GAL475 composition and method of use thereof

Abstract

Methods are provided for treating subjects suffering from metabolic syndrome or diseases, diabetes, obesity, overweight, eating disorders, bulimia, hyperlipidemia, or insulin resistance, or for reducing the weight of subjects. These methods involve administering to a subject a composition comprising, for example, a compound of formula I, including GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

Description

Technical Field

[0001] The present disclosure generally relates to compounds comprising a GAL475 molecule (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-2-methyl-propan-2-ol) or a salt, solvate, enantiomer, polymorph, crystal, diastereomer or tautomer thereof, and to use in the manufacture of a medicament for use in the treatment of a disease or condition including metabolic syndrome, overweight condition, diabetes, eating disorders, hyperphagia, hyperlipidemia, insulin resistance, obesity and related comorbidities.

Background Art

[0002] Metabolic syndrome may arise from a set of factors reflecting overnutrition, a sedentary lifestyle, and excessive fat accumulation, and includes conditions such as obesity and diabetes. These conditions can lead to a variety of unhealthy conditions including elevated blood pressure, hyperglycemia, excess body fat around the waist and organs, abnormal levels of cholesterol and triglycerides, pro-thrombotic states, inflammatory conditions, fatty liver disease, and comorbidities such as reproductive disorders. The prevalence of metabolic syndrome has increased to epidemic proportions not only in the United States and other urbanized nations, but also in developing countries.

[0003] The main root causes of metabolic syndrome are abdominal obesity and insulin resistance. Diabetes mellitus is characterized by hyperglycemia in one of two forms: non-insulin-dependent or adult-onset (also called type 2 diabetes) and insulin-dependent or juvenile-onset (also called type 1 diabetes). The clinical symptoms of type 2 diabetes and the underlying signs of obesity usually appear after 40 years of age. In contrast, type 1 diabetes typically onset rapidly in people under 30 years of age. This disease is a metabolic disorder in humans, affecting about 1 percent of the general population, with one quarter being type 1 diabetes and the remainder being type 2 diabetes. Treatment for diabetes is determined based on its etiology, and the most common treatments include insulin administration and lifestyle modifications such as diet and exercise.

[0004] Chronic hyperglycemia in diabetes is associated with damage, dysfunction and failure of end organs such as the retina, kidneys, nervous system, heart and blood vessels (Uazman Alam et al., Handbook of Clinical Neurology Volume 126, 2014).

[0005] Obesity is a chronic disease that is highly prevalent in modern society and is associated with numerous medical problems including insulin resistance, hypertension, hypercholesterolemia, coronary artery disease, cancer, and sleep-disordered breathing. Obesity has now become very common among people around the world, and is replacing undernutrition and infectious diseases as the most important cause of health impairment and morbidity. As of 2021, approximately 650 million adults and 340 million children and adolescents suffer from obesity, and obesity ranks fourth among global risk factors for death (Tchang BG et al., Endotext. The World Health Organization (WHO) defines overweight as a body mass index (BMI) of 25–29.9 kg / m2 and obesity as a BMI ≥ 30 kg / m2, but this does not take into account the morbidity and mortality associated with milder obesity, or the harmful effects of visceral fat. The global obesity epidemic is caused by a combination of factors, including genetic predisposition, increased access to high-energy foods, and a decreased need for physical activity in modern society. Obesity should no longer be viewed simply as a cosmetic issue affecting specific individuals, but as an epidemic threatening global health (Peter G. Kopelman Nature 404, 2000).

[0006] The foundation of obesity treatment is a sustainable lifestyle change that combines a healthy diet and exercise. Other treatment options include surgery (e.g., sleeve gastrectomy) and medication. The FDA has approved several drugs for short-term use in obesity treatment (e.g., phentermine, diethylpropion). These drugs increase the secretion of norepinephrine in neurons and, to a lesser extent, dopamine, resulting in a reduction of appetite. Side effects include impotence, anxiety, nausea, and cardiovascular side effects. The FDA has also approved several drugs for long-term use in obesity treatment. These include orlistat (a lipase inhibitor that reduces the absorption of fatty acids in the blood), phentermine-topiramate (an amphetamine-related appetite suppressant that may induce adrenaline release and suppress appetite), bupropion-naltrexone (an appetite suppressant that reduces the reuptake of norepinephrine and dopamine, similar to short-term drugs), and liraglutide, cetomelanotide, and semaglutide (injectable peptides that function as glucagon-like peptide-1 (GLP-1) receptor agonists).

[0007] GLP-1 is a hormone secreted in the gastrointestinal tract in response to meals. One of GLP-1's roles is to stimulate glucose-dependent insulin secretion from pancreatic β-cells, thereby lowering blood glucose levels. Furthermore, GLP-1 suppresses glucagon secretion by α-cells and reduces hepatic glucose production in a glucose-dependent manner (Reshma Ramracheya et al., Physiol Rep. September 2018; 6(17)). Glucagon may be paracrinely regulated by somatostatin secretion from adjacent delta cells. GLP-1 receptor agonists have been used to treat type 2 diabetes by mimicking the action of innate GLP-1 on pancreatic islet cells, stimulating glucose-dependent insulin secretion and suppressing glucagon secretion. High concentrations of GLP-1 also interact with parts of the brain that suppress appetite and transmit satiety signals. Observations of weight loss led to an exploration of its potential as an anti-obesity agent, and liraglutide 3.0 mg / day was approved for weight management in the United States on December 23, 2014, and in the EU on March 23, 2015 (Donna Ryan and Andres Acosta. Obesity (Silver Spring). June 2015; 23(6)). Currently, there are two specific GLP-1 agonists approved for the treatment of diabetes and obesity (liraglutide and semaglutide), and other agonists are often used off-label for the treatment of obesity. Several studies have shown that GLP-1 agonists reduce cardiovascular events and mortality and protect chondrocytes from endoplasmic reticulum stress, apoptosis, and inflammation by reducing the release of inflammatory mediators (Wei Peng et al., Aging Dis. April 2022; 13(2)). Other effects of GLP-1 agonists include improving β-cell function through gene regulation, suppressing glucagon production, and delaying gastric emptying. (Peyton W. Moore Adv Ther. March 2023; 40(3)). One of the main problems with GLP-1 agonists in the treatment of obesity is side effects, which include gastrointestinal problems, nausea, diarrhea, constipation, indigestion, abdominal pain, and vomiting.This may necessitate gradual titration to allow patients to better tolerate the medication. Furthermore, because these medications are peptides, they can only be administered via intraparietal injection and cannot be taken orally.

[0008] Currently, there are three FDA-approved semaglutide products: Ozempic® injection, Rybelsus® tablets, and Ugobi® injection. Ozempic and Rybelsus are approved to lower blood glucose levels in adults with type 2 diabetes, in addition to diet and exercise. Ozempic® is also approved to reduce the risk of heart attack, stroke, or death in adults with type 2 diabetes and heart disease. Ugobi® injection is approved for obese adults and children 12 years of age and older, or certain adults (overweight) with weight-related medical problems, in addition to diet and exercise, to help them lose and maintain their weight.

[0009] There is an unmet need for new treatments for metabolic syndrome, diabetes, obesity, and weight loss that provide more tolerable routes of administration while avoiding the side effects of existing treatments. [Overview of the project] [Means for solving the problem]

[0010] In one embodiment, the Disclosure includes a method of administering to subjects suffering from metabolic syndrome or metabolic disorders a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0011] The present invention provides compounds of formula (I), or pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants thereof. [Chem 1] TIFF2026529640000003.tif47170TIFF2026529640000004.tif49170R 1 , R 5 and R 7 are each independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl, R 2 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or heteroaryl group is each independently optionally substituted, R 6 and R 8 are each independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or heteroaryl group is each independently optionally substituted, R 9 and R 10 are each independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl, or R 9 and R 10 bind together with the carbon atom to which they are attached to form an optionally substituted C3-C6 cycloalkyl group, R 11 each is each independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl, and the -C(R 11 )2-C(R 11 )2- group in ring b is optionally replaced by an optionally substituted 1,2-phenylene group fused to ring b, each C1-C3 alkylene is independently optionally substituted, m and n are independently selected from the group consisting of 1, 2, 3, and 4, and satisfy 2 ≤ (m + n) ≤ 4. p and q are independently selected from the group consisting of 0, 1, 2, 3, and 4, and satisfy 2 ≤ (p + q) ≤ 4. However, this is conditional on the alkyl group not being substituted with a hydroxyl group.

[0012] In certain embodiments, the compound of formula (I) may include the compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof. [Case 2] TIFF2026529640000005.tif47170TIFF2026529640000006.tif49170R 1 , R 5 and R 7 Each is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups. R 2 The group is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted. R 6 and R 8 Each of these is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted. R 9 and R 10Each is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups, or R 9 and R 10 These bond to the carbon atoms to which they are attached, forming optionally substituted C3-C6 cycloalkyl groups. R 11 Each of them is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups, and -C(R) in ring b 11 )2-C(R 11 The 2-group can be optionally replaced with an optionally substituted 1,2-phenylene group condensed with ring b, Each of the C1-C3 alkylenes can be substituted independently and arbitrarily. m and n are independently selected from the group consisting of 1, 2, 3, and 4, and satisfy 2 ≤ (m + n) ≤ 4. p and q are independently selected from the group consisting of 0, 1, 2, 3, and 4, and satisfy 2 ≤ (p + q) ≤ 4. However, this is conditional on the alkyl group not being substituted with a hydroxyl group.

[0013] In certain embodiments, the compound of formula (I) is the compound of formula (IIb). [C3] TIFF2026529640000007.tif47170TIFF2026529640000008.tif39162 Each is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups, R 2 L is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted, L is an arbitrarily substituted C1-C3 alkylene, and R 6 and R 8Each of these is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and optionally substituted, R 11 Each of the elements is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups, L is optionally substituted C1-C3 alkylene, and m and n are independently selected from the group consisting of 1, 2, 3, and 4, and satisfying 2 ≤ m + n ≤ 4, provided that the alkyl group is not substituted with a hydroxyl group.

[0014] In certain embodiments, the compound of formula (I) is the compound of formula (IIc). [C4] TIFF2026529640000009.tif47170TIFF2026529640000010.tif41164 Each is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups, R 2 The group is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted, R 6 and R 8 Each of these is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and optionally substituted, R 9 and R10 Each is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups, or R 9 and R 10 These bond to the carbon atoms to which they are bonded, forming optionally substituted C3-C6 cycloalkyl groups, R 11 Each of them is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups, and -C(R) in ring b 11 )2-C(R 11 The 2-group is optionally replaced with an optionally substituted 1,2-phenylene group condensed with ring b, each of L is independently an optionally substituted C1-C3 alkylene, and p and q are independently selected from the group consisting of 0, 1, 2, 3, and 4, satisfying 2 ≤ p + q ≤ 4, provided that the alkyl group is not substituted with a hydroxyl group.

[0015] In certain embodiments of the compounds of formulas (I), (IIa), (IIb), and (IIc), each alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, F, Cl, Br, I, and CN. Each cycloalkyl, alkenyl, or alkynyl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, F, Cl, Br, I, and CN. Each phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl group is C1-C6 alkyl, C1-C6 alkoxy, hydroxy, F, Cl, Br, I, nitro, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -S(=O) 0-2 The molecule is arbitrarily substituted with one or more substituents independently selected from the group consisting of (C1-C6 alkyl), -C(=O)OH, and -C(=O)OC1-C6 alkyl.

[0016] In certain embodiments of the compound of formula (I), R 1 , R 5 and R 7is hydrogen. In certain embodiments of the compound of formula (I), R 1 , R 5 and R 7 These are each independently and arbitrarily substituted C1-C3 alkyl groups. In certain embodiments of the compound of formula (I), R 1 , R 5 and R 7 is hydrogen, R 9 and R 10 is hydrogen. In certain embodiments of the compound of formula (I), R 1 , R 5 and R 7 is hydrogen, R 9 is hydrogen, R 10 It is CH3.

