in the intestinal lumen of the subject.

[0025] The SGLT1 inhibitor compounds of Formula I or Formula II administered in methods of the invention inhibit SGLT1 in the intestinal lumen of the subject. Accordingly, the SGLT1 inhibitor compounds of Formula I or Formula II are locally acting in the gut and have poor systemic exposure. Particular locally acting compounds have a maximum plasma concentration (Cmax) of less than 250, 100, 50, or 10 nM when orally administered at a dose of 10 mg / kg to a mouse, rat or human. Systemic exposure (e.g., Cmax) can be measured by methods well known in the art, including liquid chromatography mass spectrometry. For example, after oral administration of mizagliflozin at doses of 3, 10, and 30 mg / kg to fasted male rats, exposure of mizagliflozin, maximal observed concentration (Cmax) and the area under the plasma concentration versus time curve from time zero to last measurable concentration (AUCt) increased with dose, but not in a clear dose proportional manner. The oral bioavailability of mizagliflozin in the rat was very low (range 0.01 to 0.08%). The majority of mizagliflozin remains in the intestine after oral dosing and is excreted almost exclusively in the feces in rats (>97% of orally administered dose) and in non-human primates (>82% of orally administered dose).

[0026] "Pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing, Easton Pa.: 1990) and Remington: The Science and Practice of Pharmacy, 19th ed. (Mack Publishing, Easton Pa.: 1995).

[0027] Unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A "therapeutically effective amount" of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0028] The terms "treat," "treating," and "treatment" contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder, or retards or slows the progression of the disease or disorder.

[0029] The term "subject" refers to a human or animal in need of treatment for gastroparesis or related conditions. This includes human or animals diagnosed with gastroparesis or gastrointestinal disorders including but not limited to irritable bowel syndrome (IBS), non-ulcer dyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, gastroesophageal reflux disease (GERD), ileus inflammation (e.g., post-operative ileus), heartburn (high acidity in the Gl tract).

[0030] It should also be noted that if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it. Moreover, any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences. In addition, chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit.

[0031] In certain embodiments, this invention relates to treating gastroparesis along with, but not limited to gastrointestinal disorders include for example, irritable bowel syndrome (IBS), non-ulcerdyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, gastroesophageal reflux disease (GERD), ileus inflammation (e.g., post-operative ileus), heartburn (high acidity in the Gl tract).

[0032] For the methods of the invention, SGLT1 inhibitors of Formula I and Formula II can be prepared by methods known in the art. See, e.g., U.S. Patent No. 7,635,684, and U.S. Patent No. 9,200,025.

[0033] In a preferred method of the invention, SGLT1 inhibitors of Formula I and Formula II are selected from the group consisting of:

[0034] In some preferred methods of the invention, the SGLT1 inhibitor is selected from LX2671 and mizagliflozin. In an even more preferred method of the invention, the SGLT1 inhibitor is mizagliflozin. Mizagliflozin, 3-(3-{4-[3-(P-D-glucopyranosyloxy)-5-isopropyl-lH-pyrazol-4-yl methyl- ]-3- methylphenoxy}propylamino)-2,2-dimethylpropionamide, can be converted to a pharmaceutically acceptable salt according to methods known in the art. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, acid addition salts 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 and the like, salts with inorganic bases such as a sodium salt, a potassium salt and the like, and salts with organic bases such as N-methyl-D-glucamine, N,N'- dibenzyletylenediamine, 2-aminoethanol, tris (hydroxymethyl)aminomethane, arginine, lysine and the like.

