GAL475 compositions and methods of use thereof

Abstract

Methods of treating a subject having a metabolic syndrome or disease, diabetes, obesity, overweight, eating disorders, polyphagia, hyperlipidemia, insulin resistance, or methods of reducing body weight in a subject are provided. The methods involve administering to the subject a composition comprising a compound of formula I, including, for example, GAL475 (l-(2, 6-dimethylamino-8-propylamino-pyrimido [5, 4-d] pyrimidin-4-ylamino)-2-methyl-propan-2-ol), e.g., GAL475 (l-(2, 6-dimethylamino-8-propylamino-pyrimido [5, 4-d] pyrimidin-4-ylamino)-2-methyl-propan-2-ol), e.g., GAL475 (l-(2, 6- or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer or isotope variant thereof, and a pharmaceutically acceptable carrier or excipient.

Description

Technical Field

[0001] This disclosure generally relates to compounds comprising the molecule GAL475 (l-(2,6-bis(2,6-dimethylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) or salts thereof, solvates, enantiomers, polymorphs, crystals, diastereomers or tautomers thereof, used in compositions or in the manufacture of medicaments for the treatment of diseases or conditions including metabolic syndrome, overweight, diabetes, eating disorders, polyphagia, hyperlipidemia, insulin resistance, obesity and related complications. Background Technology

[0002] Metabolic syndrome can be caused by a range of factors reflecting overnutrition, a sedentary lifestyle, and excessive obesity, including conditions such as obesity and diabetes. These conditions can lead to a variety of unhealthy states, including high blood pressure, high blood sugar, excess body fat in the abdomen and around organs, abnormal cholesterol or triglyceride levels, and comorbidities such as prethrombotic states, inflammatory diseases, fatty liver, and reproductive disorders. The prevalence of metabolic syndrome is rising to an epidemic not only in the United States and other urbanized areas around the world, but also in developing countries.

[0003] The main underlying causes of metabolic syndrome are abdominal obesity and insulin resistance. Diabetes is characterized by high blood sugar in one of two forms: one is non-insulin-dependent, or adult-onset, also known as type 2 diabetes; the other is insulin-dependent, or juvenile-onset, also known as type 1 diabetes. Clinical manifestations of type 2 diabetes and its underlying obesity typically appear after age 40. In contrast, type 1 diabetes usually presents with rapid onset before age 30. This disease is a metabolic disorder affecting approximately one percent of the general population, with one-quarter being type 1 and the remainder type 2. Treatment for diabetes is subsequently determined based on its etiology and pathology, with the most common methods including insulin administration and lifestyle modifications (diet, exercise, etc.).

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

[0005] Obesity is a highly prevalent chronic disease in modern society, associated with a variety of medical problems, including insulin resistance, hypertension, hypercholesterolemia, coronary heart disease, cancer, and sleep apnea. Obesity is so prevalent in today's world population that it is beginning to overtake malnutrition and infectious diseases as the leading cause of poor health and morbidity. As of 2021, approximately 650 million adults and 340 million children and adolescents were obese, and obesity has become the fourth leading risk factor for death globally (Tchang BG et al., Endotext. South Dartmouth: MDtext.com; 2021; Sørensen TIA et al., Handb Exp Pharmacol. 2022;274:3–27). 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 definition does not take into account the morbidity and mortality associated with milder degrees of overweight, nor the harmful effects of abdominal fat. The global obesity epidemic is the result of a combination of genetic susceptibility, increased availability of high-energy foods, and reduced physical activity demands in modern society. Obesity should no longer be simply viewed as a problem affecting the appearance of a particular individual, but rather as an epidemic threatening global well-being (Peter G. Kopelman, Nature 404, 2000).

[0006] The cornerstone of obesity treatment lies in sustainable lifestyle changes, including a combination of healthy eating and physical activity. Other treatment options include surgery (such as sleeve gastrectomy) and medication. The FDA has approved several drugs for short-term treatment of obesity (e.g., phentermine and amphetamine). These drugs reduce appetite by increasing the secretion of norepinephrine in neurons and, to a lesser extent, dopamine secretion. Side effects include erectile dysfunction, anxiety, nausea, and cardiovascular side effects. The FDA has also approved several drugs for the long-term treatment of obesity, including orlistat (a lipase inhibitor that reduces the absorption of fatty acids in the blood), phentermine-topiramate (an appetite suppressant associated with amphetamines, whose mechanism of action may be through inducing adrenaline release and suppressing appetite), bupropion-naltrexone (an appetite suppressant that, similar to short-term drugs, reduces the reuptake of norepinephrine and dopamine), and liraglutide, sermelatide, and smegglutide (injectable peptides that act as glucagon-like peptide-1 (GLP-1) receptor agonists).

[0007] GLP-1 is a hormone released in the gastrointestinal tract in response to food intake. One of the functions of GLP-1 is to stimulate the body to increase glucose-dependent insulin secretion from pancreatic β cells, thereby lowering blood glucose. In addition, GLP-1 reduces hepatic glucose production in a glucose-dependent manner by inhibiting glucagon secretion from α cells (Reshma Ramracheya et al., Physiol Rep. 2018 Sep; 6(17)). Glucagon may be regulated in a paracrine manner through somatostatin secreted by adjacent δ cells. GLP-1 receptor agonists have been used to treat type 2 diabetes because they mimic the effect of natural GLP-1 on pancreatic islet cells, stimulating insulin release in a glucose-dependent manner while inhibiting glucagon release. Higher doses of GLP-1 also interact with portions of the brain that reduce appetite and signal satiety. The observed weight loss effect has prompted exploration of its potential as an anti-obesity drug, with liraglutide 3.0 mg / day approved for weight management in the United States on December 23, 2014, and in the European Union on March 23, 2015 (Donna Ryan and Andres Acosta. Obesity (Silver Spring). 2015 Jun; 23(6)). Currently, two specific GLP-1 agonists (liraglutide and smegglutide) have been approved for the treatment of diabetes and obesity, while other agonists are often used off-label for the treatment of obesity. Multiple studies have shown that GLP-1 agonists can reduce the incidence of 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. 2022 Apr; 13(2)). Other mechanisms of action of GLP-1 agonists include improving β-cell function through gene regulation, inhibiting glucagon production, and delaying gastric emptying (Peyton W. Moore Adv Ther. 2023 Mar;40(3)). One of the main problems with using GLP-1 agonists to treat obesity is the side effects, which include gastrointestinal problems, nausea, diarrhea, constipation, indigestion, abdominal pain, and vomiting; this may require slow dose titration so that patients can better tolerate the drug. In addition, because these drugs are peptides, they can only be administered via intraperitoneal injection and cannot be taken orally.

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

[0009] Currently, there is an unmet need for new therapies for metabolic syndrome, diabetes, obesity, and weight loss. These therapies need to avoid the side effects of existing treatments while providing more tolerable routes of administration. Summary of the Invention

[0010] In one aspect, this disclosure includes a method of treating a subject suffering from metabolic syndrome or disease, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0011] This invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants thereof: (I), where in (I): Selected from Y 1 and Y 2 One of the substituents in the group is selected from -N(R) 1 )-LC(R 9 (R) 10 )OH、 and The group consists of another substituent, -N(R). 1 )R 2 ; R 1 R 5 and R 7 Independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups; R 2It is selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted. R 6 and R 8 Independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl. The alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl groups are optionally substituted independently; R 9 and R 10 Independently selected from the group consisting of H and optionally substituted C1-C3 alkyl groups; or R 9 and R 10 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl group; R 11 Each instance is independently selected from H and optionally substituted C1-C3 alkyl groups; wherein the cyclo b -C(R) inside 11 )2-C(R 11 The 2-group is optionally combined with a ring. b Fused optional substituted 1,2-phenylene substitution; Each time it appears, the substituted C1-C3 alkylene group is independently selected; m and n are independently selected from the group consisting of 1, 2, 3 and 4, such that 2≤(m+n)≤4; p and q are independently selected from the group consisting of 0, 1, 2, 3 and 4, such that 2≤(p+q)≤4; The condition is that the alkyl group is not substituted with a hydroxyl group.

[0012] In some embodiments, a compound of formula (I) may include a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof: (I), where in (I): Selected from Y 1 and Y 2 One of the substituents in the group is selected from -N(R) 1 )-LC(R 9 (R) 10 )OH、 and The group consists of another substituent, -N(R). 1 )R 2; R 1 R 5 and R 7 Independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups; R 2 It is selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted. R 6 and R 8 Independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted; R 9 and R 10 Independently selected from the group consisting of H and optionally substituted C1-C3 alkyl groups; or R 9 and R 10 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl group; R 11 Each instance is independently selected from H and optionally substituted C1-C3 alkyl groups; wherein the cyclo b -C(R) inside 11 )2-C(R 11 The 2-group is optionally combined with a ring. b Fused optional substituted 1,2-phenylene substitution; Each time it appears, the substituted C1-C3 alkylene group is independently selected; m and n are independently selected from the group consisting of 1, 2, 3 and 4, such that 2≤(m+n)≤4; p and q are independently selected from the group consisting of 0, 1, 2, 3 and 4, such that 2≤(p+q)≤4; The condition is that the alkyl group is not substituted with a hydroxyl group.

[0013] In some embodiments, the compound of formula (I) is a compound of formula (IIb): (IIb), where in (IIb): Selected from Y 1 and Y 2 One of the substituents in the group is The other substituent is –N(R) 1 )R 2 ;R 1 R 5 and R7 Independently selected from the group consisting of H and optionally substituted C1-C3 alkyl groups; R 2 The compound is selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, benzoalkyl, aryl, aralkyl, heteroaryl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, benzoalkyl, aryl, aralkyl, heteroaryl, or heteroaryl is optionally substituted independently; L is an optionally substituted C1-C3 alkylene group; and R 6 and R 8 Independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, benzoalkyl, aryl, aralkyl, heteroaryl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, benzoalkyl, aryl, aralkyl, heteroaryl, or heteroaryl is independently optionally substituted; R 11 Each instance is independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups; L is an optionally substituted C1-C3 alkylene group; m and n are independently selected from the group consisting of 1, 2, 3 and 4, such that 2 ≤ m + n ≤ 4; provided that the alkyl group is not substituted with a hydroxyl group.

[0014] In some embodiments, the compound of formula (I) is a compound of formula (IIc): (IIc), where in (IIc): selected from Y 1 and Y 2 One of the substituents in the group is The other substituent is –N(R) 1 )R 2 ;R 1 R 5 and R 7 Independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups; R 2 Selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl group is independently and optionally substituted; R 6 and R 8 Independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted; R 9 and R 10 Independently selected from the group consisting of H and optionally substituted C1-C3-alkyl groups; or R 9 and R 10 It combines with the carbon atom to which it is attached to form an optionally substituted C3-C6 cycloalkyl group; R11 Each instance is independently selected from the group consisting of H and optionally substituted C1-C3 alkyl groups; wherein the ring b -C(R) inside 11 )2-C(R 11 The 2-group is optionally combined with a ring. b The fused optional substituted 1,2-phenylene substituted; L is independently an optional substituted C1-C3 alkylene each time it appears; p and q are independently selected from the group consisting of 0, 1, 2, 3 and 4, such that 2 ≤ p + q ≤ 4; provided that the alkyl group is not hydroxylated.

[0015] In certain embodiments of compounds of formulas (I), (IIa), (IIb), and (IIc), the 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 time it appears; the 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 time it appears; and the phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, F, Cl, Br, I, nitro, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -S(=O) each time it appears. 0-2 Substituent substitutions of the group consisting of (C1-C6 alkyl), -C(=O)OH and -C(=O)OC1-C6 alkyl.

