Compositions and methods for treating glucose-dependent insulinotropic peptide-dependent cushing's syndrome

Abstract

This disclosure relates to compositions and methods for treating glucose-dependent insulinotropic peptide (GlP)-dependent Cushing's Syndrome 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 conditions such as GH-secreting pituitary tumors and neuroendocrine tumors ectopically expressing GIPR. 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 GLUCOSE-DEPENDENT INSULINOTROPIC PEPTIDE– DEPENDENT CUSHING’S SYNDROME Cross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 605,200, filed onDecember 1, 2023; the disclosure of which is incorporated herein by reference. Field of the Invention

[0002] The invention relates to compositions and methods for treating and ameliorating glucose-dependent insulinotropic peptide (GIP)-dependent Cushing’s syndrome. Background

[0003] In patients with primary adrenal Cushing’s syndrome (CS), either from unilateral tumors orfrom bilateral adrenal hyperplasia etiologies, excess cortisol secretion leads to progressive suppression of hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH) secretion. The mechanisms by which cortisol secretion is maintained despite the lack of ACTH, the main stimulator of the MC2R-Gsα-cAMP-protein kinase A signaling pathway of steroidogenesis in adrenocortical zona fasciculata cells, were largely unknown until the last two decades, when several cellular mechanisms and genetic alterations were identified and summarized in several recent reviews.

[0004] The concept of ectopic adrenal membrane receptor expression was proposed initially byRobert L. Ney in 1971. Southerland identified the initial mechanism of action of G-protein coupled receptors following his demonstration that epinephrin mobilized glucose from the liver by activating adenyl cyclase (AC) to generate cAMP, which then stimulated phosphorylase. Grant W. Liddle proposed to Ney to investigate whether ACTH regulated steroidogenesis via cAMP production in the adrenal cortex. In normal rat adrenal cell membranes preparations, only ACTH was capable of stimulating AC and cAMP production; however, in corticosterone-producing rat adrenocortical carcinoma 494 membranes, cAMP was stimulated by hormones other than ACTH, including epinephrine, norepinephrine, and thyroid-stimulating hormone (TSH). In further studies, AC from this tumor was also stimulated by follicle- stimulating hormone (FSH), luteinizing hormone (LH), and slightly by prostaglandin E1 (PGE1), but not by glucagon, insulin, vasopressin, parathyroid hormone (PTH), or calcitonin. The illicit hormones exerted no additive or synergistic actions, suggesting that the tumor possessed multiple specific receptors which activated a common AC. High-affinity β-adrenergic binding sites and AC stimulation were observed in rat adrenocortical carcinoma 494 membranes, but not in normal adrenal membranes. In one androgen- secreting carcinoma removed from a patient with CS, AC stimulation was induced by TSH and ACTH, but not by epinephrine, LH, or glucagon; in one of three cortisol-secreting adenomas, AC was stimulated slightly only by TSH and ACTH. The authors concluded that “at present the physiological significance of these aberrant tumor responses is uncertain, and their relationship to tumor function has to remainspeculative. However, it is possible that, in certain cases, the “autonomous” behavior of endocrine tumors may be more apparent than real, and that this behavior is the result of stimulation of the tumor by hormones other than the appropriate ones for the parent gland”.

[0005] In 1978, Dr Leslie J DeGroot in Chicago reported a female patient with CS secondary to anadrenal adenoma in whom plasma cortisol levels were low in the morning and increased during the day, but the relationship with meals was not studied; in retrospect, her “persistent diurnal cortisol secretory rhythm” pattern was probably secondary to food-dependent CS.

[0006] Pavel Hamet was the first to identify “food-dependent” cortisol production in a 41-year-oldmale patient with CS secondary to a cortisol-secreting unilateral adenoma and periodic hormonogenesis. Plasma cortisol was consistently low in the morning or during fasting but increased to high levels following meals; food-induced elevations of plasma cortisol were not suppressed by high oral doses of dexamethasone. Adenyl cyclase activity in the resected adrenal adenoma membrane preparation was stimulated 27% by ACTH and 62% by vasopressin, but not by FSH, glucagon, or Ang-II; the effects of various gastrointestinal hormones were not examined in this case.