[0035] In some methods of the invention where mizagliflozin is administered, the pharmaceutical salt is selected from mizagliflozin monosebacate and mizagliflozin hemifumarate dehydrate. Mizagliflozin hemifumarate dihydrate, from U.S. Patent No. 8,354,382, is shown below:

[0036] Mizagliflozin monosebacate, from U.S. Patent No. 8,399,418, is shown below:

[0037] In a method of the invention, the SGLT inhibitor compound of Formula I or Formula II is administered at a dosage of from about 0.1 mg / day to about 160 mg / day. For example the dosage is 0.1 mg / day, 0.2 mg / day, 0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, or 160 mg / day. Preferably , the dosage is from about 1 mg / day to about 60 mg / day. For example, the dosage is 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 24 mg / day, 27 mg / day, 30 mg / day, 33 mg / day, 36 mg / day, 39 mg / day, 42 mg / day, 45 mg / day, 48 mg / day, 51 mg / day, 54 mg / day, 57 mg / day, or 60 mg / day. In some methods of the invention the SGLT inhibitor compound of Formula I or Formula II is administered as a pharmaceutically acceptable salt thereof. In such methods, the daily dose refers to the mg / day of the compound. A therapeutically effective amount for administration is determined by a treating physician.

[0038] The daily dose can be divided into one or more, for example, two-, three-, or four-unit doses administered per day. A unit dose is the amount of compound administered at one time. In a preferred method of the invention, SGLT inhibitor compound of Formula I or Formula II is administered at a unit dose of from about 0.1 mg to about 20 mg, three times a day. For example, the dosage is 0.1 mg, three times a day; 0.2 mg, three times a day; 0.5 mg, three times a day; 1 mg, three times a day; 2 mg, three times a day; 3 mg, three times a day; 4 mg, three times a day; 5 mg, three times a day; 6 mg, three times a day; 7 mg, three times a day; 8 mg, three times a day; 9 mg, three times a day; 10 mg, three times a day; 11 mg, three times a day; 12 mg, three times a day; 13 mg, three times a day; 14 mg, three times a day; 15 mg, three times a day; 16 mg, three times a day; 17 mg, three times a day; 18 mg, three times a day; 19 mg, three times a day; or 20 mg, three times a day. In some methods of the invention the SGLT inhibitor compound of Formula I or Formula II is administered as a pharmaceutically acceptable salt thereof. In such methods, the unit dose refers to the mg of the compound.

[0039] In a preferred method of the invention, the SGLT inhibitor compound of Formula I or Formula II, or pharmaceutically acceptable salt thereof, is administered before a meal. For example, the SGLT inhibitor compound of Formula I or Formula II, or pharmaceutically acceptable salt thereof, is administered once before breakfast, once before lunch, and once before dinner, daily.

[0040] In methods according to the invention pharmaceutical compositions of SGLT1 inhibitor compounds of Formula I or Formula II, or pharmaceutically acceptable salt thereof, are employed using various dosage forms depending on their uses. Examples of orally administered dosage forms include powders, granules, fine granules, dry syrups, tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, uncoated tablets, enteric coated tablets, capsules and the like. Enteric-coated tablets are compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered, press-coated, and dry-coated tablets. Tablets may also be coated using microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. The pharmaceutical compositions of SGLT1 inhibitor compounds of Formula I or Formula II also include sustained release formulation including gastrointestinal mucoadhesive formulation (e.g., International publications Nos. W099 / 10010, WO99 / 26606, and Japanese patent publication No. 2001-2567).

[0041] The pharmaceutical compositions can be prepared by admixing with or by diluting and dissolving with an appropriate pharmaceutical additive such as excipients, disintegrators, binders, fillers, lubricants, diluents, buffers, isotonicities, antiseptics, moistening agents, emulsifiers, dispersing agents, stabilizing agents, dissolving aids and the like, and formulating the mixture in accordance with conventional methods. In case of the uses of the compound of SGLT1 inhibitor compounds of Formula I or Formula II in combination with the drug(s) other than SGLT1 inhibitors, they can be prepared by formulating each active ingredient together or individually.