[0016] In some embodiments of the compound of formula (I), R 1 R 5 and R 7 For H. In some embodiments of the compound of formula (I), R 1 R 5 and R 7 Independently, it is an optionally substituted C1-C3 alkyl group. In some embodiments of compounds of formula (I), R 1 R 5 and R 7 For H; and R 9 and R 10 For H. In some embodiments of the compound of formula (I), R 1 R 5 and R 7 For H; R 9 For H; and R 10 It is CH3.

[0017] In some embodiments, the compound of formula (I) is selected from the group consisting of: 2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-ethanol (4); 2-[(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-yl)-methyl-amino]-ethanol (6); 3-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-1-ol (8); 1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-2-ol (10); (S)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-2-ol -Methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-2-ol (12); (R)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-2-ol (14); 2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-2-methyl-propane-1-ol (16); (S)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-1-ol (18); (R)-2-(2,6-bis-methylamino-8-propylamino-pyrimidin [5,4-d]-pyrimidin-4-ylamino)-propane-1-ol (20); 3-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-1,1,1-trifluoro-propane-2-ol (22); 1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-butane-2-ol (24); 3-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-butane-2-ol (26); 2-(2,6-bis-ethylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-ethanol (27) ; 2-[8-propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidin-4-ylamino]-ethanol (28); 1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-2-methyl-propane-2-ol (31); 1-(2,6-bis-ethylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-2-methyl-propane-2-ol (32); 1-[2,6-bis-(2,2-difluoro-ethylamino)-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-2-methyl-propane-2-ol (33);2-Methyl-1-[8-propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidin-4-ylamino]-propane-2-ol (34); 1-[8-(2,2-difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-2-methyl-propane-2-ol (36); 1-{2,6-bis-methylamino-8-[(pyrimidin-2-ylmethyl)-amino]pyrimido[5,4-d]pyrimidin-4-ylamino}-2-methyl-propane-2-ol (38); 1-[8-((R)-sec-butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-pyrimidin-4-ylamino]-2-methyl-propane-2-ol [8-((S)-sec-butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-2-methyl-propane-2-ol (42); 1-(8-benzylamino-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-2-methyl-propane-2-ol (44); 1-[8-(cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-2-methyl-propane-2-ol (46); 1-[8-(2,2-difluoro-ethylamino)-2,6-bis-ethylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-2-methyl-propane-2-ol 2-[8-(2,6,8-tri-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-2-ol (47); 2-methyl-1-(2,6,8-tri-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-2-ol (48); 2-methyl-1-(2,6,8-tri-ethylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-propane-2-ol (49); 2-(2,6,8-tri-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-ethanol (52); 2-[8-(cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-ethanol (54); 2-[8-(2-methoxy-ethylamino)-2,6-bis-methylamino ... 2-(2,6-bis-methylamino-8-prop-2-ynylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-ethanol (58); 2-[8-(2,2-difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino]-ethanol (60); 2-[2,6-bis-methylamino-8-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidin-4-ylamino]-ethanol (62); 2-(8-benzylamino-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-ethanol (64);3-(8-ethylamino-2,6-bis-methylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-propane-1-ol (67); 1-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-yl)-pyrrolidin-3-ol (71); 1-[(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-methyl]-cyclobutanol (72); 1-[(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-yl)-methyl-amino]-propane-2-ol (73); 3-[(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-yl)-methyl-amino]-propane-2-ol [5,4-d]pyrimidin-4-ylamino)-methyl]-pentane-3-ol (74); 1-[(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-yl)-methyl-amino]-2-methyl-propane-2-ol (76); (1R,2S)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]-pyrimidin-4-ylamino)-indane-2-ol (77); (1S,2S)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]-pyrimidin-4-ylamino)-indane-2-ol (78); (1S,2R)-1-(2,6-bis-methylamino-8-propylamino) (79) (1R,2R)-1-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]-pyrimidin-4-ylamino)-indene-2-ol (80); (2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]-pyrimidin-4-ylamino)-indene-1-ol (81); (1R,2S)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]-pyrimidin-4-ylamino)-cyclohexanol (82); (1S,2S)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]-pyrimidin- (4-ylamino)-cyclohexanol (83); (1S,2R)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-cyclohexanol (84); (1R,2R)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-cyclohexanol (85); (1S,2S)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-cyclopentanol (86); (1R,2R)-2-(2,6-bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-ylamino)-cyclopentanol (87);2-[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-ethanol (90); 2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-ethanol (91); 2-(6-dimethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-ethanol (92); 1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-2-methyl-propane-2-ol (94); 1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin -2-ylamino)-propane-2-ol (95); 1-[(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-yl)-methyl-amino]-2-methyl-propane-2-ol (96); 1-[(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-yl)-methyl-amino]-propane-2-ol (97); 1-[6-((R)-sec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-2-methyl-propane-2-ol (99); (R)-1-[6-((R)-sec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-2-methyl-propane-2-ol] [5,4-d]pyrimidin-2-ylamino]-propane-2-ol (100); (S)-1-[6-((R)-sec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (101); 1-[6-((S)-sec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-2-methyl-propane-2-ol (103); (R)-1-[6-((S)-sec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (104); (S)-1-[6-((S)-sec-butylamino]-[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (104); 1-[4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (105); 1-[6-(2,2-difluoro-ethylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-2-methyl-propane-2-ol (107); 1-{4,8-bis-methylamino-6-[(pyrimidin-2-ylmethyl)-amino]pyrimido[5,4-d]pyrimidin-2-ylamino}-2-methyl-propane-2-ol (109); 3-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-1,1,1-trifluoro-propane-2-ol (111);(S)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (113); (R)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (115); 1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-butane-2-ol (117); 3-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-butane-2-ol (119); (1R,2S)-1-(4,8-bis-methylamino-6-propylamino- (123) (1S,2S)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]-pyrimidin-2-ylamino)-indene-2-ol (125) (1S,2R)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]-pyrimidin-2-ylamino)-indene-2-ol (127) (1R,2R)-1-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]-pyrimidin-2-ylamino)-indene-2-ol (129) (1R,2S)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]-pyrimidin-2-ylamino)-indene-2-ol (1S,2S)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-cyclohexanol (131); (1S,2S)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-cyclohexanol (133); (1S,2R)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-cyclohexanol (135); (1R,2R)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-cyclohexanol (137); (1S,2S)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-cyclopentanol Alcohol (139); (1R,2R)-2-(4,8-bis-methylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-cyclopentanol (141); (S)-1-[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (142); (S)-1-(6-allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (143); (R)-1-[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (144);(R)-1-(6-allylamino-4,8-bis-methylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (145); 1-[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino]-butane-2-ol (146); 1-(6-ethylamino-4,8-bis-methylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino)-butane-2-ol (147); 2-methyl-1-(4,6,8-tri-methylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (149); 2-(6-allylamino-4,8-bis-methylamino-pyrimidino)-propane-2-ol [5,4-d]pyrimidin-2-ylamino)-ethanol (154); (S)-1-[(6-allylamino-4,8-bis-methylamino-pyrimidino[5,4-d]-pyrimidin-2-yl)-propyl-amino]-propane-2-ol (155); (S)-1-[(6-allylamino-4,8-bis-methylamino-pyrimidino[5,4-d]pyrimidin-2-yl)-methyl-amino]-propane-2-ol (156); (R)-1-[6-(2-methyl-allylamino)-4,8-bis-methylamino-pyrimidino[5,4-d]-pyrimidin-2-ylamino]-propane-2-ol (158); (S)-1-[6-(2-methyl-allylamino)-4,8-bis- Methylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (159); 2-(4,8-bis-ethylamino-6-propylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino)-ethanol (162); 1-(4,8-bis-ethylamino-6-propylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino)-2-methyl-propane-2-ol (163); (S)-1-(4,6,8-tri-ethylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (165); (S)-1-(4,8-bis-ethylamino-6-propylamino-pyrimidino[5,4-d]pyrimidin-2-ylamino)-propane-2- Alcohol (166); (R)-1-(4,6,8-tri-ethylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (168); (R)-1-(4,8-bis-ethylamino-6-propylamino-pyrimido[5,4-d]pyrimidin-2-ylamino)-propane-2-ol (169); (R)-1-[4,8-bis-ethylamino-6-(2-methyl-allylamino)-pyrimido[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (174); (S)-1-[4,8-bis-ethylamino-6-(2-methyl-allylamino)-pyrimido[5,4-d]pyrimidin-2-ylamino]-propane-2-ol (175);Pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, isotopic variants, and any combination thereof.

[0018] A detailed description of the compound is disclosed in U.S. Patent No. US10294228B2, the contents of which are incorporated herein by reference.

[0019] In one aspect, this disclosure includes a method for reducing the weight of a subject in need, 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, and in a particular aspect comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0020] In one aspect, this disclosure includes a method of treating a subject with diabetes or at risk of 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, and in a particular aspect comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0021] In one aspect, this disclosure includes a method of treating a subject suffering from obesity, 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, and in a particular aspect comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0022] In one aspect, this disclosure includes a method of treating a subject suffering from 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, and in a particular aspect comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0023] In one aspect, this disclosure includes a method of treating a subject suffering from polyphagia, 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, and in a particular aspect comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0024] In one aspect, this disclosure includes a method of treating a subject suffering from 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, and in a particular aspect comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0025] In one aspect, this disclosure includes a method of treating a subject with insulin resistance, 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, and in a particular aspect comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0026] In some respects, the composition is an immediate release composition.

[0027] In some respects, the composition is a modified-release composition.

[0028] In some respects, the modulated release composition is an oral modulated release composition.

[0029] In some respects, the composition comprises an enteric coating.

[0030] In some respects, the composition comprises a gelatin coating.

[0031] In some aspects, the composition comprises excipients, wherein the excipients include binders, disintegrants, diluents, buffers, lubricants, flow aids, antioxidants, antimicrobial preservatives, colorants, or flavorings.

[0032] In some cases, compounds are coated onto matrix particles to form a core.

[0033] In some respects, the core is coated with an enteric coating, thereby forming enteric-coated microspheres.

[0034] In some aspects, the dosage form is oral.

[0035] In some respects, the oral dosage form is a capsule, tablet, or pharmaceutically acceptable solution.

[0036] In some aspects, the composition comprises 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 of the compound.

[0037] In some respects, the composition is encapsulated in a capsule.

[0038] In some respects, the capsule contains particles or powder of the compound, or particles or powder comprising a mixture of the compound and the pharmaceutically acceptable carrier or excipient.

[0039] In some respects, the capsules are coated with an enteric coating, but the granules or powders are not coated with an enteric coating.

[0040] In some respects, at least some of the particles or powders have an enteric coating.

[0041] In some respects, at least some of the particles or powders are coated with enteric coating before being encapsulated.

[0042] In some respects, particles or powders of a first sub-part coated with an enteric coating, and particles or powders of at least a second sub-part coated with a different enteric coating, wherein the release area of ​​the first sub-part in the subject’s intestine is different from that of the second sub-part.

[0043] In some respects, the capsule is a liquid-filled capsule that further comprises the composition and a pharmaceutically acceptable liquid, mixed to form a liquid formulation.

[0044] In some respects, the capsule is coated with an enteric coating, and the liquid formulation within the capsule does not contain an enteric coating.

[0045] In some aspects, the method further comprises administering at least one agent known for treating the underlying disease.

[0046] In some aspects, the method further comprises 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 some aspects, the method further comprises administering the composition or capsule separately from at least one pharmaceutical agent.

[0048] In some aspects, the method further comprises co-administering the composition or capsule with at least one pharmaceutical agent.

[0049] In some respects, the compound is physically mixed in the composition with at least one additional pharmaceutical agent.

[0050] In some respects, the compound and at least one additional agent are configured in the composition as physically separate structures.

[0051] In some respects, the subjects are mammals or birds.

[0052] In some respects, the subjects were human.

[0053] In some respects, administration is carried out via at least one route selected from the group consisting of: nasal, inhalation, local, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, intrathecal, and intravenous.

