Compositions and methods for treating hyperinsulinemic hypoglycemia

Abstract

Disclosed herein are methods for treating and ameliorating hyperinsulinemic hypoglycemia using sodium-dependent glucose transporter (SGLT)l inhibitor compounds and compositions comprising them.

Description

COMPOSITIONS AND METHODS FOR TREATING HYPERINSULINEMIC HYPOGLYCEMIA Cross Reference to Related Applications

[0001] This application claims priority to U.S. Application Nos.63 / 506,589 and 63 / 605,195, filed on June 6, 2023, and December 1, 2023, respectively, the disclosures of which are incorporated by reference. Field of Invention

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

[0003] Hyperinsulinemic hypoglycemia (HH) is biochemically characterized by the unregulated secretion of insulin from the pancreatic β-cells in the presence of low blood glucose levels. Under normal physiological conditions, β-cells synthesize, store, and secrete insulin in a precisely controlled manner so that the fasting blood glucose level is kept within a narrow range of 3.5-5.5 mmol / L. Unregulated insulin secretion promotes glucose uptake into the skeletal muscles, liver, and adipose tissue, exacerbating hypoglycemia further. Simultaneously, glucose production (via gluconeogenesis and glycogenolysis), lipolysis, and ketogenesis are all inhibited. In addition to the actions of insulin in inhibiting glucose production, there are also defects in the glucose counter regulatory hormones such as cortisol and glucagon. The lack of glucose, which is the brain’s primary source of energy, accompanied by the deprivation of alternative substrates in the form of ketone bodies and lactate, increases the risk of brain damage in these patients. Effective treatments for congenital HI and post-prandial hypoglycemia are urgently needed.

[0004] Subtypes of sodium-dependent glucose transporter (SGLT) include SGLT1, which is primarily expressed in the small intestine, and SGLT2, which is expressed in the renal proximal tubule. These transporters are responsible for absorption of glucose in the small intestine and reabsorption of glucose in the proximal tubule, respectively. Blocking human SGLT1 activity inhibits absorption of carbohydrates such as glucose at the small intestine, and subsequently can prevent increase of blood sugar level. Increased SGLT1 activity in the small intestine may also contribute to increased insulin secretagogue production, the development of agents that are potent inhibitors of SGLT1 activity will be useful for preventing or treating diabetes, or both. See, e.g., U.S. Patent No.8,324,176. However, no SGLT1 inhibitors have been approved to date.

[0005] 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, and U.S. Patent No.9,200,025, herein incorporated by reference in its entirety, describes potent inhibitors of SGLT1, including selective inhibitors for SGLT1 with low systemic exposure that act locally in the gut. For example, U.S. Patent No.11,596,644 show the SGLT1 inhibitor, mizagliflozin (3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl- ]-3- methylphenoxy}propylamino)-2,2-dimethylpropionamide, developed by Kissei Pharmaceutical Co., Ltd.), as being selective for SGLT1 over SGLT2, as assessed by cellular uptake of radiolabeled methyl-α - D-glucopyranoside (α-MG) in vitro. Crystalline compounds of mizagliflozin have been described for use of prevention or treatment 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. U.S. Patent No.11,596,644 describes the use of mizagliflozin to treat post-prandial hypoglycemia associated with gastric surgery. Mizagliflozin suppresses the secretion of the insulin secretagogue, gastrointestinal inhibitory peptide-1 (GIP-1), from the digestive tract by selectively inhibiting SGLT1 over SGLT2. Gastrointestinal symptoms are not likely when the amount of glucose remaining in the gastrointestinal tract is small, without being absorbed. Summary of the Invention

[0006] Methods and compositions according to the principles and illustrative embodiments of the invention are used for the treatment of hyperinsulinemic hypoglycemia in subjects in need thereof.