[0042] Some compositions of the invention are formulated as oral dosage forms. For example, an oral dosage form of the invention may be a tablet that contains a dosage amount of mizagliflozin of 2.5 mg, 5 mg and 10 mg. A tablet of the invention, in one embodiment is a white to slightly yellowish white film- coated tablets with an oval shape of 8 mmx4.5 mm. Qualitative compositions of tablet excipients, in certain embodiments, may contain one or more of the excipients shown in Table 1. Tablets of the invention are typically stored in a tight sealed container closure system.Table 1

[0043] In some embodiments of the invention, the oral dosage form of mizagliflozin is a capsule.Table 2 shows exemplary capsule compositions.Table 2

[0044] In some methods of the invention, the SGLT1 inhibitor compound of Formula I or Formula II, or pharmaceutically acceptable salt thereof, is administered in combination with at least one glucagon-like peptide (GLP)-l receptor antagonist. Preferably, the GLP-1 receptor antagonist is the peptide fragment of Exenatide, exendin 9-39. In the methods of the invention where the SGLT1 inhibitor compound of Formula I or Formula II, or pharmaceutically acceptable salt thereof, is administered in combination with such drugs, the dosage of the SGLT1 inhibitor compound of Formula I or Formula II can be decreased, depending on the dosage of the GLP-1 receptor antagonist.Examples

[0045] Example 1: Single dose study in humans

[0046] A single oral dose of 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg of mizagliflozin were administered to healthy adult male volunteers by a placebo-controlled, randomized, double-blind method. The single dose was administered orally immediately before breakfast with approximately 200 mL of water after fasting for at least 10 hours. Pharmacodynamic effect parameters (blood glucose level, insulin, GLP 1, and gastric inhibitory polypeptide (GIP)) were measured, as indicated in Tables 3-6, respectively. Concentrations at each time point were measured, and summary statistics and coefficient variation ( CV) were calculated for AUCO-t; t was up to 6 hours post dose. The time points were before administration and at 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours after administration. Blood glucose level and insulin were measured to evaluate, in an exploratory manner, the inhibitory effect on postprandial hyperglycemia. GLP-1 and GIP were measured to evaluate, in an exploratory manner, incretin secretory action.Table 3Table 4Table 5

[0047] Concerning the effect of mizagliflozin administration on the secretory action of incretin, suppression of GIP secretion was suggested (Table 6). AUC for GIP was lower in each mizagliflozin group, which indicated elevation of GIP secretion was suppressed. GIP concentrations peaked more than 3h after treatment. No clear conclusion could be reached regarding the effect on GLP-1 (Table 5).Table 6

[0048] Example 2: Repeat dose study in humansOral doses of 2 mg, 5 mg, 10 mg, 20 mg, of mizagliflozin, placebo or miglitol 50 mg per dose three times daily to healthy adult male volunteers by a randomized, placebo-controlled, parallel-group, double-blind comparison method. The dose was orally administered with approximately 150 mL of water once daily immediately before breakfast on Days 1 and 13, and three times daily immediately before every meal on Days 3 to 12.

[0049] Changes in the following parameters and AAUC from 0 to t* hours after breakfast, lunch, and evening meal were measured: Blood glucose level, Serum insulin concentration, Blood active GLP-1 concentration, and Blood total GIP concentration, where t = 0.5, 1, 1.5, 2, and 3 (t = 0.5, 1, 1.5, 2, 3, and 5 only after breakfast), as indicated in Tabled 7, 8, 9, and 10, respectively.

[0050] In the miglitol group, hyperglycemia was suppressed after breakfast, lunch, and evening meal, as compared to the placebo group. In addition, inhibition of insulin secretion along with inhibition of hyperglycemia, an increase in total GLP-1 concentration, a tendency toward increase in active GLP-1 concentration, and inhibition of increase in total GIP concentration were seen. In the mizagliflozin group, hyperglycemia was suppressed after breakfast, lunch, and evening meal on a level equivalent to the miglitol group. In the mizagliflozin group, inhibition of insulin secretion along with inhibition of hyperglycemia was seen the same as in the miglitol group. In the mizagliflozin group, increase in total GLP-1 concentration was seen on a level equivalent to the miglitol group. In the mizagliflozin group, a tendency toward increase in active GLP-1 concentration was seen as in the case of the miglitol group. In the mizagliflozin group, decrease in total GIP concentration was seen on a level equivalent to the miglitol group. These pharmacodynamic effects more or less persisted during 10-day repeated administration. There was no correlation between plasma mizagliflozin concentration and the pharmacodynamic effects. Measurements in Tables 7-10 were performed on Day 3 after breakfast.Table 7Table 8Table 9Table 10