[0054] In some respects, 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, alginate, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, β-hydroxybutyric acid, salicylic acid, galactopyric acid, and galacturonic acid, or combinations thereof. In some respects, the salt is (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol dihydrochloride).

[0055] In one aspect, this 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 preparation of a medicament for inhibiting or treating a metabolic syndrome or disease in a subject of need, and in a particular aspect, the compound is GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof.

[0056] In one aspect, this 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 preparation of a medicament for inducing weight loss in a subject in need, and in a particular aspect, the compound is GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof.

[0057] In one aspect, this 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 preparation of a medicament for the treatment or prevention of diabetes in a subject of need, and in a particular aspect, the compound is GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof.

[0058] In one aspect, this 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 preparation of a medicament for treating eating disorders in a subject in need, and in a particular aspect, the compound is GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof.

[0059] In one aspect, this 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 preparation of a medicament for treating polyphagia in a subject in need, and in a particular aspect, the compound is GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof.

[0060] In one aspect, this 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 preparation of a medicament for the treatment or prevention of hyperlipidemia in a subject of need, and in a particular aspect, the compound is GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof.

[0061] In one aspect, this 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 preparation of a medicament for treating insulin resistance in a subject of need, and in a particular aspect, the compound is GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methyl-prop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof.

[0062] Other features and characteristics of the subject matter of this disclosure, as well as the methods of operation, the functions of the related structural elements, the combination of parts, and the economics of manufacturing, will become more apparent upon reference to the following description, the accompanying drawings, and the appended claims, all of which form part of this specification. Attached Figure Description

[0063] The features and advantages of the present invention can be understood by referring to the following detailed description and accompanying drawings, which illustrate illustrative embodiments to which the principles of the invention can be applied, and in the accompanying drawings: Figure 1 The graph shows the increase in body weight of rats after 28 days of GAL475 administration compared to solvent-treated rats.

[0064] Figure 2 The food consumption of rats after GAL475 administration is shown as a percentage of the consumption of the solvent-treated control group.

[0065] Figure 3 The study shows the weight gain in dogs, expressed as a percentage change in body weight, after 28 days of administration of GAL475 at doses of 30 mg / kg, 15 mg / kg, and 7.5 mg / kg, compared to the solvent.

[0066] Figure 4 The study showed the gastric contents retention in rats after administration of GAL475 compared to the solvent.

[0067] Figure 5 The individual changes in body weight of human subjects one week after a single oral dose of 450 mg GAL475 (left) versus placebo (right) are shown.

[0068] Detailed description

[0069] While various aspects of the subject matter of this disclosure may be implemented in many forms, the following description is intended only to disclose some of these forms as specific embodiments of the subject matter covered by this disclosure. Therefore, the subject matter of this disclosure is not intended to be limited to the forms or implementations described.

[0070] GAL-475 (1-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) is an investigational drug initially developed as a respiratory control modulator for the treatment of central and obstructive sleep apnea, two major phenotypes of sleep-disordered breathing. A description of the molecule and related compounds is found in patent number US10294228B2, which is incorporated herein by reference.

[0071] This respiratory control regulation may be mediated via the carotid body, a peripheral multimodal chemoreceptor located at the carotid bifurcation, responsible for sensing changes in O2, CO2 partial pressure, or pH and activating the brainstem respiratory center to produce hyperventilation. As illustrated in the examples below, this disclosure provides a surprising and unexpected use of the GAL475 compound in the treatment of metabolic syndrome and related disorders and conditions. The disclosures and examples included in this disclosure demonstrate that administration of GAL475 provides slowed gastric emptying, thereby reducing appetite. For example, as shown in Example 2, rats treated with GAL475 (40 mg / kg body weight daily) for 28 days showed significant weight loss in a dose-dependent manner compared to the solvent. As a further example, as shown in Example 3, dogs treated with GAL475 for 28 days showed a 25% decrease in body weight and a significant reduction in food intake in a dose-dependent manner compared to the solvent. As shown in Example 5, administration of GAL475 to human subjects also demonstrated weight loss. GAL475 is effective in promoting weight loss and reducing appetite in humans and animals. This disclosure includes the use of GAL475 to treat metabolic syndrome, eating disorders, polyphagia, hyperlipidemia, insulin resistance, obesity, diabetes, and to achieve weight loss in humans.

[0072] definition

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The methods and materials used in this disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety.

[0074] The term "a / an" refers to one or more (i.e., at least one) of the articles. For example, "a cell" encompasses one or more cells.

[0075] As used herein and as fully understood in the art, the term "treatment" refers to a means of achieving a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to: reducing or improving one or more symptoms or conditions, reducing the severity of the disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing disease progression, improving or alleviating the disease state, reducing disease relapses, and remission (whether partial or complete), whether detectable or not. "Treatment" may also refer to extended survival compared to expected survival without treatment. In addition to being used as a treatment method, the methods described herein may also be used for the prevention or control of disease.

[0076] As used herein, the phrase “co-administered” or “combined administered” means that two (or more) agents are administered sequentially over time. Co-administration or combination may include mixing two agents into a single formulation, administering two agents separately but simultaneously, or administering them separately at short intervals. For example, the two agents are typically administered co-administered over a timeframe of 0.5 to 168 hours.

[0077] In this document, concentration, amount, time, and other numerical data may be expressed or presented in range form. It should be understood that such range format is for convenience and brevity only, and therefore should be interpreted flexibly to include not only the values ​​explicitly listed as range boundaries, but also all individual values ​​or subranges contained within that range, as if each value and subrange were explicitly listed. For example, the numerical range “about 0.01 to 2.0” should be interpreted to include not only the explicitly listed values ​​of about 0.01 to about 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, and subranges such as from 0.5 to 1.7, from 0.7 to 1.5, and from 1.0 to 1.5. Furthermore, this interpretation should apply regardless of the width of the range or the characteristics described. Additionally, unless otherwise stated, all percentages are weight percentages.

[0078] In understanding the scope of this disclosure, as used herein, the terms “comprising” or “including” and their derivatives are intended as open-ended terms indicating the presence of the stated features, elements, components, groups, integers, and / or steps, but not excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. The foregoing also applies to words with similar meanings, such as “comprising,” “having,” and their derivatives. As used herein, the term “consisting of” and its derivatives are intended as closed-ended terms indicating the presence of the stated features, elements, components, groups, integers, and / or steps, but excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. As used herein, the term “substantially composed of” is intended to indicate the presence of the stated features, elements, components, groups, integers, and / or steps, as well as those that do not materially affect the basic and novel characteristics of the stated features, elements, components, groups, integers, and / or steps. It should be understood that reference to any of these transitional terms (i.e., “comprising,” “composed of,” or “substantially composed of”) provides direct support for substitution to any other transitional term not specifically used. For example, changing the term from "comprising" to "consistently consisting of" would directly support this definition. According to this definition, any element disclosed herein or incorporated by reference may be included or excluded from the claimed invention.

[0079] As used herein, the terms “substantially” and “substantially” refer to a considerable degree or extent. When used in conjunction with, for example, an event, situation, feature, or attribute, these terms may refer to a situation where the event, situation, feature, or attribute occurs precisely, or a situation where the event, situation, feature, or attribute occurs approximately, for example, taking into account the typical tolerance levels or variability of the embodiments described herein.

[0080] As used herein, the term "about" is used to provide flexibility for the endpoints of a numerical range, indicating that a given value may be "slightly above" or "slightly below" that endpoint. The degree of flexibility of this term may be determined by the specific variable and, to the knowledge of those skilled in the art, based on experience and the relevant description herein. For example, in one aspect, the degree of flexibility may be within about ±10% of the value. In another aspect, the degree of flexibility may be within about ±5% of the value. In yet another aspect, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the value.

[0081] In this document, the term "or" typically includes "and / or".

[0082] In this document, for convenience, multiple compounds, elements, or steps may be presented together in a list. However, these lists should be understood as each member being individually identified as a separate and unique member. Therefore, without indication to the contrary, any member in a list should not be interpreted as an actual equivalent of the others simply because members in the same list are presented together.

[0083] The term “exemplary” as used herein means used as an example, instance, or illustration. Any aspect or design described as “exemplary” in this document should not be construed as being better or more advantageous than other aspects or designs. Rather, the use of the term “exemplary” is intended to present the concept in a more specific manner.

[0084] As used herein, “regulated release” may include extended release (XR), long-acting (LA), sustained release (SR), controlled release (CR), delayed release (DR), enteric coating, repetitive action, pulsatile release, or combinations thereof.

[0085] In some embodiments, the composition comprises an enteric coating. In other embodiments, the compound is contained in a pharmaceutically suitable capsule. In other embodiments, the capsule contains particles or powder of the compound, or a mixture of the compound with a carrier or excipient. In still other embodiments, the excipient comprises a binder, disintegrant, diluent, buffer, lubricant, flow aid, antioxidant, antimicrobial preservative, colorant, or flavoring agent. In still other embodiments, the capsule is coated with an enteric coating, but the particles or powder of the compound are not coated with an enteric coating. In still other embodiments, the particles or powder of the compound are coated with an enteric coating before being filled into the capsule. In still other embodiments, the particles or powder of the compound are coated with multiple enteric coatings to deliver the drug to different regions of the subject's intestine. In still other embodiments, at least a portion of the particles or powder of the compound is coated with an enteric coating. In still other embodiments, the capsule is coated with an enteric coating that is different from the enteric coating that coats the particles or powder of the compound.

[0086] In some embodiments, the compound is coated onto matrix particles to form a core. In other embodiments, the matrix particles are not coated with an enteric coating, and the composition is contained in a pharmaceutically acceptable capsule coated with an enteric coating. In other embodiments, the core is coated with an enteric coating to form enteric-coated microspheres. In yet another embodiment, the enteric-coated microspheres are contained in a pharmaceutically acceptable capsule. In yet another embodiment, the capsule contains microspheres coated with multiple enteric coatings, enabling the capsule to deliver the compound to different regions of the subject's intestine. In yet another embodiment, the contents of the capsule are dissolved or suspended in a pharmaceutically acceptable liquid to provide a liquid-filled capsule. In yet another embodiment, the capsule is coated with an enteric coating, but the liquid formulation contained therein does not contain an enteric coating.

[0087] Furthermore, certain compositions, elements, excipients, ingredients, diseases, symptoms, properties, steps, etc., may be discussed in a specific embodiment or aspect of this disclosure, or in a separate paragraph or section. It should be understood that this is for convenience and brevity only, and any such disclosure is equally applicable to and intended to be combined with any other embodiment or aspect found anywhere in this disclosure and the claims, all of which together constitute the application and the claimed invention as of the filing date. For example, a list of method steps, active agents, kits, or compositions describing a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant of a compound of formula (I) or thereof, and a method of treating a particular subject with respect to GAL475 (and related compounds described herein) in a particular aspect, is intended and does provide direct support for relevant embodiments of compositions, formulations relating to a compound of formula (I) or thereof, a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant, and a method of treating a particular subject with respect to GAL475 (and related compounds described herein) in a particular aspect, even if such method steps, active agents, kits, or compositions are not restated in the context or section of that embodiment or aspect.

[0088] Similarly, references to "one" compound, salt, or stereoisomer of GAL475 in this document are intended to cover "one or more" such compounds, including their salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants. Furthermore, references to "compound" in the following discussion of pharmaceutical formulations are also intended to include salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants of that compound.

[0089] The compounds of this invention may have one or more stereocenters, each of which may exist independently in an (R) or (S) configuration. In some embodiments, the compounds described herein exist in an optically active or racemic form. The compounds described herein encompass racemic, optically active, regioisomeric, and stereoisomeric forms or combinations thereof, which have the therapeutically useful properties described herein. The preparation of the optically active form can be achieved by any suitable means, including, as a non-limiting example: resolution of the racemic form by recrystallization, synthesis from an optically active starting material, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some 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. Resolution of the compound and its isomers can be achieved by any method, including but not limited to chemical methods, enzymatic methods, fractional crystallization, distillation, and chromatography.