[0017] In certain embodiments of the present invention, the compound of formula (I) is selected from the group consisting of the following: 2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(4); 2-[(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-yl)-methyl-amino]-ethanol(6); 3-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-1-ol(8); 1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-yl (amino)-propane-2-ol(10); (S)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-2-ol(12); (R)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-2-ol(14); 2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propane-1-ol(16); (S)-2-(2 ,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-1-ol(18);(R)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-1-ol(20);3-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-1,1,1-trifluoro-propane-2-ol(22);1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-1,1,1-trifluoro-propane-2-ol(22);1-(2,6-bis-methylamino-8-propylamino-pyrimido Mido[5,4-d]pyrimidine-4-ylamino)-butan-2-ol(24); 3-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-butan-2-ol(26); 2-(2,6-bis-ethylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(27); 2-[8-propylamino-2,6-bis-(2,2,2-trifluoroethylamino)-pyrimido[5,4-d]pyrimidine-4-ylamino]-ethanol(28);1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propane-2-ol(31);1-(2,6-bis-ethylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propane-2-ol(32);1-[2,6-bis-(2,2-difluoro-ethylamino)-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino]-2-methyl-propane-2-ol(33);2-methyl-1- [8-Propylamino-2,6-bis-(2,2,2-trifluoroethylamino)-pyrimido[5,4-d]pyrimidine-4-ylamino]-propane-2-ol(34);1-[8-(2,2-difluoroethylamino)-2,6-bis-methylaminopyrimido[5,4-d]pyrimidine-4-ylamino]-2-methyl-propane-2-ol(36);1-{2,6-bis-methylamino-8-[(pyrimidine-2-ylmethyl)-amino]pyrimido[5,4-d]pyrimidine-4-ylamino}-2-methyl-propane -2-ol(38);1-[8-((R)-sec-butylamino)-2,6-bis-methylaminopyrimido[5,4-d]pyrimidine-4-ylamino]-2-methyl-propane-2-ol(40);1-[8-((S)-sec-butylamino)-2,6-bis-methylaminopyrimido[5,4-d]pyrimidine-4-ylamino]-2-methyl-propane-2-ol(42);1-(8-benzylamino-2,6-bis-methylaminopyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propane-2- ol (44); 1-[8-(cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidine-4-ylamino]-2-methyl-propane-2-ol (46); 1-[8-(2,2-difluoro-ethylamino)-2,6-bis-ethylamino-pyrimido[5,4-d]pyrimidine-4-ylamino]-2-methyl-propane-2-ol (47); 2-methyl-1-(2,6,8-tris-methylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-2-ol (48);2-Methyl-1-(2,6,8-tris-ethylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-2-ol(49); 2-(2,6,8-tris-methylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(52); 2-[8-(cyclopropylmethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidine-4-ylamino]ethanol(54); 2-[8-(2-methoxyethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidine 2-(2,6-bis-methylamino-8-prop-2-inylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(56); 2-[8-(2,2-difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidine-4-ylamino]-ethanol(60); 2-[2,6-bis-methylamino-8-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidine-4-ylamino]-ethanol(62); 2-(8-be (64)(2,6-bis-methylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(64); 3-(8-ethylamino-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-propane-1-ol(67); 1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-yl)-pyrrolidine-3-ol(71); 1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-methylamino-ethanolethanol(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-ethanol(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino [L]-cyclobutanol (72); 1-[(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-yl)-methyl-amino]-propane-2-ol (73); 3-[(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-methyl]-pentan-3-ol (74); 1-[(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-yl)-methyl-amino]-2-methyl-propane-2-ol (76);(1R,2S)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-indan-2-ol(77);(1S,2S)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-indan-2-ol(78);(1S,2R)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-indan-2-ol(79);(1R,2R)-1-( 2,6-Bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-indan-2-ol(80); 2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-indan-1-ol(81); (1R,2S)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-cyclohexanol(82); (1S,2S)-2-(2,6-bis-methylamino-8-propyl Amino-pyrimido[5,4-d]pyrimidine-4-ylamino)-cyclohexanol(83);(1S,2R)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-cyclohexanol(84);(1R,2R)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-cyclohexanol(85);(1S,2S)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d ]pyrimidine-4-ylamino)-cyclopentanol(86); (1R,2R)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-cyclopentanol(87); 2-[6-(cyclopropylmethylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino]-ethanol(90); 2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-ethanol(91);2-(6-dimethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-ethanol(92); 1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-2-methyl-propane-2-ol(94); 1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-propane-2-ol(95); 1-[(4,8-bis-methylamino-6-propylamino-pyrimidine- Mido[5,4-d]pyrimidine-2-yl)-methyl-amino]-2-methyl-propan-2-ol(96); 1-[(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-yl)-methyl-amino]-propan-2-ol(97); 1-[6-((R)-sec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino]-2-methyl-propan-2-ol(99); (R)-1-[6-((R)-sec-butylamino)-4 ,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-propan-2-ol(100);(S)-1-[6-((R)-sec-butylamino)-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-propan-2-ol(101);1-[6-((S)-sec-butylamino)-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-2-methyl-propan-2-ol(103);(R)-1-[6-((S)- sec-butylamino)-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-propan-2-ol(104);(S)-1-[6-((S)-sec-butylamino)-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-propan-2-ol(105);1-[6-(2,2-difluoroethylamino)-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-2-methyl-propan-2-ol(107);1-{4,8-bis-methylamino-6-[(pyrimidine-2-ylmethyl)-amino]-pyrimido[5,4-d]pyrimidine-2-ylamino}-2-methyl-propane-2-ol(109);3-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-1,1,1-trifluoro-propane-2-ol(111);(S)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-propane-2-ol(113);(R)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-; [d]pyrimidine-2-ylamino)-propane-2-ol(115); 1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-butan-2-ol(117); 3-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-butan-2-ol(119); (1R,2S)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-inda n-2-ol(123);(1S,2S)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-indan-2-ol(125);(1S,2R)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-indan-2-ol(127);(1R,2R)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-indan- 2-ol(129);(1R,2S)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-cyclohexanol(131);(1S,2S)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-cyclohexanol(133);(1S,2R)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-cyclohexanol (135); (1R,2R)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-cyclohexanol(137); (1S,2S)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-cyclopentanol(139); (1R,2R)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-cyclopentanol(141);(S)-1-[6-(cyclopropylmethylamino)-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-propane-2-ol(142);(S)-1-(6-allylamino-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino)-propane-2-ol(143);(R)-1-[6-(cyclopropylmethylamino)-4,8-bis-methylaminopyrimido[5,4-d]pyrimidine-2-ylamino]-propane-2-ol(144);(R)-1 -(6-allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-propane-2-ol(145);1-[6-(cyclopropylmethylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino]-butan-2-ol(146);1-(6-ethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-butan-2-ol(147);2-methyl-1-(4,6,8-tris-methylamino-pyrimido[ 5,4-d]pyrimidine-2-ylamino)-propane-2-ol(149); 2-(6-allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-ethanol(154); (S)-1-[(6-allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-yl)-propyl-amino]propane-2-ol(155); (S)-1-[(6-allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-yl)-methyl-amino ]-Propan-2-ol(156);(R)-1-[6-(2-methyl-allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino]-propane-2-ol(158);(S)-1-[6-(2-methyl-allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidine-2-ylamino]-propane-2-ol(159);2-(4,8-bis-ethylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-ethanol(162);1-(4,8-bis-ethylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-2-methyl-propane-2-ol(163);(S)-1-(4,6,8-tris-ethylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-propane-2-ol(165);(S)-1-(4,8-bis-ethylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-propane-2-ol(166);(R)-1-(4,6,8-tris-ethylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-propane-2-ol(168);(R)-1-(4 ,8-bis-ethylamino-6-propylamino-pyrimido[5,4-d]pyrimidine-2-ylamino)-propan-2-ol(169);(R)-1-[4,8-bis-ethylamino-6-(2-methyl-allylamino)-pyrimido[5,4-d]pyrimidine-2-ylamino]-propan-2-ol(174);(S)-1-[4,8-bis-ethylamino-6-(2-methyl-allylamino)-pyrimido[5,4-d]pyrimidine-2-ylamino]-propan-2-ol(175), and their pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, isotopic variants, and any combination thereof.

[0018] A detailed description of the compound is provided in U.S. Patent No. 10294228, which is incorporated herein by reference.

[0019] One aspect of the present disclosure includes a method for reducing weight in a subject requiring weight loss, the method comprising administering to a subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in particular GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, along with a pharmaceutically acceptable carrier or excipient.

[0020] One aspect of the present disclosure includes a method for treating a subject who has diabetes or is at risk of developing diabetes, the method comprising administering to the subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in particular GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, along with a pharmaceutically acceptable carrier or excipient.

[0021] One aspect of the present disclosure includes a method for treating an obese subject, the method comprising administering to the subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in particular GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, along with a pharmaceutically acceptable carrier or excipient.

[0022] One aspect of the present disclosure includes a method for treating a subject having an eating disorder, the method comprising administering to the subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in particular GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, along with a pharmaceutically acceptable carrier or excipient.

[0023] One aspect of the present disclosure includes a method for treating a subject with bulimia nervosa, the method comprising administering to the subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in particular GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, along with a pharmaceutically acceptable carrier or excipient.

[0024] One aspect of the present disclosure includes a method for treating a subject with hyperlipidemia, the method comprising administering to the subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in particular GAL475(1-(2,6-bis-methylamino-8-propylaminopyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, along with a pharmaceutically acceptable carrier or excipient.

[0025] One aspect of the present disclosure includes a method for treating an insulin-resistant subject, the method comprising administering to the subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in particular GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, along with a pharmaceutically acceptable carrier or excipient.

[0026] In one embodiment, this composition is a ready-release composition.

[0027] In one embodiment, the composition is a modified-release composition.

[0028] In one embodiment, the modified release composition is an orally administered modified release composition.

[0029] In one embodiment, the composition includes an enteric coating.

[0030] In one embodiment, the composition includes a gelatin coating.

[0031] In one embodiment, the composition contains excipients, which include binders, disintegrants, diluents, buffers, lubricants, antioxidants, antimicrobial preservatives, colorants, or flavorings.

[0032] In one embodiment, the compound is coated onto basic particles to form a core.

[0033] In one embodiment, the core is coated with an enteric coating to form enteric coated beads.

[0034] In one embodiment, this dosage form is an oral dosage form.

[0035] In one embodiment, the oral dosage form is in the form of a capsule, tablet, or pharmaceutically acceptable solution.

[0036] In one embodiment, the composition contains a compound in an amount of approximately 2 mg to approximately 5000 mg, approximately 5 mg to approximately 3000 mg, approximately 10 mg to approximately 2000 mg, approximately 20 mg to approximately 1500 mg, approximately 30 mg to approximately 1000 mg, approximately 40 mg to approximately 900 mg, approximately 50 mg to approximately 800 mg, approximately 100 mg to approximately 700 mg, approximately 150 mg to approximately 600 mg, approximately 200 mg to approximately 500 mg, approximately 250 mg to approximately 400 mg, or approximately 300 mg to approximately 350 mg.

[0037] In one embodiment, the composition is encapsulated in a capsule.

[0038] In one embodiment, the capsule comprises granules or powder of the compound, or granules or powder consisting of a mixture of the compound and a pharmaceutically acceptable carrier or excipient.

[0039] In one embodiment, the capsules are enterically coated, while the granules or powder are not.

[0040] In one embodiment, at least a portion of the granules or powder is enterically coated.

[0041] In one embodiment, at least a portion of the granules or powder is coated with an enteric coating before being encapsulated.

[0042] In one embodiment, the granules or powder comprises a first portion coated with one enteric coating and at least a second portion coated with a different enteric coating, wherein the first portion is released in a different region of the intestine from the second portion.

[0043] In one embodiment, the capsule is a liquid-filled capsule further comprising a composition and a pharmaceutically acceptable liquid, which are mixed to form a liquid formulation.

[0044] In one embodiment, the capsule is enterically coated, while the liquid formulation inside the capsule does not contain the enteric coating.

[0045] In one embodiment, the method further includes administering at least one known drug for treating an underlying disease.

[0046] In one embodiment, the method further includes at least one additional agent selected from the group consisting of antidiabetic agents, weight-loss agents, metabolic syndrome treatment agents, and anti-obesity agents.

[0047] In one embodiment, the method further comprises administering a composition or capsule separately from at least one drug.

[0048] In one embodiment, the method further comprises administering the composition or capsule simultaneously with at least one drug.

[0049] In one embodiment, the compound and at least one additional agent are physically mixed in the composition.

[0050] In one embodiment, the compound and at least one additional agent form a physically separated structure in the composition.

[0051] In one aspect, the subject is a mammal or a bird.

[0052] In one aspect, the subject is human beings.

[0053] In one embodiment, administration is carried out by at least one route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, pleural, peritoneal, transvaginal, intramuscular, subcutaneous, percutaneous, epidural, intrathecal, and intravenous.

[0054] In one embodiment, pharmaceutically acceptable salts include acid addition salts selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, sulfanilic acid, stearic acid, alginic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid, or combinations thereof. In one embodiment, the salt is (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propane-2-ol dihydrochloride).

[0055] In one aspect, the Disclosure includes the use of a compound of formula (I), or its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants, in the manufacture of a pharmaceutical product for the suppression or treatment of a target metabolic syndrome or metabolic disease. In certain aspects, the compound is GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants, in the manufacture of a pharmaceutical product for the suppression or treatment of a target metabolic syndrome or metabolic disease.

[0056] In one aspect, the disclosure includes the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a drug for inducing weight loss in a subject. In certain aspects, the compound is GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), and the use of a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a drug for inducing weight loss in a subject.

[0057] In one aspect, the Disclosure includes the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment or prevention of diabetes in a subject area. In a particular aspect, the compound is GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), and a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment or prevention of diabetes in a subject area.

[0058] In one aspect, the Disclosure includes the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target eating disorder. In certain aspects, the compound is GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), and includes the use of a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target eating disorder as needed.

[0059] In one aspect, the Disclosure includes the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target bulimia nervosa. In certain aspects, the compound is GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), and includes the use of a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target bulimia nervosa.

[0060] In one aspect, the disclosure includes the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target hyperlipidemia. In certain aspects, the compound is GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), and includes the use of a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target hyperlipidemia as needed.

[0061] In one aspect, the disclosure includes the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target insulin resistance. In certain aspects, the compound is GAL475(1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol), and includes the use of a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, in the manufacture of a pharmaceutical product for the treatment of a target insulin resistance as needed.

[0062] Other features and characteristics of the subject matter of this disclosure, as well as the methods of operation, the functions of the structural elements, the combination of components, and the economics of manufacture, will become more apparent by considering the following description, drawings, and appended claims, all of which constitute part of this specification. [Brief explanation of the drawing]

[0063] The features and advantages of the present invention will be understood by referring to the following detailed description, which sets out explanatory embodiments that can utilize the principles of the present invention, and the accompanying drawings.

[0064] [Figure 1] This graph shows the weight gain of rats administered GAL475 for 28 days compared to the vehicle-administered group. [Figure 2] The food intake of rats after GAL475 administration is shown as a percentage (%) of the food intake of the vehicle-administered control group. [Figure 3] The weight gain in dogs after 28 days of GAL475 administration at doses of 30 mg / kg, 15 mg / kg, and 7.5 mg / kg is shown as a percentage change in body weight compared to the vehicle control group. [Figure 4] The amount of gastric contents retained in rats after GAL475 administration is shown in comparison to the vehicle group. [Figure 5] This graph shows the inter-individual variation in body weight one week after a single oral administration of 450 mg of GAL475 in human subjects, comparing the GAL475 group (left) and the placebo group (right). [Modes for carrying out the invention]

[0065] While aspects of the subject matter of this disclosure may manifest in various forms, the following description is intended to disclose some of these forms as specific examples of the subject matter included in this disclosure. Therefore, the subject matter of this disclosure is not limited to the forms or embodiments described herein.

[0066] GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methyl-propan-2-ol) is an investigational drug initially developed as a respiratory control modifier for the treatment of two major phenotypes of sleep-disordered breathing: central sleep apnea and obstructive sleep apnea. A description of the molecule and related compounds is provided in U.S. Patent No. 10294228, which is incorporated herein by reference.

[0067] This respiratory control activity is likely mediated via the carotid body, a peripherally diverse chemoreceptor located at the carotid bifurcation, which senses partial pressure changes in O2, CO2, or pH and activates the brainstem respiratory center to induce hyperventilation. As shown in the following examples, this disclosure provides surprising and unexpected uses of the GAL475 compound in the treatment of metabolic syndrome and related disorders and conditions. This disclosure includes disclosures and examples showing that administration of GAL475 slows gastric emptying and consequently reduces appetite. For example, as shown in Example 2, rats administered GAL475 (40 mg / kg per day) for 28 days showed dose-dependent significant weight loss compared to the vehicle. As a further example, as shown in Example 3, dogs administered GAL475 for 28 days showed a 25% weight loss compared to the vehicle and a dose-dependent dramatic decrease in food intake. And, as shown in Example 5, administration of GAL475 to human subjects resulted in weight loss in humans as well. GAL475 can effectively induce weight loss and appetite suppression in humans and animals. This disclosure includes the use of GAL475 for the treatment of metabolic syndrome, eating disorders, bulimia, hyperlipidemia, insulin resistance, obesity, diabetes, and for achieving weight loss effects in humans.

[0068] ==Definition== Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the invention pertains. While methods and materials used herein are described, other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety.