[0051] Example 3: Single dose study in post-bariatric hypoglycemia patientsA single oral dose of 2.5 mg, 5.0 mg, and 10 mg of mizagliflozin were administered to post-bariatric hypoglycemia patients by a randomized open label method. The single dose was administered orally approximately 20 minutes before a mixed meal tolerance test (MMTT) with approximately 50 mL of water after fasting for at least 8 hours. Pharmacodynamic effect parameters (blood glucose level, insulin, GLP-1, and GIP) were measured. Concentrations at each time point were measured, and summary statistics and coefficient variation (CV) were calculated for AUCO-t; t was up to 6 hours postdose. The time points were: before administration and 5, 10, 20, 40, 60, 80, 100, 120, 150, 180, 240, and 360 minutes after MMTT initiation. Blood glucose level and insulin were measured to evaluate in anexploratory manner the inhibitory effect on postprandial hyperglycemia. GLP-1 and GIP were measured to evaluate in an exploratory manner the incretin secretory action. See Tables 11 and 12 and FIG. 1.Table 11*N.S.Table 12* Peak GIP (0-3 h) post-meal challenge was reduced in all doses examined** For the All Capsules, performing an exact non-parametric test resulted in a p-value = 0.0476References(1) Camilleri M, Parkman HP, Shafi MA, Abell TL, & Gerson L. American College of Gastroenterology clinical guideline: management of gastroparesis. Am. J. Gastroenterol. 108, 18-37 (2013).(2) Mearin F, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 129, 98-104 (2005).(3) Thumshirn M et al. Gastric accommodation in non-ulcer dyspepsia and the roles of Helicobacter pylori infection and vagal function. Gut 44, 55-64 (1999).(4) Tack J et al. Clinical and pathophysiological characteristics of acute-onset functional dyspepsia. Gastroenterology 122, 1738-1747 (2002).(5) Vassallo M, Camilleri M, Caron BL, & Low PA. Gastrointestinal motor dysfunction in acquired selective cholinergic dysautonomia associated with infectious mononucleosis. Gastroenterology 100, 252-258 (1991).(6) Pasricha PJ & Parkman HP. Gastroparesis: definitions and diagnosis. Gastroenterol. Clin. N. Am. 44, 1-7 (2015).(7) Enck P et al. Functional dyspepsia. Nat. Rev. Dis. Primers 3, 17081 (2017).(8) Park SY et al. Gastric motor dysfunction in patients with functional gastroduodenal symptoms. Am. J. Gastroenterol. 112, 1689-1699 (2017).(9) Sta nghell in i V et al. Gastroduodenal disorders. Gastroenterology 150, 1380-1392 (2016).(10) Chang J, Rayner CK, Jones KL, Horowitz M. Diabetic gastroparesis and its impact on glycemia. Endocrinol Metab Clin North Am 2010;39:745-762(11) Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368:1696-1705.(12) Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007;132: 2131-2157.(13) Chang J, Rayner CK, Jones KL, Horowitz M. Diabetic gastroparesis and its impact on glycemia. Endocrinol Metab Clin North Am 2010;39:745-762.(14) Rayner CK, Samsom M, Jones KL, Horowitz M. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 2001;24:371-381.(15) Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273:E981- E988.(16) Meier JJ, Gallwitz B, Salmen 5, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagonlike peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab 2003;88: 2719-2725.(17) Little TJ, Pilichiewicz AN, Russo A, et al. Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses. J Clin Endocrinol Metab 2006;91:1916-1923(18) Dahl K, Brooks A, Almazedi F, Hoff ST, Boschini C, Baekdal TA. Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes. Diabetes Obes Metab. 2021 Ju l;23(7) : 1594-1603.(19) Meier JJ, Goetze O, Anstipp J, et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol Endocrinol Metab 2004;286: E621-E625(20) Edholm T, Degerblad M, Gryback P, Hilsted L, Holst JJ, Jacobsson H, et al. Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis. Neurogastroenterol Motil. 2010;22:1191-1200, e315.(21) Prevost G, Ducrotte P, Cailleux A, Khalfi K, Basuyau JP, Lefebvre H, Kuhn JM. Glucose-induced incretin hormone release and insulin sensitivity are impaired in patients with idiopathic gastroparesis: results from a pilot descriptive study. Neurogastroenterol Motil. 2013 Aug;25(8):694-9.