[0090] The methods and formulations described herein include the use of N-oxides (where applicable), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having any of the compound structures of this invention, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include hydrates, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohols (e.g., ethanolates), acetates, etc. In some embodiments, the compounds described herein are present in solvate form with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein are present in a non-solventized form.

[0091] In some embodiments, the compounds of the present invention are present in tautomer form. All tautomers are included within the scope of the compounds described herein.

[0092] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" is a pharmaceutical agent that is converted into a parent drug in vivo. In some embodiments, after administration in vivo, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is converted into a biologically, pharmaceutically, or therapeutically active form of the compound via one or more enzymatic metabolic steps or processes.

[0093] In some embodiments, sites on the aromatic ring moiety of the compounds of the present invention are susceptible to various metabolic reactions. Introducing appropriate substituents into the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway. In some embodiments, by way of example only, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions are deuterium, halogens, or alkyl groups.

[0094] The compounds described herein also include isotopically labeled compounds, wherein one or more atoms are replaced by atoms having the same atomic number but with a different atomic mass or mass number than those normally found in nature. Examples of isotopes suitable for the compounds described herein include, but are not limited to: 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 35 S. In some embodiments, the isotopically labeled compound can be used for tissue distribution studies of the drug and / or substrate. In other embodiments, substitution with a heavier isotope (such as deuterium) can provide greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In still other embodiments, positron-emitting isotopes (such as...) are used. 11 C 18 F, 15 O and 13 Substitution with N) can be used in positron emission tomography (PET) studies to detect substrate acceptor occupancy. Isotopically labeled compounds can be prepared by any suitable method, or by using appropriate isotopically labeled reagents to replace the originally used unlabeled reagents through corresponding processes.

[0095] In some embodiments, the compounds described herein may be labeled in other ways, including but not limited to using chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0096] The method for synthesizing the molecules described in this disclosure is disclosed in U.S. Patent No. 10,294,228, the entire contents of which are incorporated herein by reference for all purposes.

[0097] Pharmaceutical compositions and formulations

[0098] This invention also covers methods of carrying out the invention using pharmaceutical compositions comprising at least one compound of the invention or a salt, solvate, enantiomer, diastereomer, or tautomer thereof. The pharmaceutical composition may consist of at least one compound of the invention or a salt, solvate, enantiomer, diastereomer, or tautomer thereof, in a form suitable for administration to a subject; or the pharmaceutical composition may comprise at least one compound of the invention or a salt, solvate, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these substances. At least one compound of the invention may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, for example, bound to a physiologically acceptable cation or anion, as is known in the art.

[0099] In one embodiment, the pharmaceutical composition that can be used to carry out the method of the present invention can be administered at a dose of 1 ng / kg / day to 5000 mg / kg / day. In other embodiments, the pharmaceutical composition that can be used to carry out the present invention can be administered at a dose of 1 ng / kg / day to 1000 mg / kg / day.

[0100] The effective dose provided in the composition may include a dosage unit containing one or more of the compounds disclosed herein, at a dose of about 0.01-500 mg / kg, about 1-100 mg / kg / day, or about 5-50 mg / kg / day. In some aspects, the dosage unit is administered every other day, every two weeks, or weekly.

[0101] The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any additional ingredients in the pharmaceutical compositions of the present invention will vary depending on the identity, size, and condition of the patient being treated, and further depend on the route of administration of the composition. For example, the composition may contain 0.1% to 100% (w / w) of the active ingredient.

[0102] Pharmaceutical compositions that can be used in the methods of the present invention can be suitably developed for administration via nasal, inhalation, oral, rectal, vaginal, pleural, peritoneal, parenteral, topical, percutaneous, pulmonary, intranasal, buccal, ocular, epidural, intrathecal, intravenous, or other routes of administration. Compositions that can be used in the methods of the present invention can be applied directly to the brain, brainstem, or any other part of the central nervous system of mammals or birds. Other envisioned formulations include: projected nanoparticles, microspheres, liposome formulations, coated particles, polymer conjugates, resealed erythrocytes containing the active ingredient, and immunologically based formulations.

[0103] In some embodiments, the compositions of the present invention form part of a pharmaceutical matrix capable of modulating insoluble substances and improving their bioavailability, developing immediate-release, controlled-release, or sustained-release products, and forming homogeneous compositions. For example, the pharmaceutical matrix can be prepared using hot-melt extrusion, solid solutions, solid dispersions, size reduction techniques, molecular complexes (e.g., cyclodextrins and others), micronization, and particle and formulation coating processes. Amorphous or crystalline phases can be used in such processes.

[0104] The route of administration will be obvious to those skilled in the art and will depend on factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated.

[0105] The formulations of the pharmaceutical compositions described herein may be prepared by any method known or to be developed in the fields of pharmacology and pharmaceutical science. Typically, such preparation methods involve combining the active ingredient with a carrier or one or more auxiliary ingredients, and then, if necessary or required, shaping or packaging the product into the desired single-dose or multi-dose units.

[0106] In this document, "unit dose" refers to a discrete amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is typically equal to the dose of the active ingredient to be administered to a subject, or a convenient fraction of that dose, such as half or one-third of the dose. Unit dosage forms may be used for a single daily dose or for multiple daily doses (e.g., about 1 to 4 or more times daily). When using multiple daily dosing, the unit dosage form for each dosing may be the same or different.

[0107] Although the pharmaceutical compositions described herein are primarily intended for ethical administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to a wide variety of animals. It is well known that pharmaceutical compositions suitable for human use can be modified to be administered to a wide variety of animals, and veterinary pharmacologists of ordinary skill levels can design and implement such modifications with only routine experiments (if necessary). The pharmaceutical compositions of this invention are intended for administration to, but are not limited to, humans and other primates and mammals, including commercially viable mammals such as cattle, pigs, horses, sheep, cats, and dogs.

[0108] In some embodiments, the compositions of the present invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In some 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. Pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, physiological saline, ethanol, recombinant human albumin (e.g., Recombumin®), soluble 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).

[0109] According to the principles of the invention, the compounds disclosed herein can be present in the composition in the form of a free base or its salts or mixtures thereof. Salts according to the principles of the invention can be prepared, for example, by reacting the free base with an equivalent or multiple equivalent of a suitable base or acid in a solvent or medium in which the salt is insoluble, or by reacting in a solvent such as water, followed by removal of the solvent by vacuum, freeze-drying, or by exchanging the ions of the existing salt with another ion on a suitable ion exchange resin. Each possibility represents a separate embodiment of the invention.

[0110] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), recombinant human albumin, dissolved gelatin, suitable mixtures thereof, and vegetable oils. For example, appropriate flowability can be maintained by using a coating such as lecithin, maintaining the desired particle size in the dispersed state, and using surfactants. Microbial activity can be prevented by a variety of antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars, sodium chloride, or polyols like mannitol and sorbitol, are preferably included in the composition. The absorption time of the injectable composition can be prolonged by including an absorption-retarding agent, such as aluminum monostearate or gelatin.

[0111] The compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients selected from, but not limited to: co-surfactants / solvents, solvents / co-solvents, water-immiscible solvents, water, water-miscible solvents, oily components, hydrophilic solvents, emulsifiers, preservatives, antioxidants, defoamers, stabilizers, buffers or pH adjusters, penetrants, pore-forming agents, permeation regulators, or any other excipients known in the art. Each possibility represents a separate embodiment. Suitable co-surfactants or solubilizers include, but are not limited to: polyethylene glycols; polyoxyethylene-polyoxypropylene block copolymers known as "poloxams"; polyglycerol fatty acid esters, such as decaglycerol monolaurate and decaglycerol monomyristate; sorbitan fatty acid esters, such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monooleate (Tween); polyethylene glycol fatty acid esters, such as polyoxyethylene monostearate; polyoxyethylene alkyl ethers, such as polyoxyethylene lauryl ether; polyoxyethylene castor oil and hydrogenated castor oil, such as polyoxyethylene hydrogenated castor oil; and the like or mixtures thereof. Each possibility represents a separate embodiment of the invention. Suitable solvents / co-solvents include, but are not limited to: alcohols, triacetin, dimethylisosorbitol, glyceryl formal, propylene carbonate, water, dimethylacetamide, and the like or mixtures thereof. Each possibility represents a separate embodiment of the invention. Suitable defoamers include, but are not limited to, silicone emulsions or dehydrated sorbitan sesquioleate. Each possibility represents a separate embodiment of the invention. Suitable stabilizers for preventing or reducing the degradation of components in the compositions of the invention include, but are not limited to, antioxidants such as glycine, α-tocopherol or ascorbate, BHA, BHT, and their analogues or mixtures thereof. Each possibility represents a separate embodiment of the invention. Suitable isotonic adjusters include, but are not limited to, mannitol, sodium chloride, and glucose. Each possibility represents a separate embodiment of the invention. Suitable buffers include, but are not limited to, acetates, phosphates, and citrates having suitable cations. Each possibility represents a separate embodiment of the invention.

[0112] The formulation may be mixed with conventional excipients, namely pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalation, intravenous, subcutaneous, transdermal, enteral, or any other suitable route of administration known in the art. Pharmaceutical formulations may be sterilized and optionally mixed with excipients, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting osmotic pressure, buffers, coloring, flavoring, and / or aroma compounds, etc. They may also be used in combination with other active agents, such as other analgesics, anxiolytics, or hypnotics, as needed. As used herein, “additional ingredients” include, but are not limited to, one or more ingredients that can be used as a drug carrier.

[0113] The compositions of the present invention may contain a preservative in an amount of about 0.005% to 2.0% of the total weight of the composition. The preservative is used to prevent spoilage upon exposure to environmental contaminants. According to the present invention, examples of usable preservatives include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidazolidinyl urea, and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

[0114] The composition preferably includes an antioxidant and a chelating agent, which inhibit the degradation of the compound. For certain compounds, preferred antioxidants are BHT, BHA, α-tocopherol, and ascorbic acid, with a preferred weight range of about 0.01% to 0.3% by weight, more preferably, BHT ranging from 0.03% to 0.1% by weight, based on the total weight of the composition. Preferably, the chelating agent is present at a content of 0.01% to 0.5% by weight, based on the total weight of the composition. Particularly preferred chelating agents include edetates (e.g., disodium edetate) and citric acid, ranging from about 0.01% to 0.20% by weight, more preferably from 0.02% to 0.10% by weight, based on the total weight of the composition. The chelating agent is suitable for chelating metal ions in the composition that may adversely affect the shelf life of the formulation. Although BHT and disodium edetate are particularly preferred antioxidants and chelating agents, for certain compounds, as known to those skilled in the art, other suitable and equivalent antioxidants and chelating agents may be substituted.

[0115] Liquid suspensions can be prepared by 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, ethanol, vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil), fractionated vegetable oils, and mineral oils (such as liquid paraffin). Liquid suspensions may also contain one or more additional ingredients, including but not limited to suspending agents, dispersants or wetting agents, emulsifiers, modifiers, preservatives, buffers, salts, flavoring agents, coloring agents, 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, gum arabic, and cellulose derivatives (such as sodium carboxymethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose). Known dispersants or wetting agents include, but are not limited to, naturally occurring phospholipids such as lecithin, condensation products of olefins and fatty acids, condensation products of olefins and long-chain fatty alcohols, condensation products of olefins and partial esters derived from fatty acids and hexitols, or condensation products of olefins and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecanol hexadecyl ether, polyoxyethylene sorbitan monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifiers include, but are not limited to, lecithin, gum arabic, and ionic or nonionic surfactants. Known preservatives include, but are not limited to, methylparaben, ethylparaben, or n-propylparaben, ascorbic acid, and sorbic acid. Known sweeteners include, for example, glycerin, propylene glycol, sorbitol, sucrose, and saccharin.