[0007] According to one aspect of the invention, a method of treating hyperinsulinemic hypoglycemia 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: ormula I;wherein R1represents H, or an optionally substituted C1-6alkyl group; one of Q and T represents a group:while the other represents a C1-6alkyl group, a halo(C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group; R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-6alkyl group, a C1-6alkoxy group, a C1-6alkylthio group, a halo(C1-6alkyl) group, a halo(C1-6alkoxy) group, a C1-6alkoxy-substituted (C1-6alkoxy) group, a C3-7cycloalkyl-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 C3-7cycloalkyl group, a C2-6heterocycloalkyl 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 C1-6alkyl group, a C1-6alkoxy group, a C2-6alkenyloxy group, a halo(C1-6alkyl) group, a hydroxy(C1-6alkyl) 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 C1-6alkyl group; X represents a single bond, an oxygen atom or a sulfur atom; Y represents a C1-6alkylene group which may be substituted by a hydroxy group or a C2-6alkenylene group; Z represents —RB, —CORC, —SO2RC, —CON(RD)RE, —SO2NHRFor —C(═NRG)N(RH)RI; 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of ahalogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of R4 and 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group; RG, RHand RIare 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 C1-6alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6alkyl 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 RIbind 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group; R3, R5 and R6 are the same or different, and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6alkoxy group; and substituent group (i) consists of a hydroxy group, a C1-6alkoxy group, a C1-6alkylthio group, an amino group, a mono or di(C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6alkyl)ureido group, a mono or di(C1-6alkyl)sulfamide group, a C2-7acylamino group, a C1-6alkylsulfonylamino group, a C1-6alkylsulfonyl 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 C1-6alkyl 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(C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a mono or di(C1-6alkyl)ureido group, a C2-7acylamino group, a C1-6alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from thegroup consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, an aryl(C1-6alkoxy) 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 C1-6alkyl group and a C1-6alkoxy group on the ring, an aryl(C1-6alkylthio) 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 C1-6alkyl group and a C1-6alkoxy group on the ring, a C3-7cycloalkyl group, a C2-6heterocycloalkyl 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, and a C1-4aromatic cyclic amino group which may have a C1-6alkyl group as a substituent; and wherein the compound of Formula II is:Formula II; wherein R7 is hydrogen or optionally substituted C1-10-alkyl, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7A; each R7Ais independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7B; each R7B is independently C1-4-alkyl, halo, or hydroxyl; n is 0, 1, or 2; each R8 is independently F or OR8A, wherein each R8A is independently hydrogen, C1-4-alkyl, or acyl; each R9 is independently halo, hydroxyl, or optionally substituted C1-10-alkyl or C1-10-alkoxy, which optional substitution is with one or more R9A; each R9A is independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle,which optional substitution is with one or more R9B; each R9Bis independently C1-4-alkyl, amino, cyano, halo, or hydroxyl; p is 0, 1, or 2; each R10is independently R10A, —N(R10A)(R10B), —OR10A, —SR10A, —S(O)R10A, or —S(O)2R10A; R10Ais optionally substituted C4-20-alkyl or 4-20-membered heteroalkyl, which optional substitution is with one or more R10C, and which is optionally attached to another R10A moiety to provide a dimer or trimer; R10B is hydrogen or R10A; each R10C 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 X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein each of X1, X2 and X3 is independently optionally substituted C1-4-alkyl, C1-6-cycloalkyl, 5- or 6-membered heterocycle, or aryl, which optional substitution is with one or more R10D, and each of L1 and L2 is independently optionally substituted C1-6-alkyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of R10E; each R10D is independently R10E or C1-6-alkyl optionally substituted with one or more of R10E; each R10E 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.

[0008] Differential diagnosis of hypoglycemia in the non-diabetic adult patient is complex and comprises various diseases, including endogenous hyperinsulinism caused by functional β-cell disorders. The latter is also designated as nesidioblastosis or non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS). Clinically, this rare disease presents with unspecific adrenergic and neuroglycopenic symptoms and is, therefore, often overlooked. A combination of careful clinical assessment, oral glucose tolerance testing, 72 h fasting, sectional and functional imaging, and invasive insulin measurements can lead to the correct diagnosis. Due to a lack of a pathophysiological understanding of the condition, conservative treatment options are limited and mostly ineffective. Therefore, nearly all patients currently undergo surgical resection of parts or the entire pancreas. Consequently, apart from faster diagnosis, more elaborate and less invasive treatment options are needed to relieve the patients from the dangerous and devastating symptoms.

[0009] The method treats hyperinsulinemic hypoglycemia associated with, but not limited to noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS), focal and diffuse nesidioblastosis, congenital hyperinsulinism, maternal diabetes mellitus (gestational and insulin dependent), intrauterine growth restriction, perinatal asphyxia, Rhesus isoimmunization, congenital disorders of glycosylation, tyrosinaemia type 1, Beckwith–Wiedemann syndrome, Kabuki syndrome, trisomy 13, central hypoventilationsyndrome, leprechaunism (insulin resistance syndrome), Mosaic Turner syndrome, Sotos syndrome, Usher syndrome, Timothy syndrome, and Costello syndrome.

[0010] The method of the invention may administer various SGLT1 inhibitor compounds, including, but not limited to:.

[0011] 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.

[0012] In another aspect of the invention, an SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered in combination with at least one GLP1 receptor antagonist. For example, in a method of the invention, the GLP1 receptor-antagonist is exendin 9-39.