Claims

Claims:

1. A method of treating glucose-dependent insulinotropic peptide (GlP)-dependent Cushing's Syndrome in a subject, comprising orally administering an effective amount of an SGLT1 inhibitor compound of Formula I or II, or orally administering an effective amount of a pharmaceutically acceptable salt of an SGLT1 inhibitor compound of Formula I or II, to the subject, wherein the compound of Formula I is:Formula I; whereinRi is H, or an optionally substituted C1-6 alkyl group; one of Q. and T is a group:and the other of Q or T is a Ci-6alkyl group, a halo(Ci-6alkyl) group, a Ci-6alkoxy-substituted ( Ci-Salkyl) group or a C3.7cycloalkyl group;R2is a hydrogen atom, a halogen atom, a hydroxy group, a Ci-6alkyl group, a Ci-6alkoxy group, a Ci-6alkylthio group, a halo(Ci-5alkyl) group, a halo(Ci-6alkoxy) group, a Ci-6alkoxy-substituted (Ci-6alkoxy) group, a C3.7 cycloalkyl-substituted (C2-6 alkoxy) group, or — A— RA, wherein A is a single bond, an oxygen atom, a methylene group, an ethylene group, — OCH2— , or — CH2O— , andRAis a C3-7 cycloalkyl group, a C2.sheterocycloalkyl group, an aryl group, wherein the aryl group has the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-6alkyl group, a Ci-6alkoxy group, a C2-6 alkenyloxy group, a halo(Ci-6 alkyl) group, a hydroxy(Ci-6 alkyl) group, a carboxy group, a C2-7alkoxycarbonyl group, a cyano group, and a nitro group, or a heteroaryl group, wherein the heteroaryl group has a substituent selected from the group consisting of a halogen atom and a Ci-6alkyl group;X is a single bond, an oxygen atom, or a sulfur atom;Y is a Ci-6 alkylene group which may be substituted by a hydroxy group or a C2-6 alkenylene group;Z is — RB, — CORC, — SO2RC, — CON(RD) RE, — SO2N H RF, or — C(=NRG)N (RH)R', wherein Rcis an aryl group, wherein the aryl group can have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci e alkylsulfonylamino group, a Ci-e alkyl group, and a Ci-6 alkoxy group, a heteroaryl group, wherein the heteroaryl group can have a substituent selected from the group consisting of a halogen atom, an amino group, and a Ci.6alkyl group, or a Ci-6 alkyl group, wherein the Ci-6alkyl group can have the same or different 1 to 5 groups selected from substituent group (i), wherein substituent group (i) consists of a hydroxy group, a Ci-5alkoxy group, a Ci-6alkylthio group, an amino group, a mono or d i(Ci-6 alkyl)amino group, a mono or di[hydroxy(Ci-6alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(Ci-6a Ikyl) ureido group, a mono or d i(Ci-6a lkyl)sulfam ide group, a C2-7acylamino group, a Ci-6 alkylsulfonylamino group, a Ci-6alkylsulfonyl group, a carboxy group, a C2-7 alkoxycarbonyl group, — CON(RJ)RK, wherein RJand RKare the same or different, and each of RJand RKrepresent a hydrogen atom or a Ci-6alkyl group,wherein the Ci.6alkyl group can have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(Ci-6alkyljamino group, a mono or di[hydroxy(Ci-Galkyl)]amino group, an ureido group, a mono or di(Ci-6alkyljureido group, a C2-7 acylamino group, a Ci-Galkylsulfonylamino group, and a carbamoyl group, or wherein both of RJand RKbind together with the neighboring nitrogen atom to form a C2-Gcyclic amino group, wherein the C2-Gcyclic amino group can have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-5alkyl group, an oxo group, a carbamoyl(Ci.Galkyl) group, a hydroxy(Ci-6 alkyl) group, and a Ci.Galkylsulfonylamino-substituted (Ci-6alkyl) group, an a ryl(Ci-6alkoxy) group, wherein the a ryl (Ci.Galkoxy) group can have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-5alkyl group, and a Ci-6alkoxy group on the ring, an aryl(Ci-6 alkylthio) group, wherein the aryl(Ci-6 alkylthio) group can have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-Galkyl group, and a Ci-Galkoxy group on the ring, a C3-7 cycloalkyl group, a C2-6 heterocycloalkyl group, an aryl group, wherein the aryl group can have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a Ci-Galkylsulfonylamino group, a Ci-Galkyl group and a Ci-6 alkoxy group, a heteroaryl group, wherein the heteroaryl group can have a substituent selected from the group consisting of a halogen atom, an amino group and a Ci-6alkyl group, a C2-6 cyclic amino group, wherein the C2-6cyclic amino group can have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-6alkyl group, an oxo group, a carbamoyl(Ci-6alkyl) group, a hydroxy(Ci.Galkyl) group, a Ci.Galkylsulfonylamino-substituted (Ci-Galkyl) group, and a Ci-4 aromatic cyclic amino group,wherein the C1.4 aromatic cyclic amino group can have a Ci-6alkyl group as a substituent,R4, Rs, R~, R\ and R? are the same or different, end each is a hydrogen atom, an aryl group, wherein the aryl group can have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group,, an amino group, a Cv6aikylsulfonylarnino group, a Ci 6 alkyl group, and a G g alkoxy group, a heteroaryi group, wherein the heteroaryl group can have a substituent selected from the group consisting of a halogen atom, an amino group, and a C3.r, alkyl group, a Ci-6 alkyl group, wherein the Ci-« alkyl group can have the same or different 1 to 5 groups selected from substituent group (I), or both of R4and RBbind together with the neighboring nitrogen atom to form a C2.