[0007] A 48-year-old French Canadian woman with primary bilateral macronodular adrenalhyperplasia (PBMAH) presented with overt symptoms of CS progressing during the previous 2-3 years. Strikingly, she also presented with low plasma cortisol levels fasting in the morning and higher fluctuating levels during the day, while plasma ACTH was always suppressed. We demonstrated a correlation between meals and post-prandial cortisol peaks, similar to the previous case with food- dependent cortisol-secreting unilateral adenoma. The identification of the central role of a gastrointestinal hormone resulted from the observation that plasma cortisol was stimulated by oral administration either of 75 g of glucose or lipid-rich or protein-rich meals, but not by intravenous glucose. In addition, somatostatin pretreatment inhibited the cortisol stimulatory effect of oral glucose. A review of the various secretagogues of gastrointestinal hormones indicated that only GIP and the glucagon-like peptide-I were stimulated equally by oral glucose and lipids, and to a lesser extent by proteins. Plasma cortisol levels were correlated with plasma GIP concentrations during the various test meals. In vivo infusion of GIP, to reproduce its physiological post-prandial concentrations, stimulated cortisol production in the PBMAH patient, but not in four normal controls. In the patient, plasma cortisol was stimulated by the administration of ACTH but not by CRH, glucagon, insulin-induced hypoglycemia, pentagastrin, or vasopressin. The hypothesis of functional ectopic GIP receptors (GIPR) in adrenal tissues was supported by adrenal imaging after the injection of [123I]-GIP in vivo. The incubation of bilaterally resected dispersed PBMAH adrenal cells in vitro confirmed GIP-mediated cortisol secretion in the patient’s cells, but not in normal adult or fetal adrenal cells, or in other cortisol- or aldosterone-secreting adenomas; there was no stimulation of cortisol production in the patient’s adrenal cells after in vitro incubation with secretin, cholecystokinin, VIP, substance P, bombesin, calcitonin gene-related peptide,glucagon, vasopressin, atrial natriuretic peptide (ANP), CRH, TRH, growth hormone–releasing hormone (GHRH), neurotensin, or neurokinin A. It was thus concluded that food-dependent cortisol secretion resulted from the abnormal responsiveness of adrenal cells to the physiologic secretion of GIP; ectopic GIPR expression on adrenal cells was presumably responsible for this new etiology of CS, but this could not be verified as this receptor had not been cloned yet.

[0008] Cloning of GIPR cDNA from rat and human sources allowed the investigation of GIPR expressionin the tissues of such patients. In situ hybridization demonstrated abundant GIPR mRNA in unilateral adrenal adenoma cells from a patient with GIP–dependent CS; this signal was not present in the adenoma from a patient with non-food–dependent CS but was not examined in the normal adrenal cortex. Using RT-PCR amplification, pronounced adrenal GIPR overexpression in adrenal adenoma and PBMAH tissues from two index cases of GIP–dependent CS compared to the normal human pancreas, normal adult or fetal adrenal cortex or non-GIP–dependent adrenal CS tissues was demonstrated. A small amount of GIPR mRNA was detected in normal fetal and adult adrenal tissues after at least 35 cycles of amplification and hybridization with the labeled cDNA but was not coupled efficiently to steroidogenesis. Sequence analysis of the full-length cDNA of normal and GIP–dependent adrenal glands revealed no mutation of GIPR in the affected adrenal tissues; similar proportions of isoforms lacking exons 4 and 9 were identified in normal adrenal glands and GIP–dependent tumors. Chabre et al. confirmed the presence of the same overexpressed GIPR isoforms in a GIP–dependent adenoma by reverse transcription–polymerase chain reaction (RT–PCR) and sequencing; no GIPR bands could be detected in the atrophic adrenal cortex adjacent to the tumor or in normal adult adrenals. The ACTH receptor (MC2R) was found to be expressed at a lower level in GIP–dependent adenoma compared to normal tissues.