[0069] The terms "a" and "an" refer to a grammatical object of the article that is one or more (in other words, at least one). For example, "a cell" includes one or more cells.

[0070] As used herein, the terms “treatment” or “treatment” mean an approach to obtain beneficial or desirable results, in particular clinical outcomes, as is widely understood in the art. Beneficial or desirable clinical outcomes include, but are not limited to, relief or improvement of one or more symptoms or conditions, reduction in disease progression, stabilization of the disease state (in other words, no worsening), delay or slowing of disease progression, improvement or relief of the disease state, reduction in disease relapses, and partial or complete remission (whether detectable or undetectable). “Treatment” and “treatment” also mean extending survival compared to the expected survival without treatment. Methods described herein may be useful not only as treatments but also as prevention or preventive measures for disease.

[0071] As used herein, the phrases “simultaneous administration” or “combined administration” mean that two (or more) drugs are administered in parallel over time. Simultaneous or combined administration may include mixing two drugs into a single formulation, administering two drugs separately at the same time, or administering them separately within a short period of time. For example, typically, two drugs are administered simultaneously within a time range of 0.5 to 168 hours.

[0072] Concentration, quantity, time, and other numerical data may be expressed or presented in range form in this specification. Such range forms are used for convenience and conciseness and should therefore be interpreted flexibly to include not only the numerical limits explicitly stated as range limits, but also all individual numerical values ​​and subranges within that range. For example, a numerical range of "approximately 0.01 to 2.0" should be interpreted to include not only the explicitly stated values ​​from approximately 0.01 to approximately 2.0, but also the individual values ​​and subranges within the indicated range. Therefore, this numerical range includes individual values ​​such as 0.5, 0.7, and 1.5, as well as subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5. Furthermore, such interpretation should apply regardless of the width of the range or the characteristics described. Additionally, note that all percentages are weight percentages unless otherwise specified.

[0073] In understanding the scope of this specification, the terms “contains” or “includes” and their derivatives as used herein are open-ended terms that identify the presence of the described features, elements, components, groups, integers, and / or steps, and are not intended to exclude the presence of other features, elements, components, groups, integers, and / or steps not described herein. The foregoing also applies to similar terms such as “contains,” “have,” and their derivatives. The terms “consist of” and their derivatives as used herein are closed terms that identify the presence of the described features, elements, components, groups, integers, and / or steps, and are not intended to exclude the presence of other features, elements, components, groups, integers, and / or steps not described herein. The terms “essentially consist of” as used herein are intended to identify the presence of the described features, elements, components, groups, integers, and / or steps, and are intended to include those that do not substantially affect the basic and novel properties of these features, elements, components, groups, integers, and / or steps. References to any of these transition terms (in other words, “including,” “consisting of,” or “essentially consisting of”) are understood to directly support substitution of other transition terms not specifically used. For example, amending a term from “including” to “essentially consisting of” can find direct support based on this definition. Based on this definition, elements disclosed herein or incorporated by reference may be included in or excluded from the claimed invention.

[0074] As used herein, the terms “substantially” and “substantial” refer to a considerable degree or range. For example, when used in conjunction with events, situations, characteristics, or properties, these terms can refer to both the exact occurrence of an event, situation, characteristic, or property and the approximate occurrence of an event, situation, characteristic, or property, such as taking into account the typical tolerance levels and variations of the examples described herein.

[0075] As used herein, the term “about” is used to provide flexibility to the endpoints of a numerical range, indicating that a given value may be “slightly above” or “slightly below” the endpoint. The degree of flexibility in this term is determined by certain variables and is within the range that a person skilled in the art can determine based on experience and the descriptions relating herein. For example, in one embodiment, the degree of flexibility may be within about ±10% of the numerical value. In another embodiment, the degree of flexibility may be within about ±5% of the numerical value. In yet another embodiment, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value.

[0076] In this specification, the term "or" generally includes "and / or".

[0077] In this specification, multiple compounds, elements, or steps may be presented in common lists for convenience. However, these lists should be interpreted as if each member of the list were individually identified and distinct. Therefore, individual members of such lists should not be interpreted as de facto equivalents of other members of the same list simply because they are presented as a common group, unless otherwise indicated.

[0078] In this specification, the term “exemplary” means that it serves as an example, case, or illustration. Any aspect or design described herein as “exemplary” should not be construed as necessarily preferable or advantageous to other aspects or designs. Rather, the use of the word “exemplary” is intended to present the concept in a more concrete way.

[0079] As used herein, "modified release" may include sustained release (XR), long-acting (LA), sustained release (SR), controlled release (CR), delayed release (DR), enteric coating, repeat action, pulsed release, or a combination thereof.

[0080] In certain embodiments, the composition includes an enteric coating. In other embodiments, the compound is encapsulated in a pharmaceutically appropriate capsule. In other embodiments, the capsule contains granules or powder of the compound, or a mixture of the compound and a carrier or excipient. In other embodiments, the excipient includes a binder, disintegrant, diluent, buffer, lubricant, antimicrobial preservative, colorant, or flavoring agent. In other embodiments, the capsule is enteric coated, but the granules or powder of the compound is not. In other embodiments, the granules or powder of the compound are coated with an enteric coating before being filled into capsules. In other embodiments, the granules or powder of the compound are coated with multiple enteric coatings to provide delivery of the drug to different parts of the target intestine. In other embodiments, at least a portion of the granules or powder of the compound is enteric coated. In other embodiments, the capsule is coated with an enteric coating different from the enteric coating that coats the granules or powder of the compound.

[0081] In certain embodiments, the compound is coated onto base particles to form a core. In other embodiments, the base particles are not enterically coated, and the composition is encapsulated in an enterically coated, pharmaceutically acceptable capsule. In other embodiments, the core is coated with an enteric coating to form enterically coated beads. In other embodiments, the enterically coated beads are encapsulated in a pharmaceutically acceptable capsule. In other embodiments, the capsule contains multiple enterically coated beads, thereby allowing the capsule to deliver the compound to different parts of the target intestine. In other embodiments, the contents of the capsule are dissolved or suspended in a pharmaceutically acceptable liquid to provide a liquid-filled capsule. In other embodiments, the capsule is enterically coated, but the liquid formulation contained within it does not contain an enteric coating.

[0082] Furthermore, specific compositions, elements, excipients, components, problems, conditions, characteristics, steps, or similar matters may be discussed in the context of specific embodiments or aspects of this disclosure, or in other paragraphs or sections. This is merely for convenience and brevity, and it is understood that all such disclosures are equally applicable to and intended to be combined with other embodiments and aspects found anywhere in this disclosure and claims. All of these constitute the claimed invention as of the filing date. For example, the list of steps, active ingredients, kits, or compositions described with respect to the compound of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants, particularly GAL475 (and related compounds described herein) or embodiments of methods for treating specific targets, are intended and actually provide direct support to embodiments relating to compositions, formulations, or formulations of compound formula (I) or its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants, even if those steps, activators, kits, or compositions are not described again within the context or section of the embodiments or embodiments.

[0083] In this specification, references to “compounds, salts, or stereoisomers of GAL475” are intended to include “one or more” such compounds, including salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants thereof. Furthermore, in the following descriptions of pharmaceutical formulations, the term “compound” is intended to include salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants of such compounds.

[0084] The compounds of the present invention may have one or more stereocenters, each stereocenter may exist independently in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in the form of optically active compounds or racemates. The compounds described herein include racemates, optically active compounds, positional isomers and stereoisomers, or combinations thereof, which have the therapeutically useful properties described herein. Preparation of optically active compounds can be achieved by any suitable method, including, but not limited to, recrystallization techniques for racemates, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds can be prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. The separation of compounds and their isomers is achieved by means including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0085] The methods and formulations described herein include N-oxides (where appropriate), crystalline forms (also called polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of any compound having the structure of the compounds of the present invention, as well as metabolites and active metabolites having the same activity as these compounds. Solvates include water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohols (e.g., ethanol) solvates, acetates, and the like. In certain embodiments, the compounds described herein exist in solvated form with a pharmaceutically acceptable solvent such as water or ethanol. In other embodiments, the compounds described herein exist in non-solvated form.

[0086] In certain embodiments, the compounds of the present invention exist as tautomers. The scope of compounds described herein includes all tautomers.

[0087] In certain embodiments, the compounds described herein are prepared as prodrugs. A prodrug is a drug that is converted to a parent drug in the body. In certain embodiments, after in vivo administration, the prodrug is chemically converted to a biologically, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to a biologically, pharmaceutically, or therapeutically active form of the compound.

[0088] In certain embodiments, for example, a moiety in the aromatic ring portion of the compound of the present invention is sensitive to various metabolic reactions. By introducing appropriate substituents to the aromatic ring structure, it is possible to reduce, minimize, or eliminate these metabolic pathways. In certain embodiments, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions are, for illustrative purposes only, deuterium, halogens, or alkyl groups.

[0089] The compounds described herein also include isotope-labeled compounds in which one or more atoms have the same atomic number but are replaced by atoms with different atomic weights or mass numbers than those normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35This includes, but is not limited to, S. In certain embodiments, isotope-labeled compounds are useful for studying the tissue distribution of drugs and / or substrates. In other embodiments, substitution with a heavier isotope (e.g., deuterium) results in greater metabolic stability (e.g., extension of in vivo half-life or reduction of dosage). In other embodiments, 11 C, 18 F, 15 O, 13 The use of positron-emitting isotopes such as 13N is useful in positron emission topography (PET) studies to investigate the occupancy status of substrate receptors. Isotope-labeled compounds are prepared by any suitable method, or by a process using a suitable isotope-labeling reagent instead of the normally used unlabeled reagent.

[0090] In certain embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores, fluorescent groups, bioluminescent labels, or chemiluminescent labels.

[0091] Methods for synthesizing the molecules of this disclosure are disclosed, for example, in U.S. Patent No. 10,294,228, which is incorporated herein by reference in its entirety for all purposes.

[0092] ==Pharmaceutical Compositions and Preparations==

[0093] The present invention also includes the use of a pharmaceutical composition of at least one compound of the present invention or a salt, solvate, enantiomer, diastereomer, or tautomer thereof for carrying out the method of the present invention. Such a pharmaceutical composition may consist of at least one compound of the present invention or a salt, solvate, enantiomer, diastereomer, or tautomer thereof in a form suitable for administration to a subject, or may include at least one compound of the present invention or a salt, solvate, enantiomer, diastereomer, or tautomer thereof, along with one or more pharmaceutically acceptable carriers, one or more additional components, or some combination thereof. At least one compound of the present invention may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, in combination with a physiologically acceptable cation or anion, as is well known to those skilled in the art.

[0094] In one embodiment, a pharmaceutical composition useful for carrying out the method of the present invention may be administered in doses ranging from 1 ng / kg / day to 5,000 mg / kg / day. In another embodiment, a pharmaceutical composition useful for carrying out the present invention may be administered in doses ranging from 1 ng / kg / day to 1,000 mg / kg / day.

[0095] In compositions comprising one or more compounds of the present disclosure, the effective dose may include dose units of approximately 0.01 to 500 mg / kg, or approximately 1 to 100 mg / kg per day, or approximately 5 to 50 mg / kg per day. In some embodiments, the dose units are administered every other day, every other week, or every week.

[0096] The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and additional components in the pharmaceutical composition of the present invention vary depending on the specific target, size, and condition of the target, and also on the route through which the composition is administered. For example, the composition may contain 0.1% to 100% (w / w) of the active ingredient.

[0097] Pharmaceutical compositions useful in the methods of the present invention can be developed in forms suitable for nasal, inhalation, oral, rectal, vaginal, pleural, peritoneal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, epidural, intrathecal, intravenous, or other routes of administration. Compositions useful in the methods of the present invention can be directly administered to the brain, brainstem, or other parts of the central nervous system of mammals or birds. Other conceivable formulations include spray nanoparticles, microspheres, liposome formulations, coated particles, polymer complexes, reencapsulated red blood cells containing active ingredients, and immunological formulations.

[0098] In certain embodiments, the compositions of the present invention are part of a pharmaceutical base material, enabling the manipulation of insoluble materials, improvement of their bioavailability, development of immediate, controlled, or sustained-release formulations, and production of homogeneous compositions. For example, pharmaceutical base materials can be prepared using hot-melt extrusion, solid solutions, solid dispersions, pulverization techniques, molecular complexes (e.g., cyclodextrins), microparticles, and particle and formulation coating processes. Amorphous or crystalline phases may be used in such processes.

[0099] The route of administration is obvious to a skilled technician and depends on various factors, such as the type and severity of the disease being treated, and the type and age of the animal or human patient being treated.

[0100] Formulations of the pharmaceutical compositions described herein may also be prepared by any methods known or to be developed in the fields of pharmacology and pharmacy. Generally, such pretreatment methods include a step of binding the active ingredient to a carrier or one or more other auxiliary components, and, if necessary or desirable, forming or packaging the product into desired single-dose or multi-dose units.

[0101] As used herein, "unit dose" refers to a predetermined amount of a pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient administered to a subject, or corresponds to a convenient fraction of that dose, for example, half or one-third of that dose. The unit dosage form may be either a once-daily dose or a multiple-daily dose (e.g., approximately one to four or more times per day). If multiple daily doses are administered, the unit dosage form may be the same or different for each dose.

[0102] The descriptions of pharmaceutical compositions provided herein primarily concern pharmaceutical compositions suitable for ethical administration to humans, but those skilled in the art will understand that such compositions are generally suitable for administration to all kinds of animals. It is well known that pharmaceutical compositions suitable for administration to humans can be modified to be suitable for administration to various animals, and a veterinary pharmacologist with ordinary skill can design and carry out such modifications by ordinary experiments if necessary. Subjects for which administration of the pharmaceutical compositions of the present invention is considered include, but are not limited to, humans and other primates, as well as commercially important mammals such as cattle, pigs, horses, sheep, cats, and dogs.

[0103] In certain embodiments, the compositions of the present invention are formulated using one or more pharmaceutically approved excipients or carriers. In certain embodiments, the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one compound of the present invention and a pharmaceutically acceptable carrier. Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, physiological saline, ethanol, recombinant human albumin (e.g., Recombumin®), dissolved gelatin (e.g., Gelofusine®), and other pharmaceutically acceptable salt solutions such as phosphates and organic acid salts. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0104] In accordance with the principles of the present invention, the compounds of this disclosure may exist in a composition in the form of a free base, a salt thereof, or a mixture thereof. Salts in accordance with the principles of the present invention can be prepared, for example, by reacting the free base with one or more equivalents of a suitable base or acid in a solvent in which the salt is insoluble, or by preparing it in a solvent such as water, then removing it under vacuum and freeze-drying it, or by exchanging the ions of an existing salt with other ions on a suitable ion-exchange resin. Each possibility represents a distinct embodiment of the invention.