£;cyclic amino group, wherein the C2 6cyclic amino group can have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci.6alkyl group, ari oxo group, a carbamoylfCi-g alkyl; group, a hydroxy(C3.<5 alkyl) group, and a Cj,5alkylsuifonyiamino-substituted (C;.r, alkyl) group, or both of RDand R!;bind together with the neighboring nitrogen atom to form a C2e cyclic amino group, wherein the C2-6 cyclic amino group can have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a CM alkyl group, an oxo group, a carbamoyi(Ci-f, alkyl; group, a hydroxy(Ci-6 alkyl) group, and s Ci-s alkylsuifonylamino-substituted (Ci-s alkyl) group;R,J, RHand R.' are the same or different, and each is a hydrogen atom, a cyano group, a carbamoyl group, a C?-7 acyl group, a C2-7 alkoxycarbonyl group, an aryltC?.? alkoxycarbonyl) group, a nitro group, a CH alkylsulfonyl group, a sulfamide group, a carbarn imidoyl group, or a C2.s alkyl group, wherein the Ci-a alkyl group can have the same or different 1 to 5 groups selected from the following substituent group (I), or both of Rband RHbind to form an ethylene group, or both of RHand R1bind together with the neighboring nitrogen atom to form a C2.(;cyclic amino, wherein the C2 5cyclic amino group can have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a Ci-e alkyl group, ari oxo group, 3 C3rbamoyl(Ci.g alkyl; group, a hyciroxyfCi-r, alkyl) group, and a (b-s alkylsuifonylamino-substitutedalkyl) group;R3, Rs and R6are the same or different, and each is a hydrogen atom, a halogen atom, a Ci6alkyl group or a Ci-6 alkoxy group; and wherein the compound of Formula II is:whereinR7is hydrogen, an optionally substituted Ci-io alkyl, an optionally substituted C1.5 cycloalkyl, or an optionally substituted 5-membered heterocycle, wherein each optional substitution of the C1-10 alkyl, C15 cycloalkyl, and 5-membered heterocycle is with one or more R7A, wherein each R7Ais independently selected from amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, optionally substituted Ci-4-alkoxy, optionally substituted C1.5 cycloalkyl, and optionally substituted 5-membered heterocycle, wherein each optional substitution of R7Ais with one or more R7B, wherein each R7Bis independently Ci 4-alkyl, halogen, or hydroxyl; n is 0, 1, or 2; each Rs is independently F or ORsA, wherein each RsAis independently hydrogen, Ci-4-alkyl, or acyl; each Rg is independently a halogen, a hydroxyl, an optionally substituted Ci-10-al kyl, or an optionally substituted Ci-io-alkoxy, wherein each optional substitution of Ci-10-a Ikyl or Ci-10-alkoxy is with one or more RgA, wherein each RgAis independently amino, ester, amide, thiol, carboxylic acid, cyano, halogen, hydroxyl, optionally substituted Ci-4-alkoxy, optionally substituted Ci-5-cycloalkyl, or optionally substituted 5-membered heterocycle, wherein each optional substitution of RgAis with one or more RgB, wherein each RgBis independently Ci-4-alkyl, amino, cyano, halogen, or hydroxyl; p is 0, 1, or 2; each Rio is independently RI0A, — N(RIOA)(RIOB), — ORI0A, — SRI0A, — S(O)Ri0A, or — S(O)2RI0A, wherein RIOAis an optionally substituted C4-2o-alkyl or an optionally substituted 4-20 membered heteroalkyl, wherein each optional substitution of the C4-2o-a I ky I or 4-20 membered heteroalkyl is with one or more Rioc, and which is optionally attached to another RI0Amoiety to provide a dimer or trimer,RIOB is hydrogen or RI0A, each Rioc is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, thiourea, urea, or Xi, X1-L1-X2, or X1-L1-X2-L2-X3, wherein each of Xi, X2 and X3 is independently an optionally substituted Ci-4-alkyl, an optionally substituted Ci.6-cycloalkyl, an optionally substituted 5- or 6-membered heterocycle, or an optionally substituted aryl, wherein each optional substitution of the Ci-4-alkyl, Ci.s-cycloalkyl, 5- or 6-membered heterocycle, or aryl is with one or more RIOD, each of Li and L2is independently an optionally substituted Ci.6-al kyl or an optionally substituted 1-10-membered heteroalkyl, wherein each optional substitution of the Ci.6-alkyl or 1-10-membered heteroalkyl is with one or more of RIOE, each R100 is independently RIOE or Ci.6-alkyl optionally substituted with one or more RIOE, each RIOE is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halogen, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, or urea; and m is 1, 2 or 3; wherein the SGLT1 inhibitor compound has a primary site of pharmacological action in the intestinal lumen of the subject.