[0009] Other tissues have been shown to overexpress ectopically the GIP receptor. The expression of afunctional GIP / GIPR axis in a subset of patients with acromegaly exhibiting a paradoxical increase of growth hormone (GH) following oral glucose intake was first suggested by Umahara in 2003. Oral (but not intravenous) glucose loading caused an increase in GH plasma levels in two of four acromegaly patients. A similar increase was reproduced by intravenous GIP infusion only in those with paradoxical response to oral glucose. Both responses were absent after pituitary tumor removal. Later, two separate studies identified a higher GIPR expression in about 30% of GH–secreting pituitary adenomas (GH–PAs) and this was correlated to paradoxical GH increase post-oral glucose intake and always limited to GNAS1 mutation-negative cases. Stimulation with GIP was also able to induce GH secretion in a large proportion of somatotropinomas-derived primary cultures expressing GIPR. A significant male preponderance and higher serum IGF-1 levels were present at diagnosis among the GIPR–positive patients (32%). There was a strong association between the presence of paradoxical increase in GH and a lower likelihood ofhyperprolactinemia, a milder tumor phenotype (smaller, less-invasive tumors) and better response to first-generation somatostatin analog (SSA).

[0010] Neuroendocrine tumor is a heterogeneous group of tumors that vary in terms of site of origin,hormonal secretion, and clinical behavior. Neuroendocrine tumors share frequent overexpression of various hormone receptors, and this tumor phenotype has been very useful for their diagnosis, imaging, and therapy. Among such receptors, somatostatin receptors (SSTR) have been extensively targeted with specific ligands in NET for localization of primary and metastatic lesions and allowed improvement ofsymptoms, tumor regression, or disease stabilization in ∼50% of patients. Glucose-dependentinsulinotropic peptide receptor is now increasingly investigated in NET, particularly in tumors expressing little or no SSTR and / or GLP1R, such as insulinomas and undifferentiated NET. Using in vitro receptor autoradiography to examine 260 human tumors, Waser et al. reported a homogeneously strong distribution with high tumor to normal tissue (T / N) ratio of GIPR in a large variety of largely SSTR- negative, gastrointestinal, and bronchial NET. Two other studies confirmed GIPR upregulation in pancreatic, small intestine (SI-), gastric, and duodenal (GD-) NET; hypermethylation of GIPR was seen in 74% of small intestinal neuroendocrine tumors (SINET) and increased expressions of GIPR were positively correlated with the development of liver metastases. A similarly high T / N ratio of GIPR was seen in nearly 80% of medullary thyroid cancer, particularly the larger sporadic advanced cases; in vitro GIP was coupled to calcitonin secretion.

[0011] 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 overSGLT2 as assesed by cellular uptake of radiolabeled methyl-α -D-glucopyranoside (α-MG) in vitro.

[0012] Mizagliflozin, 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-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 (GIP-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.

[0013] Since an increase of SGLT1 activity in the small intestine is thought to contribute to increasedinsulin secretagogue production, fast development of agents, which have a potent inhibitory activity inhuman 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 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-bariatric hypoglycemia. Summary of the Invention

[0014] Methods and compositions according to the principles and illustrative embodiments of theinvention are used for the treatment of GIP-dependent Cushing’s Syndrome in subjects in need thereof.