[0013] In yet another aspect of the invention, an SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered before a meal.

[0014] In another aspect of the invention, an SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered in an oral dosage form. For example, in the form of a coated capsule, a coated tablet, a liquid, a powder, or an orally disintegrating tablet. Brief Description of the Drawings

[0015] 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

[0016] The invention relates to methods and compositions for the treatment of hyperinsulinemic hypoglycemia. Methods of the invention relate to treating a subject with hyperinsulinemic hypoglycemia, 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:ormula I, wherein R1represents H, or an optionally substituted C1-6alkyl group; one of Q and T represents a group:while the other represents a C1-6alkyl group, a halo(C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group; R2represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-6alkyl group, a C1-6alkoxy group, a C1-6alkylthio group, a halo(C1-6alkyl) group, a halo(C1-6alkoxy) group, a C1-6alkoxy-substituted (C1-6alkoxy) group, a C3-7cycloalkyl-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 C3-7cycloalkyl group, a C2-6heterocycloalkyl 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 C1-6alkyl group, a C1-6alkoxy group, a C2-6alkenyloxy group, a halo(C1-6alkyl) group, a hydroxy(C1-6alkyl) 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 C1-6alkyl group; X represents a single bond, an oxygen atom or a sulfur atom; Y represents a C1-6alkylene group which may be substituted by a hydroxy group or a C2-6alkenylene group; Z represents —RB, —CORC, —SO2RC, —CON(RD)RE, —SO2NHRFor —C(═NRG)N(RH)RI; 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl 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 carbamoylgroup, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group; RG, RHand RIare 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 C1-6alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6alkyl 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 RIbind 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group; R3, R5 and R6 are the same or different, and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6alkoxy group; and substituent group (i) consists of a hydroxy group, a C1-6alkoxy group, a C1-6alkylthio group, an amino group, a mono or di(C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6alkyl)ureido group, a mono or di(C1-6alkyl)sulfamide group, a C2-7acylamino group, a C1-6alkylsulfonylamino group, a C1-6alkylsulfonyl 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 C1-6alkyl 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(C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a mono or di(C1-6alkyl)ureido group, a C2-7acylamino group, a C1-6alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, an aryl(C1- 6 alkoxy) 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 C1-6alkyl group and a C1-6alkoxy group on the ring, an aryl(C1-6alkylthio) 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 C1-6alkyl group and a C1-6alkoxy group on the ring, a C3-7cycloalkyl group, a C2-6heterocycloalkyl 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl groupwhich may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, and a C1-4aromatic cyclic amino group which may have a C1-6alkyl group as a substituent; and wherein the compound of Formula II is:wherein R7 is hydrogen or optionally substituted C1-10-alkyl, C1-5-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 C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7B; each R7B is independently C1-4-alkyl, halo, or hydroxyl; n is 0, 1, or 2; each R8is independently F or OR8A, wherein each R8Ais independently hydrogen, C1-4-alkyl, or acyl; each R9is independently halo, hydroxyl, or optionally substituted C1-10-alkyl or C1-10-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 C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R9B; each R9Bis independently C1-4-alkyl, amino, cyano, halo, or hydroxyl; p is 0, 1, or 2; each R10 is independently R10A, —N(R10A)(R10B), —OR10A, —SR10A, —S(O)R10A, or —S(O)2R10A; R10A is optionally substituted C4-20-alkyl or 4-20-membered heteroalkyl, which optional substitution is with one or more R10C, and which is optionally attached to another R10A moiety to provide a dimer or trimer; R10B is hydrogen or R10A; each R10C 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 X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein each of X1, X2and X3is independently optionally substituted C1-4-alkyl, C1-6-cycloalkyl, 5- or 6-membered heterocycle, or aryl, whichoptional substitution is with one or more R10D, and each of L1and L2is independently optionally substituted C1-6-alkyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of R; each R10Dis independently R or C1-6-alkyl optionally substituted with one or more of R; eachis 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.

[0017] 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).

[0018] “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,Nʹ- 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, EastonPa.: 1990) and Remington: The Science and Practice of Pharmacy, 19th ed. (Mack Publishing, Easton Pa.: 1995).

[0019] 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.

[0020] 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.

[0021] 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.

[0022] Hyperinsulinemic hypoglycemia includes, but is not limited to NIPHS, focal and diffuse nesidioblastosis, GIP-dependent Cushing’s Syndrome, congenital hyperinsulinism, maternal diabetes mellitus (gestational and insulin dependent), intrauterine growth restriction, perinatal asphyxia, Rhesus isoimmunization, congenital disorders of glycosylation, tyrosinaemia type 1, Beckwith–Wiedemann syndrome, Kabuki syndrome, trisomy 13, central hypoventilation syndrome, leprechaunism (insulin resistance syndrome), Mosaic Turner syndrome, Sotos syndrome, Usher syndrome, Timothy syndrome, and Costello syndrome.