[0116] Liquid solutions of active ingredients dissolved in aqueous or oily solvents can be prepared by substantially the same method as liquid suspensions, the main difference being that the active ingredient is dissolved rather than suspended in the solvent. As used herein, an "oily" liquid refers to a liquid containing carbon-containing liquid molecules and exhibiting a lower polarity than water. Liquid solutions of the pharmaceutical compositions of the present invention may comprise the various components described with respect to liquid suspensions, but it should be understood that suspending agents do not necessarily contribute to the dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethanol, vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil), fractionated vegetable oils, and mineral oils (such as liquid paraffin).

[0117] The powder and granule formulations of the pharmaceutical preparations of this invention can be prepared using known methods. Such formulations can be administered directly to a subject, for example, used to form tablets, fill capsules, or to prepare aqueous or oily suspensions or solutions by adding an aqueous or oily carrier. Each of these formulations may further comprise one or more of a dispersant or wetting agent, a suspending agent, an ionic or nonionic surfactant, and a preservative. Additional excipients, such as fillers and sweeteners, flavoring agents, or coloring agents, may also be included in these formulations.

[0118] The pharmaceutical compositions of the present invention can also be prepared, packaged, or marketed as oil-in-water or water-in-oil emulsions. The oil phase can 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 comprise one or more emulsifiers, such as natural gums (such as gum arabic or tragacanth), natural phospholipids (such as soybean lecithin or soybean lecithin), esters or metaesters derived from combinations of fatty acids and hexitanium (such as sorbitan monooleate), and condensation products of such metaesters with ethylene oxide (such as polyoxyethylene sorbitan monooleate). These emulsions may also contain additional ingredients, including, for example, sweeteners or flavorings.

[0119] Methods of impregnating or coating materials with chemical compositions are known in the art, including but not limited to: methods of depositing or bonding chemical compositions to a surface; methods of incorporating chemical compositions into the material structure during material synthesis (i.e., using physiologically degradable materials); and methods of absorbing aqueous or oily solutions or suspensions into absorbent materials, followed by drying or not drying. Methods of mixing components include physical milling, using granules in solid and suspension formulations, and mixing in transdermal patches, as known to those skilled in the art.

[0120] Application / Dosage

[0121] Administration regimens may affect the composition of the effective dose. Therapeutic agents can be administered to patients before or after a respiratory distress event. Furthermore, they can be administered daily or sequentially in multiple divided doses or staggered doses, or as a continuous infusion, or by bolus injection. Additionally, the dosage of therapeutic agents may be increased or decreased proportionally according to the urgency of the treatment or prevention situation.

[0122] The compositions of the present invention can be administered to patients (preferably mammals, more preferably humans) using known methods at appropriate doses and times to effectively treat respiratory control disorders. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary depending on a variety of factors, such as the activity of the specific compound used; the time of administration; the rate of excretion of the compound; the duration of treatment; other drugs, compounds, or materials used in combination with the compound; the patient's disease or condition, age, sex, weight, physical condition, general health status, and medical history; and similar factors well known in the medical field. Dosing regimens can be adjusted to provide an optimal therapeutic response. For example, several fractionated doses may be administered daily, or the dose may be reduced proportionally according to the urgency of the treatment situation. A non-limiting example of an effective dose range for the therapeutic compounds of the present invention is from about 0.01 mg / kg to 100 mg / kg body weight per day. Those skilled in the art can investigate the relevant factors and determine the effective amount of the therapeutic compound without excessive experimentation.

[0123] This compound can be administered to animals multiple times daily, or less frequently, such as once daily, once weekly, once every two weeks, once monthly, or even less frequently, such as once every few months or once a year or less. It should be understood that, as a non-limiting example, the amount of the compound administered daily can be given daily, every other day, every two days, every three days, every four days, or every five days. For example, for an alternate-day administration regimen, administration could begin on Monday with a dose of 5 mg / day, followed by the first subsequent 5 mg / day dose on Wednesday, the second subsequent 5 mg / day dose on Friday, and so on. The frequency of administration will be apparent to those skilled in the art and will depend on a variety of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.

[0124] The actual dose level of the active ingredient in the pharmaceutical composition of the present invention can be varied in order to achieve an effective therapeutic response for a specific patient, a specific composition, and a specific route of administration, and to achieve a non-toxic amount of the active ingredient to the patient.

[0125] A medical professional with ordinary skills in the art, such as an internist or veterinarian, can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, an internist or veterinarian can begin administering the compound of the invention used in the pharmaceutical composition at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0126] In specific embodiments, it is particularly advantageous to formulate the compound into dosage units, which facilitates administration and ensures uniform dosage. As used herein, dosage unit form refers to a physically discrete unit suitable for a single patient dose; each unit contains a predetermined amount of the therapeutic compound, which is calculated to bind with a desired drug carrier to produce the desired therapeutic effect. The dosage unit form of the present invention depends on and is directly dependent on: (a) the unique properties of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent technical limitations in compounding / formulating such therapeutic compounds for treating respiratory disorders in patients.

[0127] In some embodiments, the compositions of the present invention are administered to a patient at doses from once daily to five or more times daily. In other embodiments, the compositions of the present invention are administered to a patient at a range of doses, including but not limited to once daily, once every two days, once every three days to once weekly, and once every two weeks. Those skilled in the art will readily understand that the frequency of administration of the various combinations of the present invention will vary from subject to subject, depending on a variety of factors, including but not limited to age, the disease or condition to be treated, sex, overall health status, and other factors. Therefore, the present invention should not be construed as limited to any particular dosage regimen, and the precise dose and composition administered to any patient will be determined by the attending physician after considering all other factors of the patient.

[0128] The compounds of the present invention applied may be in the following ranges: about 1 μg to about 7500 mg, about 20 μg to about 7000 mg, about 40 μg to about 6500 mg, about 80 μg to about 6000 mg, about 100 μg to about 5500 mg, about 200 μg to about 5000 mg, about 400 μg to about 4000 mg, about 800 μg to about 3000 mg, about 1 mg to about 5500 mg, about 2 mg to about 5000 mg, about 10 mg to about 4000 mg, about 15 mg to about 3750 mg, about 20 mg to about 3000 mg, about 30 mg to about 2500 mg, about 40 mg to about 2000 mg, about 50 mg to about 1500 mg, about 60 mg to about 1000 mg, about 70 mg to about 900 mg, about 80 mg to about 800 mg, and any and all integer or partial increments therein.

[0129] In some embodiments, the dosage of the compound of the present invention is from about 0.5 μg to about 5,000 mg. 。In some embodiments, the dosage of the compound of the invention used in the compositions described herein is less than about 5000 mg, or less than about 4000 mg, or less than about 3000 mg, or less than about 2000 mg, or less than about 1000 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 dose of the second compound described herein is less than about 1000 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, and any and all of these integer or partial increments.

[0130] In some embodiments, the present invention relates to an encapsulated pharmaceutical composition comprising: a container holding a therapeutically effective amount of the compound of the present invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or alleviate one or more symptoms of respiratory distress in a patient.

[0131] The term "container" includes any container used to contain a pharmaceutical composition or to manage stability or moisture absorption. For example, in some embodiments, the container is packaging for containing a pharmaceutical composition, such as a liquid (solution and suspension), semi-solid, lyophilized solid, solution, powder, or lyophilized formulation present in a two-chamber configuration. In other embodiments, the container is not packaging for containing a pharmaceutical composition; rather, it is a receptacle, such as a box or vial containing a packaged or unpackaged pharmaceutical composition and instructions for use. Furthermore, packaging techniques are well known in the art. It should be understood that the packaging containing the pharmaceutical composition may include instructions for use of the pharmaceutical composition, thus creating an enhanced functional association between the instructions and the packaged product. However, it should be understood that the instructions may contain information about the compound's ability to perform its intended function, such as treating, preventing, or alleviating respiratory distress in a patient.

[0132] application

[0133] The routes of administration for any composition of the present invention include inhalation, oral administration, nasal administration, rectal administration, parenteral administration, sublingual administration, transdermal administration, transmucosal administration (e.g., sublingual, lingual surface, buccal, urethral, ​​vaginal administration (e.g., vaginal and perivallary), nasal administration, and rectal administration), intravesical administration, intrapulmonary administration, intraduodenal administration, intragastric administration, intrathecal administration, intrathecal administration, epidural administration, intrapleural administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intradermal administration, intraarterial administration, intravenous administration, intrabronchial administration, inhalation, and topical administration.

[0134] Suitable compositions and dosage forms include, for example, tablets, capsules, pouches, pills, gelatin capsules, lozenges, emulsions, dispersions, suspensions, solutions, syrups, granules, microcapsules, transdermal patches, gels, powders, granules, emulsions, lozenges, creams, pastes, ointments, lotions, tablets, suppositories, liquid sprays for nasal or oral administration, dry powder or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions used in this invention are not limited to the specific formulations and compositions described herein.

[0135] This invention provides a method for treating or delaying the progression or onset of diabetes (especially type 2 diabetes) and its complications (such as retinopathy, neuropathy, nephropathy, and delayed wound healing) and related diseases (such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, overweight, obesity, hyperlipidemia (including hypertriglyceridemia), metabolic syndrome, atherosclerosis, hypertension, cardiovascular diseases and events (such as coronary heart disease, cerebrovascular disease, peripheral artery disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, and pulmonary embolism), nonfatal myocardial infarction, or nonfatal stroke), as well as a method for increasing high-density lipoprotein levels.

[0136] Obesity involves excessive body fat accumulation and is generally defined as a body mass index (BMI; weight (kg) divided by height squared (m)) of 30 or higher. The most common cause of obesity is an energy imbalance (i.e., a "positive energy balance") resulting from long-term overeating and insufficient energy expenditure. As a systemic metabolic disease, obesity increases the likelihood of developing diabetes and hyperlipidemia, raises the risk of sexual dysfunction, arthritis, and cardiovascular disease, and in some cases, is associated with cancer.

[0137] Overweight involves moderate body fat accumulation and is generally defined as a body mass index (BMI; weight (kg) divided by height squared (m)) between 25 and 29.5. The most common cause of overweight is an energy imbalance resulting from chronically excessive food intake and insufficient energy expenditure. Overweight increases mortality and, in developing countries, has surpassed smoking as a leading cause of cancer. It also increases the risk of oligospermia and azoospermia and negatively impacts overall physical health.

[0138] The term “treatment” as used in this article for obesity and overweight conditions refers to 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), including morbid obesity, as well as diseases and health conditions associated with excessive weight gain, including but not limited to inflammation, gallbladder disease, and sleep apnea.

[0139] Oral administration

[0140] In one embodiment, the compounds of the present invention can be formulated into pharmaceutical compositions for oral administration. In a further embodiment, the oral administration composition can be designed to promote the modulated release of the drug, thereby regulating the location, extent, and rate of exposure of the compound upon ingestion. Factors influencing the target site of drug exposure may include the pH or enzyme stability of the drug, its reactivity with other drugs (e.g., certain antibiotics), its solubility as a salt or free base, its ionization behavior, and its pharmacodynamic and pharmacokinetic behavior in a specific environment. Some drugs are more readily absorbed in the duodenum or other intestinal sites.

[0141] Delayed release is a particularly useful modulated release mechanism that delivers drugs to the duodenum or other intestinal sites in the most concentrated form. In a preferred embodiment, the compounds of the invention are formulated to facilitate delivery to the duodenum and optionally other intestinal sites. Delayed release can be achieved by employing compositions comprising enteric coatings. Enteric coatings are insoluble in strongly acidic environments, and their polyacid coatings remain non-ionized and intact at gastric pH. However, under weakly acidic (pH > 5.5), neutral, or weakly alkaline (pH 6.5–7.6) conditions in the duodenum or other intestinal regions, the coating ionizes, swells, and decomposes, exposing the coating to the environment. Coating options exist that enable ionization at or near specific pH values ​​(e.g., Eudragit L-110, ionization threshold pH 6.0; Eudragit S-100, ionization threshold pH 7.0).