[0015] According to one aspect of the invention, a method of treating GIP-dependent Cushing’sSyndrome 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; wherein R1 is H, or an optionally substituted C1-6 alkyl group; one of Q and T is a group:, while the other is a C1-6alkyl group, a halo(C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group; R2 is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a halo(C1-6 alkyl) group, a halo(C1-6 alkoxy) group, a C1-6 alkoxy-substituted (C1-6 alkoxy) group, a C3-7 cycloalkyl-substituted (C2-6 alkoxy) group or —A—RAin which A is a single bond, an oxygen atom, a methylene group, an ethylene group, —OCH2— or —CH2O—; and RAis a C3-7 cycloalkyl group, a C2-6 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 C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a halo(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, a carboxy group, a C2-7 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 a C1-6alkyl group; X is a single bond, an oxygen atom or a sulfur atom; Y is a C1-6alkylene group which may be substituted by a hydroxy group or a C2-6alkenylene group; Z is —RB, —CORC, —SO2RC, —CON(RD)RE, —SO2NHRFor —C(═NRG)N(RH)RI; RCis 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 C1-6 alkyl group, or a C1-6 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 is 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 C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, or both of RDand REbind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group; RG, RHand RIare the same or different, and each is a hydrogen atom, a cyano group, a carbamoyl group, a C2-7 acyl group, a C2-7 alkoxycarbonyl group, an aryl(C2-7 alkoxycarbonyl) group, a nitro group, a C1-6 alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6 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 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 C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group; R3, R5 and R6 are the same or different, and each is a hydrogen atom, a halogen atom, a C1-6 alkyl group or a C1-6 alkoxy group; and substituent group (i) consists of a hydroxy group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6 alkyl)ureido group, a mono or di(C1-6 alkyl)sulfamide group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group, a C1-6 alkylsulfonyl group, a carboxy group, a C2-7 alkoxycarbonyl group, —CON(RJ)RKin which RJand RKare the same or different, and each is a hydrogen atom or a C1-6 alkyl 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(C1-6 alkyl)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(C1-6alkoxy) 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 C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 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 C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, and a C1-4 aromatic cyclic amino group which may have a C1-6 alkyl 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 R7Bis 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 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, X2and X3is 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 L1and L2is independently optionally substituted C1-6-alkyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of R10E; each R10Dis independently R10Eor 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; and wherein the SGLT1 inhibitor compound has a primary site of pharmacological action in the intestinal lumen of the subject.

[0016] The method treats GIP-dependent Cushing’s Syndrome along with, but not limited to GHsecreting pituitary tumors ectopically expressing GIPR, neuroendocrine tumors ectopically expressing GIPR, or any organ or tissue ectopically expressing GIPR.

[0017] The method of the invention may administer various SGLT1 inhibitor compounds, including,but not limited to:,,.

[0018] According to the invention, an SGLT1 inhibitor compound, or pharmaceutically acceptable saltthereof, may be administered at a dosage amount of, but not limited to, about 0.1 mg / day to about 60 mg / day.

[0019] In yet another aspect of the invention, an SGLT1 inhibitor compound, or pharmaceuticallyacceptable salt thereof, is administered before a meal. Brief Description of the Drawings

[0020] FIG.1 depicts GLP-1 and GIP levels measured in post-bariatric hypoglycemia patients afteradministration of a single oral dose of 2.5 mg, 5.0 mg, and 10 mg of mizagliflozin. Detailed Description of the Invention