2. The method of claim 1, wherein the method is for treating gastroparesis along with one or more gastrointestinal disorders selected from the group consisting of irritable bowel syndrome (IBS), non-ulcer dyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, gastroesophageal reflux disease (GERD), ileus inflammation, and heartburn.

3. The method of any one of claims 1-2, wherein the SGLT.1 inhibitor compound is selected from the group consisting of:

4. The method of any one of claims 1-2, wherein the pharmaceutical salt of the SGiTl inhibitor compound is selected from monosebacate and hemifumarate dehydrate of the compound.

5. The method of any one of claims 1-2, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered at a dosage of from about 0.1 mg / day to about 60 mg / day.

6. The method of any one of claims 1-2, wherein the SGl.Tl inhibitor compound, or pharmaceutically acceptable salt thereof, is administered as a unit dose of, from about 0.1 mg to about 20 mg, one to three times a day.

9. The method of any one of claims 1-2, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered before a meal.

10. The method of any one of claims 1-2, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered at a dosage of from 2.5 mg to 10 mg, one to three times a day.

11. The method of any one of claims 1-2, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered orally.

12. The method of any of claims 1-2, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered in an oral dosage form selected from the group consisting of a coated capsule, a coated tablet, a liquid, a powder, and an orally disintegrating tablet.

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