[0105] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, or liquid polyethylene glycol), recombinant human albumin, solubilized gelatin, suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, maintaining the required particle size in the case of dispersion, and the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents such as parabens, chlorbutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol or sorbitol. To extend the absorption of the injectable composition, this can be achieved by including an absorption-delaying agent in the composition, such as aluminum monostearate or gelatin.

[0106] The compositions of the present invention may further contain one or more pharmaceutically acceptable excipients selected from co-surfactants, solvents, solvents / co-solvents, water-insoluble solvents, water, water-miscible solvents, oily components, hydrophilic solvents, emulsifiers, preservatives, antioxidants, defoamers, stabilizers, buffers or pH adjusters, osmotic agents, pore-forming agents, osmotic pressure regulators, or other excipients known in the art. Each possibility represents a distinct embodiment. Suitable co-surfactants or solvents may include, but are not limited to, polyethylene glycol, "poloxamers" known as polyoxyethylene-polyoxypropylene block copolymers, polyglycerol fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyethylene glycol sorbitan monooleate (Tween), polyethylene glycol fatty acid esters such as polyethylene glycol monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, hydrogenated castor oils such as polyoxyethylene-derived castor oil and polyoxyethylene hydrogenated castor oil, and mixtures thereof. Each possibility represents a distinct embodiment of the present invention. Suitable solvents / co-solvents may include, but are not limited to, alcohols, triacetin, dimethyl isosorbide, glycoflore, propylene carbonate, water, dimethylacetamide, and mixtures thereof. Each possibility represents a distinct embodiment of the present invention. Suitable defoaming agents may include, but are not limited to, silicone emulsions and sorbitan sesquioleate. Each possibility represents a distinct embodiment of the present invention. Suitable stabilizers for preventing or reducing the degradation of components in the composition of the present invention may include, but are not limited to, glycine, α-tocopherol or ascorbic acid, antioxidants such as BHA and BHT, or mixtures thereof. Each possibility represents a distinct embodiment of the present invention. Suitable osmotic regulators may include, but are not limited to, mannitol, sodium chloride, and glucose. Each possibility represents a distinct embodiment of the present invention.Suitable buffers may include, but are not limited to, acetates, phosphates, citrates, etc., with appropriate cations. Each possibility represents a distinct embodiment of the present invention.

[0107] The formulations may be used as mixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalation, intravenous, subcutaneous, transdermal, enteral, or other suitable methods of administration known in the art. The pharmaceutical formulations may be sterilized and, if necessary, may be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic buffering, colorants, flavorings and / or fragrance-imparting substances. If necessary, they may be combined with other active ingredients, such as other analgesics, anxiolytics, or hypnotics. As used herein, “additional ingredients” includes, but is not limited to, one or more ingredients that can be used as pharmaceutically acceptable carriers.

[0108] The compositions of the present invention may contain preservatives in an amount ranging from about 0.005% to 2.0% of the total weight of the composition. The preservatives are used to prevent spoilage when exposed to environmental pollutants. Examples of preservatives useful according to the present invention include, but are not limited to, those selected from benzyl alcohol, sorbic acid, parabens, imidurea (imidazolidinyl urea), and combinations thereof. Particularly preferred preservatives are combinations of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

[0109] The composition preferably contains antioxidants and chelating agents to suppress the degradation of the compounds. Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol, and ascorbic acid, which are preferably present in amounts ranging from about 0.01% to 0.3% of the total weight of the composition, and more preferably BHT in amounts ranging from 0.03% to 0.1% of the total weight of the composition. The chelating agent is preferably present in amounts ranging from 0.01% to 0.5% of the total weight of the composition. Particularly preferred chelating agents include EDTA salts (e.g., disodium EDTA) and citric acid, which are present in amounts ranging from about 0.01% to 0.20% of the total weight of the composition, more preferably 0.02% to 0.10%. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. BHT and disodium edetate are particularly preferred antioxidants and chelating agents, respectively, but some compounds can be replaced with other suitable and equivalent antioxidants and chelating agents, as is known to those skilled in the art.

[0110] Liquid suspensions can be prepared using conventional methods to suspend the active ingredient in an aqueous or oily solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, and coconut oil, fractional distilled vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further contain one or more additional components, including but not limited to suspending agents, wetting agents, emulsifiers, lubricants, preservatives, buffers, salts, flavorings, colorants, and sweeteners. Oily suspensions may further contain thickeners. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, and hydroxypropyl methylcellulose. Known dispersants or wetting agents include naturally occurring phospholipids such as lecithin, condensation products of alkylene oxides with fatty acids, condensation products with long-chain aliphatic alcohols, condensation products of partial esters obtained from fatty acids and hexitol, or condensation products of partial esters obtained from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate). Known emulsifiers include, but are not limited to, lecithin, acacia, and ionic or nonionic surfactants. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl parahydroxybenzoate, ascorbic acid, and sorbic acid. Known sweeteners include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.

[0111] Liquid solutions of active ingredients in aqueous or oily solvents can be prepared in much the same manner as liquid suspensions. The main difference is that the active ingredient is dissolved in the solvent rather than suspended. As used herein, “oily” liquid refers to a liquid containing carbon-containing liquid molecules and exhibiting properties of lower polarity than water. Liquid solutions of the pharmaceutical compositions of the present invention may contain each of the components described with respect to liquid suspensions, but it should be understood that the suspending agent does not necessarily help dissolve the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, and coconut oil, fractional distilled vegetable oils, and mineral oils such as liquid paraffin.

[0112] Powdered and granular formulations of the pharmaceutical formulations of the present invention can be prepared using known methods. Such formulations can be administered directly to a target, or used, for example, to form tablets, fill capsules, or prepare aqueous or oily suspensions or solutions by adding aqueous or oily solvents. Each of these formulations may further contain one or more dispersants, wetting agents, suspending agents, ionic and nonionic surfactants, and preservatives. These formulations may also include additional excipients such as fillers, sweeteners, flavorings, and colorants.

[0113] The pharmaceutical compositions of the present invention may be prepared, packaged, or sold in the form of a water-in-oil emulsion or an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a combination thereof. Such compositions may further contain one or more emulsifiers such as naturally derived gums such as acacia gum or tragacanth gum, naturally derived phospholipids such as soybean or lecithin phospholipids, esters or partial esters obtained from a combination of fatty acids and hexitol anhydride (e.g., sorbitan monooleate), and condensation products of the partial ester and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). These emulsions may also contain additional components such as sweeteners and flavorings.

[0114] Methods for impregnating or coating materials with chemical compositions are known in the art. These methods include, but are not limited to, methods for depositing or bonding chemical compositions to a surface, methods for incorporating chemical compositions into the structure of a material during its synthesis (i.e., physiologically biodegradable materials), and methods for absorbing aqueous or oily solutions or suspensions into absorbable materials (with or without subsequent drying). Methods for mixing components include physical grinding, the use of pellets in solid and suspension formulations, and mixing in transdermal patches, which are known to those skilled in the art.

[0115] ==Dosage / Administration==

[0116] The method of administration may affect the components that constitute the effective dose. The therapeutic formulation can be administered to the patient before or after the onset of respiratory distress. Furthermore, it may be administered in multiple divided doses, staggered dosages daily or sequentially, by continuous intravenous infusion, or by bolus injection. In addition, the dosage of the therapeutic formulation may be increased or decreased proportionally depending on the urgency of the treatment or prevention situation.

[0117] The compositions of the present invention can be administered to patients, preferably mammals, and more preferably humans, using known procedures, in doses and for durations effective in treating the patient's respiratory control disorder. The effective amount of the therapeutic compound required to achieve a therapeutic effect may vary depending on factors such as the activity of the specific compound used, the timing of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds, or substances used in combination with the compound, the patient's disease or disorder, age, sex, weight, condition, overall health, medical history, and other factors well known in medical technology. The administration plan may be adjusted to obtain an optimal therapeutic response. For example, depending on the urgency of the treatment situation, several divided doses may be administered daily, or the dose may be proportionally reduced. A non-limiting example of the effective dose range of the therapeutic compound of the present invention is from about 0.01 mg to 100 mg per kg of body weight per day. Those skilled in the art can determine the effective amount of the therapeutic compound by considering the relevant factors without excessive experimentation.

[0118] This compound can be administered to animals several times a day, or at less frequent doses, such as once a day, once a week, once every two weeks, once a month, or even less frequently, for example, once every few months or once a year. The daily dose of the compound is understood to be, in non-restrictive examples, daily, every other day, every two days, every three days, every four days, or every five days. For example, in the case of every-other-day administration, a dose of 5 mg / day could be started on Monday, the first subsequent dose of 5 mg / day could be administered on Wednesday, and the second subsequent dose of 5 mg / day could be administered on Friday. The frequency of administration is obvious to a skilled technician and depends on various factors, including the type and severity of the disease being treated, the type and age of the animal, and other factors.

[0119] The actual dosage of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the active ingredient effective in obtaining a desired therapeutic response for a particular patient, composition, and method of administration, and is adjusted within a range that does not cause toxicity to the patient.

[0120] Medical professionals with ordinary skills in their respective fields, such as physicians and veterinarians, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than the level required to obtain the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0121] In certain embodiments, preparing compounds in dose unit forms is particularly advantageous for ease of administration and dose uniformity. As used herein, a unit dosage form refers to a physically separated unit suitable as a unit dose to a patient receiving treatment. Each unit contains a predetermined amount of the therapeutic compound calculated to produce a desired therapeutic effect when combined with the required formulation. The unit dosage forms of the present invention are determined and directly depend on (a) the inherent properties of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the compounding / formulation techniques of such therapeutic compounds for the treatment of respiratory disorders in patients.

[0122] In certain embodiments, the compositions of the present invention are administered to patients in doses ranging from once to five or more times a day. In other embodiments, the compositions of the present invention are administered to patients in doses ranging from once daily, once every two days, once every three days, once a week, or once every two weeks, but not limited to these. It will be apparent to those skilled in the art that the frequency of administration of the various combinations of compositions of the present invention will vary from subject to subject, depending on many factors, including age, the disease or disorder being treated, sex, overall health status, and other factors. Therefore, the present invention should not be construed as being limited to a specific dosing schedule, and the exact dosage and composition to be administered to a patient will be determined by the attending physician, taking into account all other factors concerning the patient.

[0123] The dosage compounds of the present invention are available in doses of approximately 1 μg to 7,500 mg, approximately 20 μg to 7,000 mg, approximately 40 μg to 6,500 mg, approximately 80 μg to 6,000 mg, approximately 100 μg to 5,500 mg, approximately 200 μg to 5,000 mg, approximately 400 μg to 4,000 mg, approximately 800 μg to 3,000 mg, approximately 1 mg to 5,500 mg, and approximately 2 mg to 5,000 mg. The range is 0 mg, approximately 10 mg to approximately 4,000 mg, approximately 15 mg to approximately 3,750 mg, approximately 20 mg to approximately 3,000 mg, approximately 30 mg to approximately 2,500 mg, approximately 40 mg to approximately 2,000 mg, approximately 50 mg to approximately 1,500 mg, approximately 60 mg to approximately 1,000 mg, approximately 70 mg to approximately 900 mg, approximately 80 mg to approximately 800 mg, and any or partial increments in between.

[0124] In some embodiments, the dosage of the compound of the present invention ranges from about 0.5 μg to about 5,000 mg. In some embodiments, the dosage of the compound of the present invention used in the compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, including any or partial increments thereof.

[0125] In certain embodiments, the present invention relates to a packaged pharmaceutical composition comprising a container for holding a therapeutically effective amount of the compound of the present invention alone or in combination with a second pharmaceutical agent, and includes instructions for the use of the compound to treat, prevent or alleviate one or more symptoms of respiratory impairment in a patient.

[0126] The term “container” includes any container used to hold a pharmaceutical composition or to control its stability or moisture absorption. For example, in certain embodiments, the container is packaging containing the pharmaceutical composition and may include liquids (solutions and suspensions), semi-solids, lyophilized solids, solutions and powders, or lyophilized formulations present in a double chamber. In other embodiments, the container is not packaging containing the pharmaceutical composition; i.e., the container is a box or vial containing a packaged pharmaceutical composition or an unpackaged pharmaceutical composition and its instructions for use. Furthermore, packaging technologies are widely known in this field. Instructions for use of the pharmaceutical composition may be included on the packaging containing the pharmaceutical composition, and it should be understood that these instructions enhance the functional relationship with the packaged product. However, it should be understood that these instructions may include information about the compound’s ability to perform its intended function, such as treating, preventing, or alleviating respiratory distress in a patient.

[0127] ==Administration==

[0128] The routes of administration of the compositions of the present invention include inhalation, oral, nasal, rectal, parenteral, sublingual, transdermal, mucosal (e.g., sublingual, tongue, (trans)chuccal, (trans)urethral, ​​vagina (e.g., transvaginal and perival), (intra(nasal) cavity, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and local administration.

[0129] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, lozenges, emulsions, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosol formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions useful in the present invention are not limited to the specific formulations and compositions described herein.

[0130] The present invention provides a method for treating or delaying the progression or onset of diabetes, particularly type 2 diabetes, and aims to treat or delay diabetic complications such as retinopathy, neuropathy, renal impairment, and delayed wound healing, as well as cardiovascular diseases and events such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, overweight, obesity, hyperlipidemia including hypertriglyceridemia, syndrome X, atherosclerosis, hypertension, coronary artery disease, cerebrovascular disease, peripheral artery disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, pulmonary embolism, non-fatal myocardial infarction, and non-fatal stroke, by providing a method for increasing the level of high-density lipoprotein.

[0131] Obesity is characterized by excessive accumulation of body fat and is generally defined as having a body mass index (BMI; weight (kg) divided by the square of height (m)) of 30 or higher. The most common cause of obesity is an energy imbalance ("positive energy balance") resulting from excessive food intake relative to energy expenditure over a long period. Obesity is a metabolic disorder that affects the entire body, increasing the likelihood of developing diabetes and hyperlipidemia, and increasing the risk of sexual dysfunction, arthritis, cardiovascular disease, and in some cases, cancer.

[0132] Overweight is defined as having a moderate accumulation of body fat, and is generally considered to be a body mass index (BMI; weight (kg) divided by the square of height (m)) between 25 and 29.5. Obesity is most commonly caused by an energy imbalance resulting from excessive food intake relative to energy expenditure over a long period. Overweight increases mortality and surpasses smoking as a leading cause of cancer in developing countries. Overweight also increases the risk of oligospermia and azoospermia and impacts physiological health.