[0021] The invention relates to methods and compositions for the treatment of treats GIP-dependentCushing’s Syndrome. In particular, methods of the invention relate to treating a subject with GIP- dependent Cushing’s Syndrome, 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:wherein R1is H, or an optionally substituted C1-6alkyl group; one of Q and T is a group:while the other is a C1-6alkyl group, a halo(C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group; R2is 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 C3-7 cycloalkyl-substituted (C2-6 alkoxy) group or —A—RAin which A is a single bond, an oxygen atom, a methylene group, an ethylene group, —OCH2— or —CH2O—; and RAis a C3-7 cycloalkyl group, a C2-6 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 C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a halo(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, a carboxy group, a C2-7 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 a C1-6 alkyl group; X is a single bond, an oxygen atom or a sulfur atom; Y is a C1-6alkylene group which may be substituted by a hydroxy group or a C2-6alkenylene group; Z is —RB, —CORC, —SO2RC, —CON(RD)RE, —SO2NHRFor —C(═NRG)N(RH)RI; RCis 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 C1-6 alkylsulfonylamino group, a C1-6 alkyl group and aC1-6alkoxy 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 is 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 C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 alkyl group, or a C1-6 alkyl 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 C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, or both of RDand REbind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino- substituted (C1-6 alkyl) group; RG, RHand RIare the same or different, and each is a hydrogen atom, a cyano group, a carbamoyl group, a C2-7 acyl group, a C2-7 alkoxycarbonyl group, an aryl(C2-7 alkoxycarbonyl) group, a nitro group, a C1-6alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6 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 RIbind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino- substituted (C1-6 alkyl) group; R3, R5 and R6 are the same or different, and each is a hydrogen atom, a halogen atom, a C1-6 alkyl group or a C1-6 alkoxy group; and substituent group (i) consists of a hydroxy group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6 alkyl)ureido group, a mono or di(C1-6 alkyl)sulfamide group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group, a C1-6 alkylsulfonyl group, a carboxy group, a C2-7alkoxycarbonyl group, —CON(RJ)RKin which RJand RKare the same or different, and each is 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 bindtogether 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(C1-6alkoxy) 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 C1-6 alkyl group and a C1-6 alkoxy group on the ring, an aryl(C1-6 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 C1-6 alkyl group and a C1-6 alkoxy group on the ring, a C3-7 cycloalkyl group, a C2-6 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 C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 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 C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, and a C1-4 aromatic cyclic amino group which may have a C1-6 alkyl group as a substituent; and wherein the compound of Formula II is:wherein R7is 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 R7Bis 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 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; and wherein the SGLT1 inhibitor compound inhibits SGLT1 in the intestinal lumen of the subject.

[0022] The SGLT1 inhibitor compounds of Formula I or Formula II administered in methods of theinvention 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).

[0023] “Pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptablenon-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 hydrochlorideand 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).

[0024] Unless otherwise indicated, a “therapeutically effective amount” of a compound is an amountsufficient 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.

[0025] The terms “treat,” “treating,” and “treatment” contemplate an action that occurs while apatient 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.

[0026] The term "subject" refers to a human or animal patient in need of treatment for glucose-dependent insulinotropic peptide (GIP)-dependent Cushing’s Syndrome and related conditions. This includes humans or animals diagnosed with GIP-dependent Cushing’s Syndrome, GH-secreting pituitary tumors, neuroendocrine tumors ectopically expressing GIPR, or any organ or tissue ectopically expressing GIPR.

[0027] It should also be noted that if the stereochemistry of a structure or a portion of a structure isnot 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.

[0028] In certain embodiments, this invention relates to treating GIP-dependent Cushing’s Syndromealong with, but not limited to, GH secreting pituitary tumors ectopically expressing GIPR, neuroendocrine tumors ectopically expressing GIPR, or any organ or tissue ectopically expressing GIPR.

[0029] For the methods of the invention, SGLT1 inhibitors of Formula I and Formula II can be preparedby methods known in the art. See, e.g., U.S. Patent No.7,635,684, and U.S. Patent No. 9,200,025.

[0030] In a preferred method of the invention, SGLT1 inhibitors of Formula I and Formula II areselected from the group consisting of:

[0031] In some preferred methods of the invention, the SGLT1 inhibitor is selected from LX2671 andmizagliflozin. 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.

[0032] In some methods of the invention where mizagliflozin is administered, the pharmaceutical saltis selected from mizagliflozin monosebacate and mizagliflozin hemifumarate dehydrate. Mizagliflozin hemifumarate dihydrate, from U.S. Patent No.8,354,382, is shown below:Mizagliflozin monosebacate, from U.S. Patent No.8,399,418, is shown below:

[0033] In a method of the invention, the SGLT inhibitor compound of Formula I or Formula II isadministered 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 adiministered 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.