[0023] 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.

[0024] In a preferred method of the invention, SGLT1 inhibitors of Formula I and Formula II are selected from the group consisting of:, , ,,

[0025] 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-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl- ]-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.

[0026] 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:

[0027] Mizagliflozin monosebacate, from U.S. Patent No.8,399,418, is shown below:

[0028] 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, thedaily dose refers to the mg / day of the compound. A therapeutically effective amount for administration is determined by a treating physician.

[0029] The daily dose can be divided into one or more, for example, two or 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.

[0030] 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.

[0031] 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 of stomach 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 publication Nos. WO99 / 10010, WO99 / 26606, and Japanese patent publication No.2001-2567).

[0032] 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.

[0033] Some compositions of the invention are formulated as oral dosage forms in the form of a coated capsule, a coated tablet, a liquid, a powder, or an orally disintegrating tablet. 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 tablet with an oval shape of 8 mm×4.5 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

[0034] In some embodiments of the invention, the oral pharmaceutical formulations are comprised of tablets 2.5 mg, 5 mg, and 10 mg that are white to slightly yellowish white film-coated tablets with an oval shape of 8 mm×4.5 mm. The qualitative compositions of the tablet excipients are shown in Table 10. The container closure system is tight sealed container.

[0035] In some embodiments of the invention, the oral dosage form of mizagliflozin is a capsule. Table 2 shows exemplary capsule compositions.Table 2

[0036] 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)-1 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

[0037] The following examples are presented in order to more fully illustrate certain embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. Example 1 - Single dose study in humans

[0038] 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, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP)) were measured, as reported in Tables 3-6, respectively. Blood concentrations of glucose, insulin, GLP-1 and GIP were measured at each time point after dose administrations, and summary statistics and coefficient variation (CV) were calculated for AUC0-t, where time (t) was up to 6 hours post-administration of 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.

[0039] GIP blood concentration data following mizagliflozin administration suggested suppression of GIP secretion (See Table 6). The AUC0-6 value 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). GLP-1 was higher in all mizagliflozin treatment groups but change in GLP-1 could not be evaluated due to variation in mean baseline level between subjects was large (1.9 to 9.9 pmol*h / L).Table 6Example 2 - Repeat dose study in humans

[0040] Oral doses of 2 mg, 5 mg, 10 mg, and 20 mg of mizagliflozin, placebo, or 50 mg of miglitol were administered three times daily to healthy adult male volunteers by a randomized, placebo-controlled, parallel-group, double-blind comparison method. The doses were 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.

[0041] Changes in the following parameters and ΔAUC 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 hours (t = 0.5, 1, 1.5, 2, 3, and 5 only after breakfast), as indicated in Tabled 7, 8, 9, and 10, respectively.

[0042] 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 increases in active GLP-1 concentration, and inhibition of increase in total GIP concentration were seen.

[0043] In the mizagliflozin group, hyperglycemia was suppressed after breakfast, lunch, and evening meal on a level equivalent to the miglitol group, and inhibition of insulin secretion and hyperglycemia was observed to be the same as it was in the miglitol group. Total GLP-1 concentrations were also observed to be equivalent in the mizagliflozin and miglitol groups, as were total GIP concentrations. These pharmacodynamic effects persisted over 10 days in a repeated post-administration analysis. There was no correlation between plasma mizagliflozin concentration and the pharmacodynamic effects. Measurements in Tables 7-10 were performed on Day 3 after breakfast.Example 3 - Single dose study in post-bariatric hypoglycemia patients

[0044] A 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 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 AUC0-t, where t was up to 6 hours post-dose. 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 an exploratory 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 11Table 12** For the All Capsules, performing an exact non-parametric test resulted in a p-value = 0.0476

Claims

Claims:

1. A method of treating hyperinsulinemic hypoglycemia in a subject, comprising 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; wherein R1represents H, or an optionally substituted C1-6alkyl group; one of Q and T represents a group:while the other represents a C1-6alkyl group, a halo(C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group; R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-6alkyl group, a C1-6alkoxy group, a C1-6alkylthio group, a halo(C1-6alkyl) group, a halo(C1-6alkoxy) group, a C1-6alkoxy-substituted (C1-6alkoxy) group, a C3-7cycloalkyl-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 C3-7cycloalkyl group, a C2-6heterocycloalkyl 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 C1-6alkyl group, a C1-6alkoxy group, a C2-6alkenyloxy group, a halo(C1-6alkyl) group, a hydroxy(C1-6alkyl) 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 C1-6alkyl group; X represents a single bond, an oxygen atom or a sulfur atom; Y represents a C1-6alkylene group which may be substituted by a hydroxy group or a C2-6alkenylene group; Z represents —RB, —CORC, —SO2RC, —CON(RD)RE, —SO2NHRFor —C(═NRG)N(RH)RI; 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of R4 and RBbind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the groupconsisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group; RG, RHand RIare 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 C1-6alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6alkyl 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 RIbind 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group; R3, R5 and R6 are the same or different, and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6alkoxy group; and substituent group (i) consists of a hydroxy group, a C1-6alkoxy group, a C1-6alkylthio group, an amino group, a mono or di(C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6alkyl)ureido group, a mono or di(C1-6alkyl)sulfamide group, a C2-7acylamino group, a C1-6alkylsulfonylamino group, a C1-6alkylsulfonyl 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 C1-6alkyl 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(C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a mono or di(C1-6alkyl)ureido group, a C2-7acylamino group, a C1-6alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, an aryl(C1- 6 alkoxy) 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 C1-6alkyl group and a C1-6alkoxy group on the ring, an aryl(C1-6alkylthio) 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 C1-6alkyl group and a C1-6alkoxy group on the ring, a C3-7cycloalkyl group, a C2-6heterocycloalkyl 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 C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl groupwhich may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, and a C1-4aromatic cyclic amino group which may have a C1-6alkyl group as a substituent; and wherein the compound of Formula II is:Formula II; wherein R7 is hydrogen or optionally substituted C1-10-alkyl, C1-5-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 C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7B; each R7B is independently C1-4-alkyl, halo, or hydroxyl; n is 0, 1, or 2; each R8 is independently F or OR8A, wherein each R8A is independently hydrogen, C1-4-alkyl, or acyl; each R9 is independently halo, hydroxyl, or optionally substituted C1-10-alkyl or C1-10-alkoxy, which optional substitution is with one or more R9A; each R9A is independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R9B; each R9B is independently C1-4-alkyl, amino, cyano, halo, or hydroxyl; p is 0, 1, or 2; each R10 is independently R10A, —N(R10A)(R10B), —OR10A, —SR10A, —S(O)R10A, or —S(O)2R10A; R10A is optionally substituted C4-20-alkyl or 4-20-membered heteroalkyl, which optional substitution is with one or more R10C, and which is optionally attached to another R10A moiety to provide a dimer or trimer; R10B is hydrogen or R10A; each R10C 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 X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein each of X1, X2 and X3 is independently optionally substituted C1-4-alkyl, C1-6-cycloalkyl, 5- or 6-membered heterocycle, or aryl, whichoptional substitution is with one or more R10D, and each of L1 and L2 is independently optionally substituted C1-6-alkyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of R; each R10D is independently R or C1-6-alkyl optionally substituted with one or more of R; eachis 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.

2. The method of claim 1, wherein the hyperinsulinemic hypoglycemia , selected from the group consisting of NIPHS, focal and diffuse nesidioblastosis, GIP-dependent Cushing’s Syndrome, congenital hyperinsulinism, maternal diabetes mellitus (gestational and insulin dependent), intrauterine growth restriction, perinatal asphyxia, Rhesus isoimmunization, congenital disorders of glycosylation, tyrosinaemia type 1, Beckwith– Wiedemann syndrome, Kabuki syndrome, trisomy 13, central hypoventilation syndrome, leprechaunism (insulin resistance syndrome), Mosaic Turner syndrome, Sotos syndrome, Usher syndrome, Timothy syndrome, and Costello syndrome.

3. The method of any one of claims 1-2, wherein the SGLT1 inhibitor compound is selected from the group consisting of:.

4. The method of any one of claims 1-3, wherein the pharmaceutical salt of the SGLT1 inhibitor compound is selected from monosebacate and hemifumarate dehydrate of the compound.

5. The method of any one of claims 1-4, 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 1-5 wherein the SGLT1 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.

7. The method of any one of claims 1-6, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered in combination with at least one GLP-1 receptor antagonist.

8. The method of any one of claim 7, wherein GLP1 receptor-antagonist is exendin 9-39.

9. The method of any one of claims 1-8, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered before a meal.

10. The method of any one of claims 1-9, 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 1-10, wherein the SGLT1 inhibitor compound, or pharmaceutically acceptable salt thereof, is administered orally.

12. The method of any of claims 1-11, 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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