[0142] In a further embodiment, the compounds of the present invention can be formulated using an enteric coating, which is modified by adding a plasticizer to the polymer prior to coating. The plasticizer can be added to adjust the coating's resistance to shattering or cracking, while simultaneously lowering the glass transition temperature of the coating, allowing the coating to spread smoothly and uniformly during the coating process. Suitable plasticizers include polyethylene glycol 8000 (PEG 8000), triethyl citrate (TEC), and glyceryl triacetate, which can be incorporated into the polymeric enteric coating agent.

[0143] The compounds of the present invention can be formulated in enteric coating in a variety of dosage forms, including (but not limited to) capsules, particles of the active pharmaceutical ingredient itself, microcapsules, and tablets. In one embodiment, the composition may comprise a drug encapsulated in a capsule coated with an enteric coating to release the drug in the duodenum or other intestinal environment. In one aspect of the 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 made from animal-derived collagen or hydroxypropyl methylcellulose (hydroxypropyl methylcellulose, a modified cellulose), and may be manufactured using an optional mixture of gelatin, water, and plasticizers such as sorbitol or glycerin.

[0144] In one embodiment, the molecules of the present invention may be encapsulated in pure particulate or powder form, free of carriers, excipients, or other pharmaceutically acceptable additives. In other embodiments, the molecules of the present invention may be co-encapsulated with one or more pharmaceutically acceptable carriers, excipients, antioxidants (e.g., sodium metabisulfite, butylated hydroxytoluene [BHT]), antifungal agents (e.g., benzoic acid and ascorbic acid and their salts, and phenolic compounds such as methylparaben, ethylparaben, propylparaben, and butylparaben (paraben esters)), antimicrobial preservatives (e.g., sodium benzoate, sorbic acid), colorants, and flavoring agents. Excipients may contribute to capsule filling performance, stability, and drug distribution upon capsule disintegration in vivo. In another embodiment, the compound particles and / or powders of the present invention may be coated with an enteric coating before being placed in a capsule. The enteric-coated particles and / or powders placed in the capsule may have one or more types of enteric coatings to enable drug delivery to different regions of the intestine. The capsule may be without an enteric coating, or it may be coated with an enteric coating that is either compatible with or completely different from the coating used on any material inside the capsule that is coated with an enteric coating.

[0145] In a further embodiment, the molecules of the present invention may be encapsulated in a liquid, in the form of a solution or suspension in water or in various pharmaceutically acceptable oils or other dispersion media (e.g., mineral oil, sesame oil, safflower oil, coconut oil), optionally containing excipients such as cosolvents (e.g., propylene glycol, glycerol), solubilizers (e.g., sorbitol, glucose), and wetting agents (e.g., polysorbate [Tweens], sorbitan ester [Span], hydrophobic colloids [cellulose derivatives]). Thickeners (e.g., methylcellulose, microcrystalline cellulose), buffers (e.g., disodium hydrogen phosphate), antioxidants (e.g., butylated hydroxytoluene [BHT], citric acid, potassium sorbate), antifungal agents (e.g., benzoic acid and ascorbic acid and their salts, and phenolic compounds such as methylparaben, ethylparaben, propylparaben, and butylparaben (para-hydroxybenzoate esters)), antimicrobial preservatives (e.g., sodium benzoate, sorbic acid), colorants, and flavorings. In some embodiments, the compounds of the present invention may be formulated as liquid-filled capsules, wherein the pure drug is present in the liquid in the form of granules and / or powder. In related embodiments, capsules containing the drug distributed in the liquid may be coated with enteric coating. In another embodiment, the granules and / or powders of the compounds of the present invention may be coated with enteric coating before being placed in a liquid, and then the composition is placed in a capsule. Granules and / or powders coated with enteric coating may have one or more types of enteric coating to enable drug delivery to different regions of the intestine. Capsules may not have an enteric coating, or may be coated with an enteric coating that is either compatible with or completely different from the coating used on any enteric-coated material within the capsule.

[0146] In another embodiment, the molecule of the invention may be encapsulated in a capsule made of a material capable of postgastric drug delivery without the need for additional enteric coating (e.g., Entericare enteric soft capsules). The molecule may be encapsulated in such capsules in granular or powder form (whether or not containing excipients) or in a solution or suspension as described above.

[0147] In some embodiments, the solid particles of the compounds of the present invention have a variety of particle sizes and particle size distributions, which can be mixed with excipients such as microcrystalline cellulose or lactose and formed into microspheres containing a drug-containing core, onto which an enteric coating is applied. In some embodiments, the molecules of the present invention can form a suspension or solution, optionally containing a buffer (e.g., a 1 N HCl aqueous solution containing tris(hydroxymethyl)aminomethane [TRIS]) and a binder (e.g., Opadry clear coating powder), and coat a matrix particle, such as sugar beads (e.g., Sugar Spheres, NF particles), to form microspheres. In another embodiment, the microspheres can be coated with an enteric coating. In yet another embodiment, the molecules of the present invention can be formulated into enteric-coated microspheres as described above, and the microspheres are further formulated by encapsulation. In another embodiment, microspheres with different types of enteric coatings can be encapsulated such that, once released from a capsule, the compounds of the present invention can be released in a controlled manner in different regions from the duodenum to other parts of the intestine. The capsule may be without an enteric coating, or it may be coated with an enteric coating that is either compatible with or completely different from the coating used on any material inside the capsule that is coated with an enteric coating.

[0148] In another embodiment, the compounds of the present invention may be formulated as tablets or capsules, which, alone or in combination with other formulation components, deliver the drug to the duodenum or other intestinal region. In one embodiment, the compounds of the present invention are formulated as enteric-coated tablets or capsules, constituting the dosage form to be administered. In another embodiment, tablets or capsules of suitable size and shape may be placed within a capsule. In one such embodiment, the capsule may be enteric-coated and contain tablets or capsules not encapsulated in the enteric coating, which are released from the capsule in the duodenum or other intestinal region. In another such embodiment, the capsule may be designed to disintegrate in the stomach and release enteric-coated tablets or capsules for subsequent delivery to the duodenum or other intestinal region. In yet another such embodiment, both the capsule and the tablets or capsules contained therein may be enteric-coated to further control the release of the tablets or capsules from the capsule, and the subsequent release of the drug from the tablets or capsules. In further related embodiments, tablets or capsules having various enteric coatings can be combined and placed in a capsule, which itself may optionally be coated with an enteric coating. Materials suitable for enteric coatings of tablets and capsules include, but are not limited to, those materials described above suitable for capsules.

[0149] Enteric coating may lead to premature drug release in acidic media. In another further embodiment, the compounds of the present invention may be formulated to apply a subcoating prior to the application of an enteric coating. The subcoating may comprise a soluble subcoating agent applied to an enteric matrix, such as hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, and amylopectin. The thin layer of subcoating coated on the enteric matrix prevents moisture from permeating through the enteric coating on the capsule shell or into the core region containing the active ingredient, thereby preventing premature drug release. The subcoating may also promote drug release in alkaline environments by modulating the acidic microenvironment at the core-enteric coating interface. In some embodiments, the compounds of the present invention are formulated using a subcoating containing an organic acid designed to promote faster dissolution of the capsule polymer when the coating degrades in an environment of pH 5-6, thereby promoting rapid drug release in alkaline media.

[0150] For oral administration, tablets, sugar-coated pills, liquids, drops, capsules, sac tablets, and gelatin capsules are particularly suitable. Other suitable dosage forms for oral administration include, but are not limited to, powder or granule formulations, aqueous or oily suspensions, aqueous or oily solutions, pastes, gels, toothpastes, mouthwashes, coatings, oral rinsings, or emulsions. Compositions for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from inert, non-toxic, and generally considered safe (GRAS) pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose, granulating and disintegrants such as corn starch, binders such as starch, and lubricants such as magnesium stearate.

[0151] Tablets may be uncoated or coated using known methods to achieve delayed disintegration of the active ingredient in the subject's gastrointestinal tract, thereby providing sustained release and absorption. For example, materials such as glyceryl monostearate or glyceryl distearate may be used to coat the tablets. Further examples include coating tablets using methods described in U.S. Patents 4,256,108, 4,160,452, and 4,265,874 to form tablets with controlled osmotic release. Tablets may also contain sweeteners, flavoring agents, coloring agents, preservatives, or combinations thereof to provide a pharmaceutically aesthetically pleasing and palatable formulation. Hard capsules containing the active ingredient may be prepared using physiologically degradable compositions such as gelatin. The capsule contains the active ingredient and may further contain additional ingredients, including, for example, inert solid diluents such as calcium carbonate, calcium phosphate, or kaolin.

[0152] Hard capsules containing active ingredients can be prepared using physiologically degradable compositions such as gelatin. These hard capsules contain the active ingredient and may further contain additional ingredients, including, for example, inert solid diluents such as calcium carbonate, calcium phosphate, or kaolin.

[0153] Soft gelatin capsules containing active ingredients can be prepared using physiologically degradable compositions, such as gelatin derived from animal-derived collagen or hydroxypropyl methylcellulose (a modified cellulose), and can be produced using optional mixtures of gelatin, water, and plasticizers (such as sorbitol or glycerin). The soft capsule contains an active ingredient that can be mixed with water or an oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0154] For oral administration, the compounds of the present invention may be available in tablet or capsule form, prepared by conventional methods and containing pharmaceutically acceptable excipients such as binders, fillers, lubricants, disintegrants, or wetting agents. If desired, tablets may be coated using suitable coating methods and coating materials (e.g., the OPADRY™ film coating system from Colorcon, West Point, Pennsylvania, Inc., Ltd ...

[0155] For example, tablets containing an active ingredient can be prepared by compression or molding of the active ingredient and optionally one or more additional ingredients. Compressed tablets can be prepared by compressing a free-flowing form of the active ingredient (such as a powder or granule formulation) in a suitable apparatus, optionally mixed with one or more binders, lubricants, excipients, surfactants, and dispersants. Molded tablets can be formed by molding an active ingredient, a pharmaceutically acceptable carrier, and a liquid sufficient to wet the mixture in a suitable apparatus. Pharmaceutically acceptable excipients used in tablet manufacturing 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, dicalcium phosphate, and sodium phosphate. Known granulators and disintegrants include, but are not limited to, corn starch and alginate. Known binders include, but are not limited to, gelatin, gum arabic, pregelatinized corn starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

[0156] Granulation technology is widely known in the pharmaceutical industry for modifying the initial powders or other particulate materials of active ingredients. Powders are typically mixed with binders to form larger, permanent, free-flowing aggregates or particles, a process known as "granulation." For example, "wet" granulation processes using solvents typically involve mixing powders with binder materials and wetting them with water or organic solvents to form wet aggregates under certain conditions, followed by the evaporation of the solvent.

[0157] Melt granulation typically involves using materials that are solid or semi-solid at room temperature (i.e., have a relatively low softening point or melting point range) to facilitate the granulation of powders or other materials, essentially without the addition of water or other liquid solvents. Low-melting-point solids liquefy when heated to temperatures within their melting point range to act as a binder or granulation medium. The liquefied solid spreads on the surface of the powder material it contacts, and upon cooling, forms solid granular agglomerates in which the initial materials are bound together. The resulting melt granules can then be fed into a tableting machine or encapsulated to prepare oral dosage forms. Melt granulation improves the dissolution rate and bioavailability of active substances (i.e., drugs) by forming solid dispersions or solid solutions.