[0133] In this specification, the term “treat” in relation to obesity and overweight conditions means preventing weight gain, promoting weight loss, reducing excess weight, or treating obesity / overweight (e.g., by controlling appetite, eating, food intake, calorie intake, and / or energy expenditure). This includes morbid obesity and diseases or health conditions associated with excessive weight gain, including but not limited to inflammation, gallbladder disease, and sleep apnea syndrome.

[0134] ==Oral administration==

[0135] In one embodiment, the compounds of the present invention can be formulated to prepare pharmaceutical compositions for oral administration. In a further embodiment, the compositions for oral administration are designed to facilitate the modified release of the drug, thereby adjusting the site, range, and rate of exposure of the compound upon ingestion. Factors influencing the target zone of drug exposure include the drug's pH and enzymatic stability, reactivity with other drugs (e.g., certain antibiotics), solubility as a salt or free base, ionization behavior, and pharmacokinetic and pharmacokinetic behavior in specific environments. Some drugs are better absorbed in the duodenum or other parts of the intestine.

[0136] Delayed release is a particularly useful mode of modified release that delivers a drug to the duodenum or other parts of the intestine in its most concentrated form. In preferred embodiments of the present invention, the compounds of the present invention are formulated to facilitate delivery to the duodenum and, optionally, other parts of the intestine. Delayed release can be achieved by using compositions comprising an enteric coating. Enteric coatings are insoluble in highly acidic environments, and polyacidic coatings remain unionized and intact at gastric pH. However, in the duodenum and other parts of the intestine, under slightly acidic (> pH 5.5), neutral, or slightly alkaline (pH 6.5-7.6) conditions, the coating ionizes, swells, and disintegrates, exposing the coated material to the environment. Coating options exist that enable ionization at or near specific pH levels (e.g., Eudragit L-110, ionization threshold pH 6.0; Eudragit S-100, ionization threshold pH 7.0).

[0137] In further embodiments, the compounds of the present invention may be formulated together with enteric coatings modified by adding a plasticizer to the polymer before coating. The plasticizer may be added to adjust the coating's resistance to chipping and cracking, and at the same time, to lower the coating's glass transition temperature, thereby enabling smooth and uniform ductility during application. Suitable plasticizers include polyethylene glycol 8000 (PEG 8000), triethyl citrate (TEC), and triacetin, which can be incorporated into polymeric enteric coatings.

[0138] The compounds of the present invention can be enterically formulated in a variety of dosage forms, including, but are not limited to, capsules, granules, beads, and tablets of the active ingredient itself. In one embodiment, the composition may include a drug encapsulated in a capsule with an enteric coating to release the drug in the duodenum or other intestinal environment. In one embodiment of the present invention, pharmaceutically acceptable capsules include hard capsules which may be composed of plant-derived polysaccharides, starch, cellulose, or gelatin. In another embodiment, pharmaceutically acceptable capsules include soft gelatin capsules. Gelatin capsules may be composed of hypromellose (hydroxypropyl methylcellulose), which is a modified form of animal-derived collagen or cellulose, and may be manufactured using any mixture of gelatin, water, and plasticizers such as sorbitol and glycerol.

[0139] In one embodiment, the molecule of the present invention can be encapsulated in pure granular or powder form without carriers, excipients, or other pharmaceutically acceptable additives. In other embodiments, the molecule of the present invention may be encapsulated with one or more pharmaceutically acceptable carriers, excipients, antioxidants (e.g., sodium disulfite, butylated hydroxytoluene (BHT)), antifungal agents (e.g., benzoic acid and ascorbic acid and their salts, phenolic compounds such as methyl, ethyl, propyl and butyl parahydroxybenzoate (parabens)), antimicrobial preservatives (e.g., sodium benzoate, sorbic acid), colorants, and flavorings. Excipients can assist in the behavior of capsule filling, stability, and drug distribution as the capsule disintegrates in the body. In another embodiment, the granules and / or powder of the compound of the present invention may be enterically coated before being encapsulated. The enterically coated granules and / or powder encapsulated may be characterized by having one or more enteric coatings to deliver the drug to different parts of the intestine. The capsule may lack an enteric coating, or it may be coated with an enteric coating that matches or is entirely different from the coating applied to any of the enteric-coated materials within the capsule.

[0140] In yet another embodiment, the molecules of the present invention may be encapsulated in liquid in the form of a solution or suspension of water or various pharmaceutically acceptable oils or other dispersion media (e.g., mineral oil, sesame oil, safflower oil, coconut oil), and may optionally be used with cosolvents (e.g., propylene glycol, glycerol), solubility enhancers (e.g., sorbitol, dextrose), wetting agents (e.g., polysorbates (Tweens), sorbitan esters (Span), hydrophobic colloids (cellulose derivatives)), thickeners (e.g., methylcellulose, microcrystalline cellulose), buffers (e.g., disodium hydrogen phosphate), antioxidants (e.g., butyl p-hydroxytoluene (BHT), citric acid, potassium sorbate), antifungal agents (e.g., benzoic acid and ascorbic acid and their salts, phenolic compounds such as methyl, ethyl, propyl and butyl p-hydroxybenzoate (parabens)), antimicrobial preservatives (e.g., sodium benzoate, sorbic acid), colorants and flavorings. In some embodiments, the compounds of the present invention may be formulated in the form of pure drugs as granules and / or powders in a liquid for liquid-filled capsules. In relevant embodiments, capsules containing the drug in a liquid may be enterically coated. In another embodiment, the granules and / or powders of the compounds of the present invention may be enterically coated before being placed in a liquid, and the combination thereof may be encapsulated. The enterically coated granules and / or powders may be characterized by having one or more enteric coatings to deliver the drug to different parts of the intestine. The capsule may lack an enteric coating, or may be coated with an enteric coating that matches or is entirely different from the enteric coating applied to any of the enteric-coated substances within the capsule.

[0141] In another embodiment, the molecules of the present invention can be encapsulated in a capsule made of a substance that enables drug delivery after gastric passage without the need for a separate enteric coating (e.g., EnteriCare enteric softgels). The molecules can also be encapsulated in capsules as granules or powders, or as solutions or suspensions, with or without excipients, as described above.

[0142] In one embodiment, solid particles of the compound of the present invention, having various particle sizes and particle size distributions, can be mixed with excipients such as microcrystalline cellulose or lactose to form beads containing a core with an enteric-coated drug. In another embodiment, the molecule of the present invention can be formed as a suspension or solution containing a buffer (e.g., an aqueous solution of 1N hydrochloric acid containing tris-hydroxymethylamine methane (TRIS)) and a binder (e.g., Opa Dry Clear Coat Powder) as needed, and can be coated onto basic particles such as sugar beads (e.g., sugar spheres, NF particles) to form beads. In yet another embodiment, the beads may be enterically coated. In yet another embodiment, the molecule of the present invention can be formulated as enteric-coated beads as described above, and the beads can be further formulated by encapsulation. In yet another embodiment, combinations of beads with different types of enteric coatings can be encapsulated and released from the capsule, making the compound of the present invention available in a controlled manner in different regions from the duodenum to other parts of the intestine. The capsule may lack an enteric coating, or it may be coated with an enteric coating that matches or is entirely different from the enteric coating applied to any of the enteric-coated materials within the capsule.

[0143] In yet another embodiment, the compounds of the present invention can be formulated alone or in combination with other formulation components as tablets or caplets to deliver a drug to the duodenum or other areas of the intestine. In one embodiment of the present invention, the compounds of the present invention are formulated as enteric-coated tablets or caplets, which constitute the dosage form to be administered. In another embodiment, tablets or caplets of appropriate size and shape may be placed inside a capsule. In such an embodiment, the capsule may contain enteric-coated and unenteric-coated tablets or caplets, which can be released from the capsule in the duodenum or other areas of the intestine. In another embodiment, the capsule may be designed to disintegrate in the stomach, releasing enteric-coated tablets or capsules for delivery to the duodenum or other areas of the intestine. In another embodiment, both the capsule and the tablets or caplets contained within it may be enteric-coated to control the release of the tablets or caplets from the capsule and the subsequent release of the drug from the tablets or caplets. In a further relevant embodiment, various enteric-coated tablets or caplets may be combined and placed inside a capsule, and the capsule itself may also be optionally enteric-coated. Substances useful for enteric coating of tablets and caplets include, but are not limited to, those described above for application to capsules.

[0144] Enteric coatings may allow for premature drug release in acidic media. In yet another embodiment, the compounds of the present invention may be formulated to undergo a subcoating before the enteric coating is applied. The subcoating may include the application of a soluble primer to the enteric substrate, examples of which include hydroxypropyl methylcellulose, povidone, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudo ethylcellulose, and amylopectin. A thin subcoating layer on the enteric substrate inhibits water penetration through the enteric coating on the capsule shell or into the core where the active ingredient is located, thereby preventing premature drug release. The subcoating may promote drug release in a basic environment by adjusting the acidic microenvironment at the interface between the core and the enteric coating. In some embodiments, the compounds of the present invention can be formulated with an organic acid-containing primer, which is intended to more rapidly promote the dissolution of the capsule polymer as the coating degrades in a pH 5-6 environment, thereby facilitating the rapid release of the drug in a basic medium.

[0145] Tablets, dragées, liquids, drops, capsules, caplets, and gel capsules are particularly suitable for oral administration. Other formulations suitable for oral administration include, but are not limited to, powders or granules, aqueous or oily suspensions, aqueous or oily solutions, pastes, gels, toothpaste, mouthwash, coatings, oral rinses, or emulsions. Compositions intended for oral use can be prepared according to any method known in the art, and these compositions may contain one or more components selected from a group of inert, non-toxic, and generally recognized safe (GRAS) pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose, disintegrants such as corn starch, binders such as starch, and lubricants such as magnesium stearate.

[0146] Tablets are either uncoated or coated using known methods to achieve delayed disintegration in the target gastrointestinal tract and provide sustained release and absorption of the active ingredient. For example, tablets can be coated with substances such as glyceryl monostearate or glyceryl distearate. Further examples include tablets being coated to form osmotically controlled release tablets using methods described in U.S. Patents 4,256,108, 4,160,452 and 4,265,874. Tablets may further contain sweeteners, flavorings, colorings, preservatives, or combinations thereof to provide a pharmaceutically superior and palatable formulation. Hard capsules containing the active ingredient can be manufactured using physiologically biodegradable compositions such as gelatin. The capsules contain the active ingredient and may further contain additional components, including inert solid diluents such as calcium carbonate, calcium phosphate, or kaolin.

[0147] Hard capsules containing the active ingredient can be manufactured using physiologically biodegradable compositions such as gelatin. Such hard capsules contain the active ingredient and may also contain additional components such as calcium carbonate, calcium phosphate, or inert solid diluents such as kaolin.

[0148] Soft gelatin capsules containing active ingredients are manufactured using physiologically biodegradable compositions such as gelatin derived from animal collagen or hypromellose, a modified form of cellulose, and are produced using any mixture of gelatin, water, and plasticizers such as sorbitol and glycerol. Such soft capsules contain an active ingredient, which may be mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil.

[0149] For oral administration, the compounds of the present invention can be in the form of tablets or capsules prepared by conventional means using pharmaceutically acceptable excipients such as binders, fillers, lubricants, disintegrants, or wetting agents. If necessary, the tablets can be coated using appropriate methods and coating materials, such as the OPADRY® film coating system available from Colorcon, Inc. (West Point, Pennsylvania) (e.g., OPADRY® OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and OPADRY® White, 32K18400). It is understood that similar types of film coatings or polymer products from other companies may be available.

[0150] Tablets containing an active ingredient are manufactured, for example, by compressing or molding the active ingredient, along with one or more additional ingredients as needed. Compressed tablets are prepared by mixing the active ingredient in a fluid form, such as a powder or granular formulation, with one or more binders, lubricants, excipients, surfactants, or dispersants as needed, and compressing them using appropriate equipment. Molded tablets are manufactured by molding a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least enough liquid to moisten the mixture using appropriate equipment. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulators and disintegrants, binders, and lubricants. Known dispersants include, but are not limited to, potato starch and sodium glycolate starch. Known surfactants include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating agents and disintegrants include, but are not limited to, corn starch and alginic acid. Known binders include, but are not limited to, gelatin, acacia, pre-gelatinized corn starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

[0151] In the pharmaceutical field, granulation technology is well known for modifying active ingredient starting powders and other particulate materials. Powders are typically mixed with a binder to form larger, permanently fluid aggregates or granules, a process known as "granulation." For example, a "wet" granulation process using a solvent is generally characterized by the need to mix the powder with a binder, moisten it with water or an organic solvent, and then evaporate the solvent to form a wet, granular mass.

[0152] Melt granulation generally uses a substance that is solid or semi-solid at room temperature (i.e., a substance with a relatively low softening point or melting point range) to facilitate the granulation of powders or other materials, and essentially does not involve the addition of water or other liquid solvents. When heated to a temperature within its melting point range, the low-melting-point solid liquefies and acts as a binder or granulation medium. The liquefied solid spreads across the surface of the powder material it comes into contact with, and upon cooling, forms a solid, granular mass to which the initial substance binds. The resulting molten granules may be fed into a tablet press or encapsulated to prepare oral dosage forms. Melt granulation improves the dissolution rate and bioavailability of active ingredients (i.e., drugs) by forming solid dispersions or solid solutions.

[0153] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules with improved fluidity. These granules are obtained by mixing wax in a molten state with a specific fluidity-improving additive, and then cooling the mixture to granulate it. In certain embodiments, only the wax itself melts in the molten composition of wax and additive, while in other cases, both the wax and additive melt.

[0154] The present invention also includes a multilayer tablet comprising a layer providing delayed release of one or more compounds useful in the method of the invention, and a further layer providing immediate release of one or more compounds useful in the method of the invention. By using a wax / pH-sensitive polymer mixture, a gastric-insoluble composition encapsulating the active ingredient can be obtained, thereby ensuring delayed release.

[0155] Liquid formulations for oral administration may take the form of solutions, syrups, or suspensions. Liquid formulations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible oils), emulsifiers (e.g., lecithin or acacia), non-aqueous solvents (e.g., almond oil, oily esters, or ethyl alcohol), and preservatives (e.g., methyl or propyl parahydroxybenzoate or sorbic acid). Liquid formulations of the pharmaceutical compositions of the present invention suitable for oral administration may be prepared, packaged, and sold in liquid form or in the form of a dry product intended for reconstitution with water or other suitable solvents before use.

[0156] ==Pareral administration==

[0157] As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by the physical destruction of the target tissue and the administration of the pharmaceutical composition through the destruction of the tissue. Therefore, parenteral administration includes, but is not limited to, the administration of a pharmaceutical composition by injection, surgical incision, or non-surgical wound penetrating the tissue. In particular, parenteral administration is envisioned to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal, and renal dialysis infusion techniques.