[0034] The daily dose can be divied into one or more, for example, two-, three-, or four-unit dosesadministered per day. A unit dose is the amount of compound administered at one time. In a prefered method of the invention, SGLT inhibitor compound of Formula I or Formula II is administered at a unit dose of from about 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 adiministered as a pharmaceutically acceptable salt thereof. In such methods, the unit dose refers to the mg of the compound.

[0035] In a preferred method of the invention, the SGLT inhibitor compound of Formula I or FormulaII, 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.

[0036] In methods according to the invention pharmaceutical compositions of SGLT1 inhibitorcompounds 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 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. WO99 / 10010, WO99 / 26606, and Japanese patent publication No.2001-2567).

[0037] The pharmaceutical compositions can be prepared by admixing with or by diluting anddissolving 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 cases of using 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.

[0038] Some compositions of the invention are formulated as oral dosage forms. For example, an oraldoasage 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 mm×4.5 mm. Qualitative compositions of tablet excipients, in certain embodimements, 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

[0039] In some embodiments of the invention, the oral dosage form of mizagliflozin is a capsule.Table 2 shows exemplerary capsule compositions. Table 2

[0040] In some methods of the invention, the SGLT1 inhibitor compound of Formula I or Formula II, orpharmaceutically 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

[0041] Example 1 - Single dose study in humans

[0042] A single oral dose of 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg of mizagliflozin wasadministered 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 AUC0-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

[0043] 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). 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 6

[0044] Example 2: Repeat dose study in humans

[0045] Oral doses of 2 mg, 5 mg, 10 mg, 20 mg of mizagliflozin, placebo or miglitol at 50 mg per dosewere adminsitered 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.

[0046] Changes in the following parameters and ΔAUC from 0 to t* hours after breakfast, lunch, andevening 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.

[0047] 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

[0048] Example 3: Single dose study in post-bariatric hypoglycemia patients

[0049] 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 (MMTT) with approximately 50 mL of water after fasting for at least 8 hours. Pharmacodynamic effect parameters (blood glucose level, insulin, GLP-1, and glucose-dependent insulinotropic peptide (GIP)) were measured. Concentrations at each time point were measured, and summary statistics and coefficient variation (CV) were calculated for AUC0-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 an exploratory manner the inhibitory effect on postprandial hyperglycemia. GLP-1 and GIP were measured to evaluate in an exploratory manner the incretinsecretory 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 = 0.0476

Claims

Claims:

1. A method of treating glucose-dependent insulinotropic peptide (GIP)-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:ormula I; wherein R1 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 C1-6alkyl group, a halo(C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group; R2is 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—RA, wherein A is a single bond, an oxygen atom, a methylene group, an ethylene group, — OCH2—, or —CH2O—, and RAis a C3-7 cycloalkyl group, a C2-6 heterocycloalkyl 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 C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a halo(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, a carboxy group, a C2-7 alkoxycarbonyl 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 C1-6 alkyl group; X is a single bond, an oxygen atom, or a sulfur atom; Y is a C1-6 alkylene group which may be substituted by a hydroxy group or a C2-6 alkenylene group; Z is —RB, —CORC, —SO2RC, —CON(RD)RE, —SO2NHRF, or —C(═NRG)N(RH)RI, 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 C1-6 alkylsulfonylamino group, a C1-6 alkyl group, and a C1-6 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 C1-6 alkyl group, or a C1-6 alkyl group, wherein the C1-6 alkyl 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 C1-6 alkoxy group, a C1-6 alkylthio group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]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)RK, wherein RJand RKare the same or different, and each of RJand RKrepresent a hydrogen atom or a C1-6alkyl group,wherein the C1-6alkyl 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(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 wherein both of RJand RKbind together with the neighboring nitrogen atom to form a C2-6 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 C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, an aryl(C1-6 alkoxy) group, wherein the aryl(C1-6 alkoxy) group can have the same or different 1 to 3substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group, and a C1-6 alkoxy group on the ring, an aryl(C1-6 alkylthio) group, wherein the aryl(C1-6alkylthio) 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 C1-6 alkyl group, and a C1-6 alkoxy 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 C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 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 C1-6 alkyl group, a C2-6 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 C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group, a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, and a C1-4aromatic cyclic amino group,wherein the C1-4aromatic cyclic amino group can have a C1-6alkyl group as a substituent, R4, RB, RD, RE, and RFare the same or different, and 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 C1-6alkylsulfonylamino group, a C1-6 alkyl group, and a C1-6 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 C1-6 alkyl group, a C1-6 alkyl group, wherein the C1-6 alkyl group can have the same or different 1 to 5 groups selected from substituent group (i), or both of R4 and RBbind together with the neighboring nitrogen atom to form a C2-6 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 C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, or both of RDand REbind together with the neighboring nitrogen atom to form 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 C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group; RG, RHand RIare the same or different, and each is a hydrogen atom, a cyano group, a carbamoyl group, a C2-7 acyl group, a C2-7 alkoxycarbonyl group, an aryl(C2-7 alkoxycarbonyl) group, a nitro group, a C1-6 alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6 alkyl group, wherein the C1-6 alkyl group can 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 C2-6 cyclic amino, wherein the C2-6 cyclic amino group can have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, and a C1-6 alkylsulfonylamino-substituted (Calkyl) group; R3, R5and R6are the same or different, and each is a hydrogen atom, a halogen atom, a C16alkyl group or a C1-6alkoxy group; and wherein the compound of Formula II is:wherein R7is hydrogen, an optionally substituted C1-10alkyl, an optionally substituted C1-5cycloalkyl, or an optionally substituted 5-membered heterocycle, wherein each optional substitution of the C1-10alkyl, C1-5cycloalkyl, 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 C1-4-alkoxy, optionally substituted C1-5cycloalkyl, and optionally substituted 5-membered heterocycle, wherein each optional substitution of R7Ais with one or more R7B, wherein each R7Bis independently C1-4-alkyl, halogen, 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 a halogen, a hydroxyl, an optionally substituted C1-10-alkyl, or an optionally substituted C1-10-alkoxy, wherein each optional substitution of C1-10-alkyl or C1-10-alkoxy is with one or more R9A, wherein each R9A is independently amino, ester, amide, thiol, carboxylic acid, cyano, halogen, hydroxyl, optionally substituted C1-4-alkoxy, optionally substituted C1-5-cycloalkyl, or optionally substituted 5-membered heterocycle, wherein each optional substitution of R9Ais with one or more R9B, wherein each R9Bis independently C1-4-alkyl, amino, cyano, halogen, or hydroxyl; p is 0, 1, or 2; each R10is independently R10A, —N(R10A)(R10B), —OR10A, —SR10A, —S(O)R10A, or —S(O)2R10A, wherein R10Ais an optionally substituted C4-20-alkyl or an optionally substituted 4-20 membered heteroalkyl, wherein each optional substitution of the C4-20-alkyl or 4-20 membered heteroalkyl 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 an optionally substituted C1-4-alkyl, an optionally substituted C1-6-cycloalkyl, an optionally substituted 5- or 6-membered heterocycle, or an optionally substituted aryl, wherein each optional substitution of the C1-4-alkyl, C1-6-cycloalkyl, 5- or 6-membered heterocycle, or aryl is with one or more R10D, each of L1and L2is independently an optionally substituted C1-6-alkyl or an optionally substituted 1-10-membered heteroalkyl, wherein each optional substitution of the C1-6-alkyl or 1-10-membered heteroalkyl is with one or more of R10E, each R10D is independently R10E or C1-6-alkyl optionally substituted with one or more R10E, each R10E 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 GIP-dependent Cushing’s Syndrome along with GH secreting pituitary tumors ectopically expressing GIPR, neuroendocrine tumors ectopically expressing GIPR, or any organ or tissue ectopically expressing GIPR.

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 1-2, 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 1-2, 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 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.

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 any one 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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