[0158] U.S. Patent No. 5,169,645 discloses wax-containing granules that can be directly compressed to improve flowability. Granules are obtained by mixing wax in a molten state with certain flow-improving additives, followed by cooling and granulation of the mixture. In some embodiments, only the wax itself melts in the molten combination of wax and additives, while in other cases both the wax and the additives melt.

[0159] The present invention also includes a multilayer tablet comprising a layer for delayed release of one or more compounds useful in the method of the present invention, and another layer for immediate release of one or more compounds useful in the method of the present invention. A gastric insoluble composition can be obtained using a mixture of wax / pH-sensitive polymers, wherein the active ingredient is encapsulated to ensure its delayed release.

[0160] Liquid formulations for oral administration can be solutions, syrups, or suspensions. Liquid formulations can be prepared using conventional methods with pharmaceutically acceptable additives, such as: suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible oils); emulsifiers (e.g., lecithin or gum arabic); non-aqueous carriers (e.g., almond oil, oily esters, or ethanol); and preservatives (e.g., methylparaben or propylparaben, or sorbic acid). The pharmaceutical compositions of the present invention are suitable for oral administration in liquid formulations that can be prepared, packaged, and marketed in liquid or dry product form, the dry product being reconstituted with water or other suitable solvent prior to use.

[0161] External application

[0162] As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration that involves physically destroying the subject’s tissue and administering the pharmaceutical composition through the site of destruction within the tissue. Therefore, parenteral administration includes, but is not limited to, administration of the pharmaceutical composition by injection, application through a surgical incision, or application through a non-surgical wound that penetrates tissue. In particular, parenteral administration is envisioned to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and renal dialysis infusion techniques.

[0163] Formulations of pharmaceutical compositions suitable for parenteral administration comprise an active ingredient bound to a pharmaceutically acceptable carrier (e.g., sterile water or sterile isotonic saline). The formulation may be prepared, packaged, or marketed in a form suitable for bolus or continuous administration. Injectable formulations may be prepared, packaged, or marketed in unit dose form (e.g., ampoules or multi-dose containers containing preservatives). Injectable formulations may also be prepared, packaged, or marketed in devices such as patient-controlled analgesia (PCA) devices. Parenteral administration formulations include, but are not limited to, suspensions, solutions, emulsions of oily or aqueous solvents, pastes, and implantable sustained-release or biodegradable formulations. The formulation may further comprise one or more additional ingredients, including but not limited to suspending agents, stabilizers, or dispersants. In one embodiment of a parenteral administration formulation, the active ingredient is provided in dry (i.e., powder or granules) form to allow for reconstitution with a suitable solvent (e.g., sterile, pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0164] This pharmaceutical composition can be prepared, packaged, or marketed as a sterile, injectable aqueous or oily suspension or solution. The suspension or solution can be formulated according to known techniques and may contain additional components such as dispersants, wetting agents, or suspending agents as described herein, in addition to the active ingredient. The sterile injectable formulation can be prepared using non-toxic, parenteral-acceptable diluents or solvents, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils (such as synthetic monoglycerides or diglycerides). Other useful parenteral-application formulations include those containing the active ingredient in microcrystalline form, wherein the active ingredient is present in recombinant human albumin, fluidized gelatin, liposome formulations, or as part of a biodegradable polymer system. Compositions for sustained release or implantation may contain pharmaceutically acceptable polymers or hydrophobic materials, such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts.

[0165] Topical application

[0166] The stratum corneum of the epidermis is a barrier to topical drug application. The stratum corneum is a highly resilient layer composed of proteins, cholesterol, sphingolipids, free fatty acids, and various other lipids, and includes keratinized cells and living cells. One factor limiting the rate (flux) of compound penetration through the stratum corneum is the amount of active ingredient that can be loaded or applied to the skin surface. The more active ingredient applied per unit area of ​​skin, the greater the concentration gradient between the skin surface and the subcutaneous layer, and consequently, the greater the diffusion capacity of the active ingredient through the skin. Therefore, all other things being equal, formulations containing higher concentrations of active ingredients are more likely to penetrate the skin, with greater quantity and more consistent penetration rate, compared to formulations with lower concentrations.

[0167] Formulations intended for topical application include, but are not limited to, liquid or semi-liquid formulations such as liniments, lotions, oil-in-water or water-in-oil emulsions (e.g., creams, ointments, or pastes), and solutions or suspensions. For example, a topical formulation may contain about 1% to about 10% (w / w) of the active ingredient, but the concentration of the active ingredient may be up to its solubility limit in a solvent. Formulations intended for topical application may further include one or more additional ingredients as described herein.

[0168] Penetration enhancers can be used. These materials increase the rate at which drugs penetrate the skin. Typical enhancers in the art include ethanol, glyceryl monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, etc. Other enhancers include oleic acid, oleyl alcohol, ethoxydiethylene glycol, lauryl azeladenone, alkane carboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

[0169] An acceptable solvent for the local delivery of certain compositions of the present invention may comprise liposomes.

[0170] In alternative embodiments, the topical active pharmaceutical composition may optionally be combined with other ingredients, such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifiers, thickeners, buffers, preservatives, etc. In other embodiments, the composition includes a penetration enhancer that effectively improves the transdermal penetration of the active ingredient into the stratum corneum compared to a composition without the penetration enhancer. Various penetration enhancers are known to those skilled in the art, including oleic acid, oleyl alcohol, ethoxydiethylene glycol, laurocapram, alkyl carboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In another aspect, the composition may also contain a water-soluble adjuvant that increases the disorder of the stratum corneum structure, thereby promoting stratum corneum permeability. Various water-soluble adjuvants are known to those skilled in the art, such as isopropanol, propylene glycol, or sodium xylenesulfonate.

[0171] The topical active pharmaceutical composition shall be applied in an effective amount that produces the desired change. As used herein, "effective amount" means an amount sufficient to cover the skin surface area where the change is desired. The active compound shall be present in an amount of about 0.0001% by weight to about 15% by weight, based on the weight-volume of the composition. More preferably, its content shall be about 0.0005% to about 5% of the composition; most preferably, its content shall be about 0.001% to about 1% of the composition. Such compounds may be synthetic or of natural origin.

[0172] Apply via cheek

[0173] The pharmaceutical compositions of the present invention can be prepared, packaged, or marketed in the form of formulations suitable for buccal administration. For example, such formulations can be made into tablets or lozenges using conventional methods and may contain, for example, 0.1% to 20% (w / w) of the active ingredient, with the remainder comprising an orally soluble or biodegradable composition, and optionally one or more additional ingredients as described herein. Alternatively, formulations for buccal administration may comprise a powder or atomized or sprayed solution or suspension containing the active ingredient. Such powdered, atomized, or aerosolized formulations, when dispersed, preferably have an average particle size of particles or droplets in the range of about 0.1 to about 200 nanometers 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 invention includes further modifications to these formulations and other formulations not described herein but known to those skilled in the art.

[0174] Rectal administration

[0175] The pharmaceutical compositions of the present invention can be prepared, packaged, or marketed in the form of formulations suitable for rectal administration. For example, such compositions may be in the form of suppositories, retention enemas, or rectal or colonic flushing solutions.

[0176] Suppositories can be prepared by combining an active ingredient with a non-irritating, pharmaceutically acceptable excipient that is solid at room temperature (approximately 20°C) and liquid at rectal temperature (approximately 37°C in a healthy human body). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycol, and various glycerides. Suppositories may further contain a variety of additional ingredients, including but not limited to antioxidants and preservatives.

[0177] Retention enema formulations, or solutions for rectal or colonic irrigation, can be prepared by mixing an active ingredient with a pharmaceutically acceptable liquid carrier. As is known in the art, enema formulations can be administered using a delivery device adapted to the rectal anatomy of the subject and may be encapsulated within that device. Enema formulations may further contain a variety of additional ingredients, including but not limited to antioxidants and preservatives.

[0178] Other forms of application

[0179] Other 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 and 5,007,790, U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688 and 20020051820, and PCT Application Nos. WO 03 / 35041, WO 03 / 35040, WO03 / 35029, WO 03 / 35177, WO 03 / 35039, WO 02 / 96404, WO 02 / 32416, WO 01 / 97783, WO The dosage forms described in 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 the above patent documents are incorporated herein by reference in their entirety.

[0180] Controlled release formulations and drug delivery systems

[0181] In some embodiments, the composition is designed to facilitate controlled release of the drug, thereby modulating the location, extent, and rate of compound exposure upon administration. Factors influencing the target area of ​​exposure for orally administered drugs may 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 pharmacodynamic and pharmacokinetic behavior in a specific environment.

[0182] Controlled-release or sustained-release formulations of the pharmaceutical compositions of the present invention can be prepared using conventional techniques. In some cases, the dosage form used can achieve the desired release profile by providing slow or controlled release of one or more active ingredients in varying proportions using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeation systems, multilayer coatings, microparticles, liposomes or microspheres, or combinations thereof. Suitable controlled-release formulations (including those described herein) are known to those skilled in the art and can be readily selected for use in the pharmaceutical compositions of the present invention. Therefore, the present invention covers single-unit dosage forms suitable for oral administration, such as tablets, capsules, gelatin capsules, and pouches suitable for controlled release.

[0183] The common goal of most controlled-release drug products is to improve therapeutic efficacy beyond that of their uncontrolled-release counterparts. Ideally, the use of optimized controlled-release formulations in medical treatment is characterized by curing or controlling the condition with the least amount of drug in the shortest possible time. The advantages of controlled-release formulations include targeted delivery into the gastrointestinal tract after oral administration, prolonged drug activity, reduced dosing frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to influence the onset time of drug action or other properties (such as blood drug concentration), potentially affecting the occurrence of side effects.

[0184] Most controlled-release formulations are designed to initially release a certain amount of drug to rapidly produce the desired therapeutic effect, and then release other doses of drug gradually and continuously to maintain this level of therapeutic effect over a longer period of time. In order to maintain a constant level of drug concentration in the body, the drug must be released from the dosage form at a rate sufficient to replenish the amount of drug that is metabolized and excreted from the body.

[0185] The controlled release of an active ingredient can be triggered by a variety of inducing factors, such as water, pH, temperature, enzymes, bacteria, or other physiological conditions or compounds. In the context of this invention, the term "controlled release component" is defined as one or more compounds, including but not limited to polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or combinations thereof, that contribute to the controlled release of the active ingredient.

[0186] In some embodiments, the formulations of the present invention may be, but are not limited to, short-term, rapid-elimination, immediate-release, and controlled-release formulations, such as sustained-release, delayed-release, and pulse-release formulations. The active pharmaceutical ingredient may also be encapsulated on an implantable medical device and eluted or released via a remote activation system.

[0187] The term "sustained release" is used in its conventional sense to refer to a pharmaceutical preparation that releases the drug gradually over an extended period of time and may (though not necessarily) maintain a substantially constant blood level of the drug over that extended period. This period can be as long as one month or longer, and the release time should be longer than that of the same dose administered by bolus injection.

[0188] To achieve sustained release, the compound can be formulated using a suitable polymer or hydrophobic material, which imparts sustained release properties to the compound. Therefore, the compound used in the methods of the present invention can be administered in particulate form, for example by injection, or in the form of a wafer or disc via implantation (the drug is embedded in a polymer matrix).

[0189] In a preferred embodiment of the invention, a sustained-release formulation is used to administer the compound of the invention, alone or in combination with another pharmaceutical agent, to a patient.

[0190] The term "delayed release" in its conventional sense refers to a pharmaceutical preparation that begins to release the drug after a certain delay following administration, which may (but is not necessarily) range from about 10 minutes to about 24 hours.

[0191] The term "pulse release" here refers in its conventional sense to a pharmaceutical formulation that releases the drug in a pulsed plasma distribution pattern after administration.

[0192] The term "immediate release" here refers, in its conventional sense, to a pharmaceutical preparation that releases the drug immediately after administration.