[0158] Formulations of pharmaceutical compositions suitable for parenteral administration include a combination of an active ingredient and a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations can be prepared, packaged, or sold in forms suitable for bolus or continuous administration. Injectable formulations can be prepared, packaged, or sold in unit dosage forms, such as ampoules or multi-dose containers containing preservatives. Injectable formulations can also be prepared, packaged, or sold using devices, such as patient-controlled analgesia (PCA) devices. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous media, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further include one or more additional components, including, but not limited to, suspending agents, stabilizers, or dispersants. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry state (i.e., powder or granules) and reconstituted with a suitable solvent (e.g., sterile pyrogen-free water) before parenteral administration of the reconstituted composition.

[0159] Pharmaceutical compositions may be prepared, packaged, or sold in the form of aqueous or oily suspensions or solutions for sterile injection. These suspensions or solutions may be formulated according to known techniques and may contain, in addition to the active ingredient, additional components as described herein, such as dispersants, wetting agents, or suspending agents. Such sterile injection formulations may be prepared using, for example, water or non-toxic, parenterally acceptable diluents or solvents such as 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solutions, and fixing oils such as synthetic monoglycerides or diglycerides. Other useful parenterally administered formulations include recombinant human albumin, fluidized gelatin, liposome formulations, or formulations containing the active ingredient in microcrystalline form as a component of a biodegradable polymer system. Compositions for sustained-release or embedding may include pharmaceutically acceptable polymers or hydrophobic substances such as emulsions, ion-exchange resins, poorly soluble polymers, or poorly soluble salts.

[0160] ==Local administration==

[0161] The stratum corneum of the epidermis is an obstacle to the topical administration of pharmaceuticals. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids, and various other lipids, and contains keratinized and living cells. One factor that limits the flux of compounds passing through the stratum corneum is the amount of active ingredient that can be added or applied to the skin surface. The greater the amount of active ingredient applied per unit area of ​​skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and as a result, the greater the diffusion of the active ingredient through the skin. Therefore, all other things being equal, formulations containing a higher concentration of the active ingredient are more likely to penetrate the skin, in greater quantity and at a more consistent rate than formulations containing a lower concentration of the active ingredient.

[0162] Formulations suitable for topical administration include, but are not limited to, liniments, oil-in-water or water-in-oil emulsions such as lotions, creams, ointments, and pastes, as well as liquid or semi-liquid formulations such as solutions and suspensions. A topically administered formulation may contain, for example, about 1% to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further contain one or more additional ingredients as described herein.

[0163] Penetration enhancers can also be used. These substances increase the penetration rate of drugs through the skin. Typical enhancers in this art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), and dimethyl sulfoxide. Other penetration enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

[0164] One of the acceptable media for locally delivering a portion of the composition of the present invention may include liposomes.

[0165] In another embodiment, a locally active pharmaceutical composition may be combined with other components as needed, such as adjuvant, antioxidant, chelating agent, surfactant, foaming agent, wetting agent, emulsifier, thickener, buffering agent, or preservative. In another embodiment, the composition may include a penetration enhancer or permeation enhancer, which is more effective in improving the transdermal penetration of the active ingredient into the stratum corneum compared to a composition without a penetration enhancer. Various penetration enhancers are known to those skilled in the art, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocaprum, alkane carboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In another embodiment, the composition may further include a hydrotropic agent that functions to increase the disorder of the stratum corneum structure, thereby increasing transport across the stratum corneum. Various hydrotropic agents are known to those skilled in the art, such as isopropyl alcohol, propylene glycol, and sodium xylenesulfonate.

[0166] A topically active pharmaceutical composition needs to be applied in an amount effective to produce the desired change. As used here, "effective amount" means an amount sufficient to cover the area of ​​skin surface where the change is desired. The active compound should be present in an amount of about 0.0001% to about 15% of the weight volume of the composition. More preferably, it should be present in an amount of about 0.0005% to about 5%, and most preferably, in an amount of about 0.001% to about 1%. Such a compound may be synthetic or naturally occurring.

[0167] ==Buccal administration==

[0168] The pharmaceutical compositions of the present invention can be manufactured, packaged, or sold as formulations suitable for buccal administration. Such formulations may be, for example, in the form of tablets or lozenges manufactured by conventional methods, and may contain, for example, 0.1 to 20% (w / w) of the active ingredient, with the remainder being an orally soluble or degradable composition, and may optionally contain one or more additional ingredients as described herein. Alternatively, formulations suitable for buccal administration may consist of a powder containing the active ingredient, or an aerosolized or micronized solution or suspension. Such powdered, aerosolized, or micronized formulations may have an average particle size or average droplet size in the range of about 0.1 nanometers to about 200 nanometers when dispersed, and may further contain one or more additional ingredients as described herein. The examples of formulations described herein are not exhaustive, and it should be understood that the present invention includes additional modifications of other formulations not described herein but known to those skilled in the art.

[0169] ==Rectal administration==

[0170] The pharmaceutical compositions of the present invention can be prepared, packaged, or sold as formulations suitable for rectal administration. Such compositions may take the form of, for example, suppositories, retention enema formulations, and solutions for rectal or colon cleansing.

[0171] Suppository formulations can be manufactured by combining an active ingredient with a non-irritating, pharmaceutically acceptable excipient that is solid at room temperature (i.e., approximately 20°C) and liquid at the rectal temperature of the subject (i.e., approximately 37°C in a healthy person). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycol, and various glycerides. Suppository formulations may further contain a variety of additional ingredients, including, but not limited to, antioxidants and preservatives.

[0172] Enema preparations or solutions for rectal or colon cleansing can be prepared by combining an active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema preparations can be administered using an administration device adapted to the anatomical morphology of the target rectum, and may also be packaged within the device. Enema preparations may further contain a variety of additional ingredients, including but not limited to antioxidants and preservatives.

[0173] ==Additional Dosage Forms==

[0174] Additional dosage forms of the present invention include U.S. Patent Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, 5,007,790, U.S. Patent Applications Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, 20020051820, PCT Applications WO 03 / 35041, WO 03 / 35040, WO 03 / 35029, WO 03 / 35177, WO 03 / 35039, WO 02 / 96404, WO This includes the dosage forms described in WO 02 / 32416, WO 01 / 97783, WO 01 / 56544, WO 01 / 32217, WO 98 / 55107, WO 98 / 11879, WO 97 / 47285, WO 93 / 18755, and WO 90 / 11757, the disclosures of which are incorporated in their entirety by reference in this specification.

[0175] ==Controlled-Release Formulations and Drug Delivery Systems==

[0176] In certain embodiments, the composition is designed to facilitate the controlled release of a drug, and the site, range, and rate of exposure of the compound are regulated during administration. Factors influencing the target exposure area of ​​an orally administered drug include the drug's pH and enzyme stability, reactivity with other drugs (e.g., certain antibiotics), solubility as a salt or free base, ionization behavior, and pharmacokinetic and pharmacokinetic behavior in specific environments.

[0177] Controlled-release or sustained-release formulations of the pharmaceutical compositions of the present invention can be manufactured using conventional techniques. In some cases, to provide a desired release profile in various ratios, the dosage forms used may be, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof, to provide sustained-release or controlled-release formulations of one or more active ingredients. Suitable sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use in the pharmaceutical compositions of the present invention. Therefore, unit dosage forms suitable for oral administration, such as tablets, capsules, gel capsules, and caplets adapted for controlled release, are included in the present invention.

[0178] Most controlled-release drugs share the common goal of improving pharmacotherapy compared to uncontrolled-release products. Ideally, the use of optimally designed controlled-release formulations in medical procedures is characterized by treating or controlling a disease with the minimum amount of drug and in the minimum amount of time. Advantages of sustained-release formulations include targeted delivery within the gastrointestinal tract when administered orally, sustained drug effect, reduced dosing frequency, and improved patient adherence. Furthermore, controlled-release formulations can be used to influence properties such as the time of onset of action and drug concentration in the blood, thereby also influencing the occurrence of side effects.

[0179] Most controlled-release formulations are designed to initially release a rapid amount of the drug to produce the desired therapeutic effect, and then gradually and continuously release other amounts of the drug to maintain this level of therapeutic effect over a longer period. To maintain this constant drug level in the body, the drug must be released from the formulation at a rate that can replenish the amount of drug metabolized and excreted from the body.

[0180] The controlled release of active ingredients can be stimulated by a variety of inductive factors, including water, pH, temperature, enzymes, bacteria, or other physiological conditions or compounds. In this invention, the term "controlled release ingredient" is defined as a compound or group of compounds that facilitates the controlled release of an active ingredient, and includes, but is not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or combinations thereof.

[0181] In certain embodiments, the formulations of the present invention include, but are not limited to, short-release, rapid-offset, and immediate-release formulations, as well as controlled formulations such as sustained-release, delayed-release, and pulsed-release formulations. The active drug component may also be coated onto an implantable medical device so that it is eluted or released using a remote-controlled system.

[0182] The term "sustained-release" is used in its traditional sense to refer to formulations that release a drug gradually over a long period. It can also, though not always, result in a substantially constant blood concentration of the drug over a long period. This period can extend beyond one month and should be longer than the release period of the same amount of drug administered as a bolus.

[0183] For sustained release, the compound can be combined with a suitable polymer or hydrophobic material that imparts sustained release properties to the compound. Therefore, the compound used in the method of the present invention can be administered, for example, by injection in the form of microparticles, or by implantation in the form of wafers or disks (drugs embedded in a polymer substrate).

[0184] In a preferred embodiment of the present invention, the compound of the present invention is administered to a patient alone or in combination with other pharmaceuticals using a sustained-release formulation.

[0185] In this specification, the term "delayed release" is used in its conventional sense to refer to a formulation in which the drug is first released after a certain delay following administration, and is not necessarily required, but may include delays of approximately 10 minutes to approximately 24 hours.

[0186] In this specification, the term "pulsed release" is used in its conventional sense to refer to a formulation that releases the drug in such a way that the plasma profile of the drug becomes pulsed after administration.

[0187] The term "immediate release" is used in its traditional sense to refer to formulations in which the drug is released immediately after administration.

[0188] In this specification, “short term” means a period of time up to approximately 24 hours, 12 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes after drug administration, and includes part, all, or partial increments thereof.

[0189] As used herein, “rapid offset” means a period of time up to approximately 24 hours, 12 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes after drug administration, and includes any part, all, or partial increments thereof.

[0190] Drugs can be better absorbed in the duodenum and other parts of the intestine. A particularly useful mode of controlled release is to deliver the drug to the duodenum and other parts of the intestine at the highest concentration while minimizing intragastric release of the drug. In certain embodiments, the compounds of the present invention can be formulated to facilitate delivery to the duodenum and, if necessary, other parts of the intestine. Controlled release of drugs to the duodenum and other parts of the intestine can be achieved by using compositions containing an enteric coating. Enteric coatings are insoluble in highly acidic environments and often consist of polyacidic coatings that remain non-ionized and intact at gastric pH. However, in the duodenum and other parts of the intestine, under slightly acidic (>pH 5.5), neutral, or slightly alkaline (pH 6.5-7.6) conditions, the coating ionizes, swells, and disintegrates, exposing the coated material to the environment. Coating options exist that enable ionization at or near a specific pH (e.g., Eudragit L-110, ionization threshold pH 6.0; Eudragit S-100, ionization threshold pH 7.0). It is also understood that similar types or grades of film coatings or polymer products from other companies may be used.

[0191] In certain embodiments, the compounds of the present invention may be formulated together with enteric coatings modified by adding a plasticizer to the polymer before coating. The plasticizer may be added to adjust the coating's resistance to chipping and cracking, and simultaneously to lower the coating's glass transition temperature, thereby enabling smoothness and uniform spreadability during application. Suitable plasticizers include polyethylene glycol 8000 (PEG 8000), triethyl citrate (TEC), and triacetin, which can be incorporated into polymeric enteric coatings.

[0192] The compounds of the present invention can be formulated with enteric coating in various dosage forms, including, but are not limited to, capsules, granules of the active ingredient itself, beads, microspheres, and tablets. In certain embodiments, the composition comprises a drug encapsulated within an enteric coating to release the drug in the duodenum or other intestinal environment. In other embodiments, pharmaceutically acceptable capsules include hard capsules. In other embodiments, pharmaceutically acceptable capsules include soft gelatin capsules.

[0193] In certain embodiments, the compounds of the present invention may be encapsulated in pure granular or powder form without carriers, excipients, or other pharmaceutically acceptable additives. In other embodiments, the compounds of the present invention may be encapsulated with one or more pharmaceutically acceptable carriers, excipients, antioxidants, antifungal agents (e.g., benzoic acid and ascorbic acid and their salts, as well as phenolic compounds such as methyl, ethyl, propyl, and butyl parahydroxybenzoates (parabens)), antimicrobial preservatives, colorants, and flavorings. Excipients can assist in the filling behavior, stability, and distribution of the drug when the capsule disintegrates in the body. In other embodiments, the granules and / or powders of the compounds of the present invention may be enterically coated before being encapsulated. Enterically coated granules and / or powders encapsulated may be characterized by having one or more enteric coatings to deliver the drug to different parts of the intestine. The capsules may lack an enteric coating or be coated with an enteric coating that matches or is entirely different from the coating applied to any of the enterically coated materials within the capsule.

[0194] In certain embodiments, the compounds of the present invention are encapsulated in liquid in the form of solutions or suspensions in water or various pharmaceutically acceptable oils or other dispersion media, and may optionally contain additives such as cosolvents (e.g., PEG 300, PEG 400, propylene glycol, glycerol, Tween 80, ethanol), solubility enhancers (e.g., sorbitol, dextrose), wetting agents (e.g., thickeners), buffers (e.g., disodium phosphate), antioxidants, antifungal agents, preservatives, colorants, and flavorings. In certain embodiments, the compounds of the present invention may be formulated in the form of pure pharmaceuticals as granules and / or powders in liquid for liquid-filled capsules. In other embodiments, capsules containing the compounds in liquid may be enterically coated. In other embodiments, granules and / or powders of the compounds of the present invention are enterically coated before being placed in liquid, and the mixture is placed in capsules. Enterically coated granules and / or powders may be characterized by having one or more enteric coatings to deliver the pharmaceutical to specific sites in the intestines. The capsule may lack an enteric coating, or it may be coated with an enteric coating that matches or is entirely different from the enteric coating applied to any of the enteric-coated substances within the capsule.

[0195] In certain embodiments, the compounds of the present invention are encapsulated in capsules containing a substance that enables drug delivery after gastric passage without the need for a separate enteric coating (e.g., EnteriCare enteric softgels). The compounds may also be encapsulated in capsules as granules or powders, or as solutions or suspensions, with or without excipients, as described above.

[0196] In certain embodiments, solid particles of the compound of the present invention, having varying particle sizes and particle size distributions, are mixed with excipients such as microcrystalline cellulose and lactose to form beads containing a core with an enteric-coated drug. In other embodiments, the compound of the present invention is formed as a suspension or solution optionally containing a buffer (e.g., an aqueous solution of 1N hydrochloric acid containing tris(hydroxymethyl)aminomethane) and a binder (e.g., Opa Dry Clear Coat Powder), and is coated onto basic particles such as sugar beads (e.g., sugar spheres, NF particles) to form beads. In other embodiments, the beads are enteric-coated. In other embodiments, the compound of the present invention is formulated as enteric-coated beads as described above, and the beads are further formulated by encapsulation. In other embodiments, combinations of different types of enteric-coated beads are encapsulated, and upon release from the capsule, the compound of the present invention becomes available in a controlled manner in different regions from the duodenum to other parts of the intestine. The capsule may lack an enteric coating, or it may be coated with an enteric coating that matches or is entirely different from the enteric coating applied to any of the enteric-coated materials within the capsule.

[0197] In certain embodiments, the compounds of the present invention are formulated as tablets or caplets, either alone or in combination with other formulation components, to deliver the drug to the duodenum or other parts of the intestine. In other embodiments, the compounds of the present invention are formulated as enteric-coated tablets or caplets, which constitute the dosage form to be administered. In other embodiments, tablets or caplets of appropriate size and shape are placed inside a capsule. In other embodiments, the capsule contains enteric-coated and unenteric-coated tablets or caplets, which are released from the capsule in the duodenum or other parts of the intestine. In other embodiments, the capsule is designed to disintegrate in the stomach, releasing enteric-coated tablets or capsules, which are then delivered to the duodenum or other parts of the intestine. In other embodiments, both the capsule and the tablets or caplets contained within it are enteric-coated to control the release of the tablets or caplets from the capsule and the subsequent release of the drug from the tablets or caplets. In other embodiments, various enteric-coated tablets or caplets can be combined and placed inside a capsule, and the capsule itself may also be optionally enteric-coated. Substances useful for enteric coating of tablets and caplets include, but are not limited to, those described above for application to capsules.

[0198] Enteric coatings may allow for premature drug release in acidic media. In certain embodiments, the compounds of the present invention are formulated to undergo subcoating before enteric coating. Subcoating may involve applying a soluble undercoating agent to the enteric substrate, examples of which include hydroxypropyl methylcellulose, povidone, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudo-ethylcellulose, and amylopectin. It is also understood that similar synthetic and semi-synthetic polymer products from other companies may be used. A thin subcoating layer on the enteric substrate inhibits water penetration through the enteric coating on the capsule shell or into the core where the active ingredient is located, thereby preventing premature drug release. Subcoating may also promote drug release in a basic environment by adjusting the acidic microenvironment at the interface between the core and the enteric coating. In certain embodiments, the compounds of the present invention are prepared with an organic acid-containing primer, with the aim of more rapidly promoting the dissolution of the capsule polymer as the coating degrades in a pH 5-6 environment, thereby facilitating the rapid release of the drug in a basic medium.

[0199] The present invention also includes the preparation of compositions comprising the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and in particular with respect to GAL475, embodiments thereof in which these compositions are useful as pharmaceuticals. The pharmaceutical composition comprises, as an active ingredient, a therapeutically effective amount of the compound of formula (I), GAL475, and further comprising a salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and is combined with one or more pharmaceutically acceptable diluents, preservatives, solvents, emulsifiers, adjuvant, excipients, and carriers commonly used in pharmaceutical and veterinary pharmaceutical formulations. The pharmaceutical formulation is adaptable for administration to humans and / or animals.

[0200] The pharmaceutical formulation according to the present invention preferably has at least one of the following characteristics: (i) it is adapted for administration via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical administration, and can be formulated into dosage forms suitable for each administration route; and (ii) it is a unit dosage form, each unit dosage form containing a predetermined amount of a compound of formula (I) containing GAL475 or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, the amount of which is in the range of about 2 mg to about 1000 mg.

[0201] These formulations further have the advantage of being able to be administered alone or in combination with or in combination with other compounds known to be useful in treating metabolic syndrome or inducing weight loss.

[0202] In one embodiment, the compounds of the present invention are used to treat metabolic syndrome. As used herein, “treatment” means to alleviate or cure a disease, disorder, or condition, or to reduce at least one symptom of a disease, disorder, or condition.

[0203] In another embodiment, the compounds of the present invention are used to promote weight loss and suppress appetite.

[0204] In another embodiment, the compounds of the present invention are used to treat diabetes. In a preferred embodiment, the disease or disorder is one that a person suffers from, and the compounds of the present invention are administered to a person.

[0205] The compounds of the present invention can be administered alone or in combination with other agents known to be beneficial in treating the disease, disorder, or condition to be treated. As used herein, “in combination” means that GAL475 and the other agent are administered simultaneously as a combination therapy or as a fixed physical combination, or that they are administered at different times but in a complementary manner.

[0206] In the treatment or prevention of the aforementioned condition, i.e., defined as metabolic syndrome in a broad sense, this compound is administered alone or in combination with other compounds having therapeutic properties, such as GLP-1 agonists, antidiabetic drugs, insulin, anti-inflammatory drugs, antioxidants, hypnotics, anxiolytics, antipsychotics, appetite suppressants, melatonin agonists and antagonists, melatonin, benzodiazepines, α-glucosidase inhibitors, biguanides, dopamine-2 agonists, DPP-4 inhibitors, meglitinides, SGLT2 inhibitors, sulfonylureas, thiazolidinediones, etc., as well as, for example, phentermine, diethylpropion, orlistat, phentermine. - Can be administered in combination with topiramate, bupropion-naltrexone, liraglutide, cetomelanotide, semaglutide, letatoltide, tilzepatide, danuglipron, insulin, acarbose, miglitol, metformin and metformin combination preparations, bromocriptine, alogliptin, linagliptin, saxagliptin, sitagliptin, dulaglutide, exenatide, lixenatide, nateglinide, repaglinide, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, glimepiride, gliclazide, glibride, rosiglitazone, pioglitazone, zopiclone, and salts thereof, as well as combination preparations thereof.

[0207] Combining one or more of these known therapeutic agents with GAL475 results in additional, complementary, and often synergistic effects that enhance the desirable properties of the known therapeutic agents.

[0208] GAL475 can be administered alone, in combination with any of the aforementioned known therapeutic drugs, or in combination with physical therapies such as exercise and diet.

[0209] GAL475 can be formulated into pharmaceutical compositions suitable for oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical administration routes. These compositions may contain one or more pharmaceutically acceptable diluents, preservatives, solvents, emulsifiers, adjuvant, excipients, and / or carriers.

[0210] Solid dosage forms for oral administration include capsules, tablets, pills, minitablets, pellets, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one pharmaceutically acceptable carrier, such as sucrose, lactose, or starch. Such dosage forms may, as is common practice, contain additional substances other than inert diluents, such as lubricants, for example, magnesium stearate. Examples of additives that may be incorporated into tablets, capsules, etc., include binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as microcrystalline cellulose; disintegrants such as corn starch, pregelatinized starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; and flavorings such as peppermint, wintergreen oil, or cherry. In the case of capsules, tablets, and pills, the dosage form may contain buffers. If the unit dosage form is a capsule, in addition to the above types of materials, it may also contain a liquid carrier such as fatty oil. Various other materials may be present as coatings or used to modify the physical shape of the unit dosage form. Tablets and pills may be further coated with enteric coatings, and tablets may be coated with shellac, sugar, or both. Tablets include, but are not limited to, matrix tablets, film-coated tablets, osmotic tablets, multilayer tablets (e.g., two-layer or three-layer), and conventional tablets.

[0211] Similar types of solid compositions can be used as fillers for soft and / or hard-filled gelatin capsules, with excipients such as lactose, milk sugar, and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using enteric coatings or other coatings well known in pharmaceutical technology. They may optionally contain opacifiers and can be compositions that release only in or target specific parts of the intestinal tract, or with delayed release as needed. Examples of usable embedding compositions include polymers and waxes. Similar types of solid compositions can be used as fillers for soft and / or hard-filled gelatin capsules, with excipients such as lactose, milk sugar, and high molecular weight polyethylene glycol.

[0212] In certain embodiments, the capsule may comprise a formulation of an excipient comprising one or more of hydroxypropyl methylcellulose (HPMC), gelatin, meglumine, and fish gelatin. In certain embodiments, the capsule may contain the compound of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants. The capsule may optionally further comprise one or more of lycopene, ellagic acid (polyphenol), curcumin, piperine, delphinidin, resveratrol, isothiocyanates such as sulforaphane, capsaicin, and piperlongin.

[0213] When used in the form of fine particles or nanoparticles, the compounds of the present invention may achieve higher blood concentrations. The present invention comprises fine particles and / or nanoparticles of the compounds described herein in the form of tablets or encapsulated in capsules.

[0214] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, self-micro-emulsifying emulsion drug delivery systems (SMEDDS), liposomes, syrups, and elixirs, which contain commonly used inert diluents such as water. In addition to such inert diluents, compositions may also contain additives such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, fragrances, oils, surfactants, and co-surfactants. Syrups or elixirs may contain the active ingredient, sucrose as a sweetener, methyl and propylparaben as preservatives, colorants, and flavorings such as cherry or orange flavor.

[0215] Orally administered SMEDDS formulations improve the bioavailability and pharmacokinetics of GAL475 and / or a second drug. These formulations typically contain an emulsion comprising oil or lipids, surfactants, and hydrophilic co-surfactants. Drugs or pharmaceuticals that are poorly soluble in water can be emulsified in formulations of self-emulsifying excipients, thereby improving the in vivo bioavailability of the drug or pharmaceutical formulation. Furthermore, drugs that are poorly soluble in water can be used in combination with GAL475.

[0216] The SMEDDS pharmaceutical compositions of the present invention can be formulated for oral administration of GAL475, for example, as emulsions, oily suspensions, filled hard or soft capsules, syrups, prepared powders or granules, lozenges, tablets, or lozenges. Pharmaceutically acceptable carriers or additives used in formulations include binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose, and gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch and sweet potato starch; and lubricants such as magnesium stearate, calcium stearate, and sodium stearyl fumarate.

[0217] Preparations for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Sterile compositions for injection can be prepared according to conventional pharmaceutical techniques by dissolving or suspending the active ingredient in sterile water for injection, naturally derived vegetable oils such as sesame oil, coconut oil, peanut oil, or cottonseed oil, or synthetic fatty solvents such as ethyl oleate. Buffers, preservatives, antioxidants, etc., may be added as needed. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may contain additives such as preservatives, wetting agents, emulsifiers, and dispersants. These can be sterilized, for example, by filtering through a bacterial-retaining filter, incorporating a bactericide into the composition, irradiating the composition, or heating the composition. It is also possible to manufacture them in the form of sterile solid compositions that can be dissolved immediately before use in sterile water or other sterile injection mediums.

[0218] The dosage of the active ingredient in the composition of the present invention can be varied as long as the amount necessary for treatment is administered. Preferably, the active ingredient is administered in a dose that produces the optimal pharmacological effect for the patient (human or animal) requiring such treatment. The selected dose depends on the nature and severity of the disease or disorder being treated, the expected therapeutic effect, the route of administration, and the duration of treatment. The dosage may also vary depending on the patient's weight and other factors. For example, the dose of GAL475 required to reduce weight may differ from the dose required to alleviate diabetes. The dosage will vary from patient to patient depending on the nature and severity of the disease, the patient's weight, any special dietary therapy the patient was following, concomitant medications, the bioavailability of the compound at the time of administration, and other factors recognized by those skilled in the art.

[0219] In the treatment according to the present invention, the appropriate daily dose is generally about 2 to 1000 mg. The daily dose can be administered in one or more divided doses. Preferably, the dose is about 100 to 500 mg.

[0220] Alternative therapies according to the present invention include administration twice daily, twice weekly, once weekly, every other month, and once monthly.

[0221] The formulations of the present invention may be in an immediate-release form, or in a sustained-release or controlled-release form. Sustained-release formulations include delayed-release formulations, sustained-release formulations, pulsed-release formulations, or controlled-release formulations. Suitable sustained-release formulations for the purposes of the present invention include the types of formulations described in U.S. Patents 6,106,864, 7,053,122, and 7,118,762, which are incorporated herein by reference. Details of other suitable release technologies, such as high-energy dispersion, osmotic pressure, and coated particles, are described, for example, in Verma, R. and S. Garg, "Pharmaceutical Technology On-Line," 25(2), 1-14 (2001), which are also incorporated herein by reference.

[0222] The duration for which a sustained-release formulation releases a compound varies depending on the indication and the target level of treatment. For example, in diabetes, it is desirable to limit the pharmacological effect of the compound on glucose bioavailability to several hours.

[0223] The present invention will be illustrated by the following embodiments. The following embodiments are illustrative only and are not intended to limit the scope of the present invention in any way. [Examples]

[0224] The present invention will be described with reference to the following embodiments. These embodiments are presented for illustrative purposes only, and the present invention is not limited to these embodiments, but rather includes all modifications that are apparent as a result of the teachings presented herein.

[0225] Example 1: GAL475 enhanced the binding of neurotensin to the NTSR1 receptor.

[0226] GAL475 (30 micromolar concentration) was tested in binding assays for multiple receptors. Binding was calculated as the percentage of inhibition against the binding of each target-specific radiolabeled ligand.

[0227] In the presence of a 30-micromolar concentration of GAL475, inhibition of over 50% was observed against specific receptor radioligands: 5-HT2B(h) (agonist radioligand; 75%), 5-HT5a(h) (agonist radioligand; 50.6%), 5-HT7(h) (agonist radioligand; 79%), α1 adrenergic receptor (non-selective) (antagonist radioligand; 67.1%), and Na+ channel (site 2) (antagonist radioligand; 75.1%). However, the potency of GAL475 at these receptors was below 1 micromolar concentration and therefore not considered pharmacologically interesting. An unexpected finding, however, was that at a 30-micromolar concentration, GAL475 did not inhibit NTS1(h) (agonist radioligand), but rather enhanced it by 32%, suggesting that it is a positive allosteric modulator (PAM).

[0228] Next, the PAM activity of GAL475 against human NTS1 (FAST-0330I) and NTS2 (FAST-0331I) receptors was tested at concentrations of 100–50,000 nanomoles. The agonist activity of GAL475 is expressed as the percentage of the activity of the reference agonist (neurotensin) at the EC100 (maximum response) concentration. The antagonist activity of GAL475 is expressed as the inhibition rate of the reference agonist activity at the EC80 (80% inhibition) concentration. The results are shown in Tables 1 to 3. The assays were performed using recombinant cell lines. The receptor accession numbers, cell background, and reference compounds are shown in Table 1. [Table 1]

[0229] The positive allosteric modulator (PAM) activity of GAL475 (100-50,000 nM) towards human NTS1 (FAST-0330I) and NTS2 (FAST-0331I) receptors was tested (Tables 2 and 3). The results showed that GAL475 could not bind to the NTSR2 receptor, but it bound to and activated the NTSR1 receptor, exhibiting a 50% effect at 355 nM.

[0230] [Table 2]

[0231] [Table 3]

[0232] Example 2: GAL475 in rats for 28 days with a 14-day recovery period * The effect of repeated oral administration of 2HCL on weight gain

[0233] 142 rats (71 of each sex) were randomly assigned to 4 groups, and given either a vehicle (0.1M phosphate buffer pH 7.4±0.2 containing 2% (w / v) CMC-Na and 1% (v / v) Tween 80) or Gal-475 * 2HCl was administered orally via gastric tube once daily for 28 days at doses of 20, 40, or 80 mg / kg / day.

[0234] At the end of the administration phase, the mean body weight of animals administered 40 mg / kg / day or more was significantly lower compared to the control group (-7.35% for males and -4.70% for females, respectively) (Figure 1). However, when comparing Day-1 data with Day 28 data, the overall weight gain of animals administered 80 mg / kg / day was significantly lower compared to the control group (71% for males and 79% for females, respectively). This decrease in mean body weight in this group was attributed to reduced weight gain, which was correlated with and caused by reduced food intake. During the two-week recovery period (the period when Gal-475 was not administered), animals in the 80 mg / kg / day dose group showed weight gain equivalent to or greater than that of the control group during the same period, suggesting the reversibility of the effect of GAL475 on body weight.

[0235] During the administration period, compared to the mean of the control group, food intake significantly decreased in both sexes at doses exceeding 40 mg / kg / day, which contributed to reduced weight gain (Figure 2). However, as shown in the weight figures, food intake returned to normal by the end of the recovery period.

[0236] GAL475 was administered orally via gastric tube to rats once daily for 28 days at doses of 20, 40, or 80 mg / kg / day, and good tolerance was observed. No adverse effects related to the test product were observed in terms of clinical symptoms, food intake, clinicopathology, or pathology.

[0237] Example 3: GAL475 * Effect of 2HCL: Effect of repeated oral administration over 28 days with a 14-day recovery period on weight gain in beagle dogs.

[0238] 32 dogs (16 of each sex) were randomly assigned to 4 groups, and given either a vehicle (0.1M phosphate buffer pH 7.4 containing 2% (w / v) CMC-Na and 1% (v / v) Tween 80) or Gal-475 * 2HCl was administered orally once daily at a dose of 7.5, 15, or 30 mg / kg / day for a maximum of 28 days.

[0239] During the administration period, all male and female animals that received the drug (≥7.5 mg / kg / day) showed decreased weight gain (up to 22.7% in males and up to 29.9% in females) (Figure 3) and decreased food intake (up to 81% in males and up to 98% in females). During the recovery period, weight gain and food intake were comparable to the control group.

[0240] Example 4: Effect of GAL475 on inhibiting acute gastric emptying in rats

[0241] The effect of a single intravenous administration of 3 mg / kg of GAL-475 on gastric emptying was evaluated in untreated male Sprague-Dawley rats (239-297 g).

[0242] Rats were fasted 16–18 hours prior to the start of the experiment, and then administered a single bolus via the lateral tail vein of either vehicle (1% Tween-80, 2% CMC) or GAL475 (3 mg / kg, intravenously). Five minutes after administration, the rats were given charcoal slurry (5 ml / kg, 10% charcoal in 2.5% gum arabic derived from acacia) via gastric tube feeding, and then returned to their cages. Twenty minutes after slurry administration, the rats were euthanized using CO2. The stomach was removed, weighed, emptied, washed, and weighed again. Gastric volume was calculated as the difference between the weight when full and when empty. An increase in gastric volume was interpreted as a decrease in gastric emptying (food retention).

[0243] Figure 4 shows the effects of GAL475 and vehicle (25% DMA:45% PEG300:40% D5W) on gastric emptying in rats. GAL-475 significantly reduced gastric emptying compared to the vehicle (p<0.05). Up to 25 minutes after GAL-475 administration (3 mg / kg, intravenous), gastric content retention was up to 105% higher compared to the vehicle control group.

[0244] Example 5: Weight loss in human patients who received a single oral dose of GAL475

[0245] The efficacy of oral administration of GAL-475 (450 mg capsules) in 12 healthy male volunteers was investigated in a phase 1, randomized, placebo-controlled, double-blind, first-of-its-kind human single-dose escalation study.

[0246] On the morning of day 1, subjects were administered either the study drug (GAL475) or a placebo at doses of 50 mg, 150 mg, or 450 mg. Subjects fasted for 8 hours before taking the study drug or placebo and for at least 4 hours after administration.

[0247] Participants' weight was measured using a validated balance on day 1 and at the follow-up visit (day 7). Weight was recorded to one decimal place. The treatment was well tolerated, except for mild headaches observed in 2 out of 6 participants who took 50 mg of GAL475 on the day of capsule ingestion, 0 out of 6 participants who took 150 mg of GAL475, 5 out of 6 participants who took 450 mg of GAL475, and 1 out of 6 participants who took placebo.

[0248] As shown in Figure 5, weight analysis of subjects treated with 450 mg of GAL-475 showed that weight consistently decreased in all subjects who took GAL-475 (mean -0.6 kg, range -0.1 kg to -1.6 kg), but not in subjects who received placebo (mean -0.07 kg, range +1.4 kg to -0.8 kg). Weight loss was observed only in subjects who took 450 mg of GAL-475 one week after a single capsule intake, and not in the placebo group.

[0249] The effect of 450 mg of GAL475 on weight loss was statistically significant compared to all other groups (P=0.006).

[0250] Although the present invention is described in conjunction with its detailed description, the foregoing description is illustrative and not limiting to the scope of the invention, and it should be understood that the scope of the invention is defined by the scope of the appended claims. Other aspects, advantages, and modifications are included within the scope of the claims.

[0251] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of any conflict, including definitions, this specification shall prevail. Furthermore, headings, materials, methods, and examples are illustrative and not intended to be limiting.

Claims

1. a) Methods for treating subjects suffering from metabolic syndrome or metabolic diseases, b) Methods for reducing the weight of individuals who require weight loss. c) Methods for treating individuals who have diabetes or are at risk of developing diabetes. d) Methods for treating subjects who are obese or overweight. e) Methods for treating individuals with eating disorders, f) Methods for treating individuals with bulimia, g) Methods for treating a subject with hyperlipidemia, h) A method for treating a subject who is insulin resistant, The method comprises administering to the subject a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient. 【Chemistry 1】 【change】 R １ , R ５ and R ７ These are, independently, hydrogen and optionally substituted C. １ -C ３ Selected from the group consisting of alkyl groups, R ２ The group is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted. R ６ and R ８ Each of these is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted. R ９ and R １０ are each independently selected from the group consisting of hydrogen and optionally substituted C １ -C ３ alkyl, or R ９ and R １０ bond to the carbon atom to which they are bonded to form an optionally substituted C ３ -C ６ cycloalkyl group, R １１ Each of them independently consists of hydrogen and optionally substituted C １ -C ３ Selected from the group consisting of alkyl groups, -C(R) in ring b １１ ) ２ -C(R １１ ) ２ - The group can be optionally replaced with an optionally substituted 1,2-phenylene group condensed with ring b, C １ -C ３ Each alkylene can be substituted independently and arbitrarily. m and n are independently selected from the group consisting of 1, 2, 3, and 4, and satisfy 2 ≤ (m + n) ≤ 4. p and q are independently selected from the group consisting of 0, 1, 2, 3, and 4, and satisfy 2 ≤ (p + q) ≤ 4. However, the method is provided that the alkyl group is not substituted with a hydroxyl group.

2. A method for treating a subject suffering from metabolic syndrome or a metabolic disorder, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

3. A method for reducing the weight of a subject requiring weight loss, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

4. A method for treating a subject who has diabetes or is at risk of developing diabetes, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

5. A method for treating a subject who is obese or overweight, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

6. A method for treating a subject with an eating disorder, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

7. A method for treating a subject suffering from bulimia nervosa, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

8. A method for treating a subject with hyperlipidemia, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

9. A method for treating an insulin-resistant subject, the method comprising administering to the subject a composition comprising GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

10. A method according to any one of claims 1 to 9, wherein the composition is a modified release composition.

11. A method according to claim 10, wherein the modified release composition is an orally administered modified release composition.

12. A method according to any one of claims 1 to 11, wherein the composition comprises an enteric coating.

13. A method according to any one of claims 1 to 12, characterized in that the composition comprises a gelatin coating.

14. A method according to any one of claims 1 to 13, wherein the composition comprises an excipient, the excipient comprising a binder, a disintegrant, a diluent, a buffer, a lubricant, a lubricant, an antioxidant, an antimicrobial preservative, a colorant, or a flavoring agent.

15. A method according to any one of claims 1 to 14, wherein the compound is coated onto basic particles to form a core.

16. A method according to claim 15, wherein the core is coated with an enteric coating to form enteric coated beads.

17. A method according to any one of claims 1 to 16, wherein the dosage form is an oral dosage form.

18. A method according to claim 17, wherein the oral dosage form is in the form of a capsule, a tablet, or a pharmaceutically acceptable solution.

19. A method according to any one of claims 1 to 18, wherein the composition comprises the compound in amounts of about 2 mg to about 5000 mg, about 5 mg to about 3000 mg, about 10 mg to about 2000 mg, about 20 mg to about 1500 mg, about 30 mg to about 1000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 100 mg to about 700 mg, about 150 mg to about 600 mg, about 200 mg to about 500 mg, about 250 mg to about 400 mg, or about 300 mg to about 350 mg.

20. A method according to any one of claims 1 to 19, wherein the composition is encapsulated in a capsule.

21. A method according to claim 20, wherein the capsule comprises granules or powder of the compound, or granules or powder comprising a mixture of the compound and a pharmaceutically acceptable carrier or excipient.

22. A method according to claim 21, wherein the capsule is enterically coated, but the granules or powder are not enterically coated.

23. A method according to claim 21, wherein at least a portion of the granules or powder is enterically coated.

24. A method according to claim 23, wherein at least a portion of the granules or powder is enterically coated before being encapsulated in the capsule.

25. A method according to claim 23 or claim 24, comprising a first portion of the granules or powder coated with one enteric coating and at least a second portion of the granules or powder coated with a different enteric coating, wherein the first portion is released in a different region of the intestine of the subject from the second portion.

26. A method according to any one of claims 20 to 25, wherein the capsule is a liquid-filled capsule further comprising the composition and a pharmaceutically acceptable liquid, which are mixed to form a liquid formulation.

27. A method according to claim 26, wherein the capsule is enterically coated, and the liquid formulation inside the capsule is not enterically coated.

28. A method according to any one of claims 1 to 27, further comprising administering at least one known agent for treating an underlying disease.

29. A method according to any one of claims 1 to 27, further comprising at least one additional agent selected from the group consisting of antidiabetic agents, weight-loss agents, metabolic syndrome treatment agents, and anti-obesity agents.

30. A method according to any one of claims 28 and 29, comprising administering the composition or capsule separately from the at least one drug.

31. A method according to any one of claims 28 and 29, comprising administering the composition or capsule simultaneously with at least one drug.

32. A method according to any one of claims 28 and 29, wherein the compound and the at least one additional agent are physically mixed in the composition.

33. A method according to any one of claims 28 and 29, wherein the compound and the at least one additional agent form a physically separated structure in the composition.

34. A method according to any one of claims 1 to 33, wherein the subject is a mammal or a bird.

35. A method according to any one of claims 1 to 33, wherein the subject is a human.

36. A method according to any one of claims 1 to 9, wherein the administration is carried out by at least one route selected from the group consisting of nasal, inhalation, topical, oral, buccal, rectal, pleural, peritoneal, transvaginal, intramuscular, subcutaneous, percutaneous, epidural, intrathecal, and intravenous.

37. A method according to any one of claims 1 to 36, wherein the pharmaceutically acceptable salt comprises an acid addition salt selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, sulfanilic acid, stearic acid, alginic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid, or a combination thereof.

38. Use of GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol) and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants in the manufacture of pharmaceuticals for the suppression or treatment of target metabolic syndrome or metabolic diseases.

39. Use of GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol) and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants in the manufacture of pharmaceuticals for inducing weight loss in subjects.

40. Use of GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol) and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants in the manufacture of pharmaceuticals for the treatment or prevention of diabetes.

41. Use of GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol) and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants in the manufacture of pharmaceuticals for the treatment of target eating disorders.

42. Use of GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol) and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants in the manufacture of pharmaceuticals for the treatment of bulimia nervosa.

43. Use of GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol) and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants in the manufacture of pharmaceuticals for the treatment of hyperlipidemia.

44. Use of GAL475 (1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidine-4-ylamino)-2-methylpropan-2-ol) and its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants in the manufacture of pharmaceuticals for the treatment of target insulin resistance.

45. The use of a compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant, 【Chemistry 2】 【change】 R １ , R ５ and R ７ These are, independently, hydrogen and optionally substituted C. １ -C ３ Selected from the group consisting of alkyl groups, R ２ The group is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted. R ６ and R ８ Each of these is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, and each of the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups is independently and arbitrarily substituted. R ９ and R １０ These are, independently, hydrogen and optionally substituted C. １ -C ３ Selected from the group consisting of alkyl groups, or R ９ and R １０ These are bonded to the carbon atoms to which they are bonded, and optionally substituted C ３ -C ６ Forms a cycloalkyl group, R １１ Each of them independently consists of hydrogen and optionally substituted C １ -C ３ Selected from the group consisting of alkyl groups, -C(R) in ring b １１ ) ２ -C(R １１ ) ２ - The group can be optionally replaced with an optionally substituted 1,2-phenylene group condensed with ring b, C １ -C ３ Each alkylene can be substituted independently and arbitrarily. m and n are independently selected from the group consisting of 1, 2, 3, and 4, and satisfy 2 ≤ (m + n) ≤ 4. p and q are independently selected from the group consisting of 0, 1, 2, 3, and 4, and satisfy 2 ≤ (p + q) ≤ 4. However, this is conditional on the alkyl group not being substituted with a hydroxyl group. a) Treatment of individuals suffering from metabolic syndrome or metabolic diseases, b) Weight reduction for subjects who require weight loss, c) Treatment of individuals who have diabetes or are at risk of developing diabetes. d) Treatment of subjects who are obese or overweight, e) Treatment of individuals with eating disorders, f) Treatment of individuals with bulimia, g) Treatment of patients with hyperlipidemia, or h) Treatment of patients with insulin resistance, Use in the manufacture of pharmaceuticals for this purpose.

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