[0193] As used in this text, "short term" means any period of time after drug administration that does not exceed and includes approximately 24 hours, approximately 12 hours, approximately 8 hours, approximately 7 hours, approximately 6 hours, approximately 5 hours, approximately 4 hours, approximately 3 hours, approximately 2 hours, approximately 1 hour, approximately 40 minutes, approximately 20 minutes, or approximately 10 minutes, and any integer or partial increment thereof.

[0194] As used herein, rapid elimination refers to any time period after drug administration that is not more than and includes about 24 hours, about 12 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any integer or partial increment thereof.

[0195] Drugs may be more readily absorbed in the duodenum or other intestinal sites. A particularly useful controlled release mode is to minimize drug release in the stomach while delivering the drug to the duodenum or other intestinal sites in the highest concentration. In some embodiments, the compounds of the present invention are formulated to facilitate delivery to the duodenum and optionally other intestinal sites. Controlled release of drugs to the duodenum or other intestinal regions can be achieved using compositions comprising an enteric coating. Enteric coatings are insoluble in strongly acidic environments and typically contain a polyacid coating that remains non-ionized and intact at gastric pH levels. However, under weakly acidic (pH > 5.5) or neutral or weakly alkaline (pH 6.5–7.6) conditions in the duodenum or other intestinal regions, the coating ionizes, swells, and decomposes, exposing the coating to the environment. Coating options are available to enable ionization at or near a specific pH value (e.g., Eudragit L-110, ionization threshold pH 6.0; Eudragit S-100, ionization threshold pH 7.0). It should be understood that similar types or grades of film-coated or polymeric products from other companies may also be used.

[0196] In some embodiments, the compounds of the present invention are configured with an enteric coating, which is modified by adding a plasticizer to the polymer prior to coating. The plasticizer may be added to adjust the coating's resistance to shattering or cracking, while lowering the glass transition temperature of the coating, allowing the coating to spread smoothly and uniformly during coating. Suitable plasticizers include polyethylene glycol 8000 (PEG 8000), triethyl citrate (TEC), and glyceryl triacetate, which may be incorporated into the polymeric enteric coating agent.

[0197] The compounds of the present invention can be formulated in enteric coating in a variety of dosage forms, including (but not limited to) capsules, particles of the active pharmaceutical ingredient itself, microcapsules, microspheres, and tablets. In some embodiments, the composition comprises a drug encapsulated in a capsule coated with an enteric coating to release the drug into the duodenum or other intestinal environment. In other embodiments, pharmaceutically acceptable capsules include hard capsules. In still other embodiments, pharmaceutically acceptable capsules include soft gelatin capsules.

[0198] In some embodiments, the compounds of the present invention are encapsulated in pure particulate or powder form, free of carriers, excipients, or other pharmaceutically acceptable additives. In other embodiments, the compounds of the present invention are co-encapsulated with one or more pharmaceutically acceptable carriers, excipients, antioxidants, antifungal agents (e.g., benzoic acid and ascorbic acid and their salts, and phenolic compounds such as methylparaben, ethylparaben, propylparaben, and butylparaben), antimicrobial preservatives, colorants, and flavoring agents. Excipients may contribute to capsule filling performance, stability, and drug distribution upon capsule disintegration in vivo. In other embodiments, the compound particles and / or powders of the present invention are coated with an enteric coating before encapsulation. The enteric-coated particles and / or powders placed in the capsule may have one or more types of enteric coatings to enable drug delivery to different regions of the intestine. The capsule may or may not have an enteric coating, or may be coated with an enteric coating that is the same as or different from the coating used on any material inside the capsule that is coated with an enteric coating.

[0199] In some embodiments, the compounds of the present invention are encapsulated in water or various pharmaceutically acceptable oils or other dispersion media in the form of a solution or suspension, optionally containing excipients such as cosolvents (e.g., PEG 300, PEG 400, propylene glycol, glycerol, Tween 80, ethanol), solubilizers (e.g., sorbitol, glucose), wetting agents (e.g., thickeners), buffers (e.g., disodium hydrogen phosphate), antioxidants, antifungal agents, preservatives, colorants, and flavoring agents. In some embodiments, the compounds of the present invention are formulated as liquid-filled capsules, wherein the pure drug is present in the liquid in the form of particles and / or powder. In other embodiments, capsules containing compounds distributed in the liquid are coated with enteric coating. In still other embodiments, particles and / or powders of the compounds of the present invention are coated with enteric coating before being placed in a liquid, and then the composition is placed in capsules. The particles and / or powders coated with enteric coating may have one or more types of enteric coating to enable the drug to be delivered to different regions of the intestine. The capsule may or may not have an enteric coating, or may be coated with an enteric coating that is the same as or different from the coating used on any material inside the capsule that is coated with an enteric coating.

[0200] In some embodiments, the compounds of the present invention are encapsulated in capsules made of materials capable of postgastric drug delivery without the need for additional enteric coating (e.g., Entericare enteric soft capsules). The compounds may be encapsulated in such capsules in particulate or powder form (whether or not containing excipients) or in a solution or suspension as described above.

[0201] In some embodiments, the solid particles of the compounds of the present invention have a variety of particle sizes and particle size distributions, are mixed with excipients such as microcrystalline cellulose or lactose, and formed into microspheres comprising a drug-containing core, onto which an enteric coating is applied. In other embodiments, the compounds of the present invention form a suspension or solution, optionally containing a buffer (e.g., a 1 N HCl aqueous solution containing tris(hydroxymethyl)aminomethane “TRIS”) and a binder (e.g., Opadry clear coating powder), and are coated onto matrix particles, such as sugar beads (e.g., Sugar Spheres, NF particles), to form microspheres. In still other embodiments, the microspheres are coated with an enteric coating. In still other embodiments, the compounds of the present invention are formulated as enteric-coated microspheres as described above, and the microspheres are further formulated by encapsulation. In still other embodiments, combinations of microspheres with different types of enteric coatings are encapsulated such that, once released from a capsule, the compounds of the present invention can be released in a controlled manner in different regions from the duodenum to other parts of the intestine. The capsule may or may not have an enteric coating, or may be coated with an enteric coating that is the same as or different from the coating used on any material inside the capsule that is coated with an enteric coating.

[0202] In some embodiments, the compounds of the present invention are formulated as tablets or capsules, which, alone or in combination with other formulation components, deliver the drug to the duodenum or other intestinal region. In other embodiments, the compounds of the present invention are formulated as tablets or capsules coated with enteric coating, constituting the dosage form to be administered. In still other embodiments, tablets or capsules of suitable size and shape are placed within a capsule. In still other embodiments, the capsule is coated with enteric coating and contains tablets or capsules not coated with enteric coating, which are released from the capsule in the duodenum or other intestinal region. In still other embodiments, the capsule is designed to disintegrate in the stomach and release the enteric-coated tablets or capsules for subsequent delivery to the duodenum or other intestinal region. In still other embodiments, both the capsule and the tablets or capsules contained therein are coated with enteric coating to further control the release of the tablets or capsules from the capsule, and the subsequent release of the drug from the tablets or capsules. In other embodiments, tablets or capsules having various enteric coatings are combined and placed in a capsule, which may also optionally be coated with an enteric coating. Materials suitable for enteric coatings of tablets and capsules include, but are not limited to, those materials described above suitable for capsules.

[0203] Enteric coating can lead to premature drug release in acidic media. In some embodiments, the compounds of the present invention are formulated to apply a subcoating prior to the application of an enteric coating. The subcoating may comprise a soluble subcoating agent applied to an enteric matrix, such as hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, and amylopectin. It should be understood that similar types of synthetic and semi-synthetic polymer products from other companies may also be used. The thin layer of subcoating coated on the enteric matrix prevents moisture from permeating through the enteric coating on the capsule shell or into the core region where the active ingredient is located, thereby preventing premature drug release. The subcoating can also promote drug release in alkaline environments by modulating the acidic microenvironment at the core-enteric coating interface. In some embodiments, the compounds of the present invention are formulated with a subcoating containing an organic acid designed to promote faster dissolution of the capsule polymer when the coating degrades in an environment of pH 5-6, thereby promoting rapid drug release in alkaline media.

[0204] The present invention also includes, within its scope, the preparation of compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and, in a particular respect, GA475, wherein the compositions are suitable for use as pharmaceuticals. The pharmaceutical compositions comprise, as the active substance, a therapeutically effective amount of a compound of formula (I) (including GAL475) and its salts, solvates, hydrates, enantiomers, stereoisomers, tautomers, or isotopic variants thereof; and are combined with one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, and carriers conventionally used in pharmaceutical and veterinary formulations. These pharmaceutical formulations are suitable for administration to humans and / or animals.

[0205] The pharmaceutical formulation of the present invention preferably has at least one of the following characteristics: (i) it is suitable for administration by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implantation), nasal, vaginal, rectal, sublingual or local administration, and can be formulated into a dosage form suitable for each route of administration; and (ii) it is a unit dosage form, each unit dose comprising a compound of formula (I) (including GAL475) in the range of about 2 mg to about 1000 mg or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer or isotopic variant thereof.

[0206] A further feature of this formulation is that it can be administered alone, or in combination or in combination with other compounds known in the art, for the treatment of metabolic syndrome or for guiding weight loss.

[0207] In one aspect, the compounds of the present invention are used to treat metabolic syndrome, wherein the term “treatment” as used herein means to relieve or cure a disease, disorder or symptom, or to reduce at least one symptom of said disease, disorder or symptom.

[0208] On the other hand, the compounds of the present invention are used to induce weight loss and decreased appetite.

[0209] In another aspect, the compounds of the present invention are used to treat diabetes. In a preferred embodiment, the disease or condition is a human disease or condition, and the compounds of the present invention are applied to humans.

[0210] The compounds of this invention can be administered alone or in combination with other agents known to be beneficial for the treatment of a target disease, symptom, or condition. As used herein, “combination” means that GAL475 can be administered together with other agents, whether as concomitant therapy or as a fixed physical combination, or that they can be administered separately at different times but complement each other.

[0211] In treating or preventing the aforementioned conditions (broadly defined as metabolic syndrome), the compounds may be 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, alpha-glucosidase inhibitors, biguanides, dopamine-2 agonists, DPP-4 inhibitors, meglitinides, SGLT2 inhibitors, sulfonylureas, etc. Thiazolidinediones, such as: phentermine, amphetamine, orlistat, phentermine-topiramate, amphetamine-naltrexone, liraglutide, setmelanotide, semaglutide, retatrutide, tirzepatide, danuglipron, insulin, acarbose, miglitol, metformin and its combination products. Preparations, bromocriptine, alogliptin, linagliptin, saxagliptin, sitagliptin, dulaglutide, exenatide, lixisenatide, nateglinide, repaglinide, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, glimepiride, gliclazide, glyburide, rosiglitazone, pioglitazone, zopiclone, and their salts and combinations thereof.

[0212] Combining one or more known therapeutic agents with GAL475 will provide additional, complementary, and often synergistic effects to enhance the desired properties of the known therapeutic agents.

[0213] GAL475, when used alone or in combination with one of the aforementioned known therapeutic agents, can also be administered in conjunction with physical therapy methods such as exercise and diet.

[0214] GAL475 can be formulated into pharmaceutical compositions suitable for oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, or subcutaneous injection, or implantation), nasal, vaginal, rectal, sublingual, or topical administration. The composition may contain one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, and / or carriers.

[0215] Orally administered solid dosage forms include capsules, tablets, pills, microtablets, granules, powders, and particles. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable carrier (such as sucrose, lactose, or starch). In addition to inert diluents, these dosage forms may contain other additional substances, such as lubricants like magnesium stearate. Examples of adjuvants that can be incorporated into tablets, capsules, etc., include: binders such as gum arabic, gum arabic, corn starch, or gelatin; excipients such as microcrystalline cellulose; disintegrants such as corn starch, pregelatinized starch, alginic acid, etc.; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; and flavoring agents such as peppermint, wintergreen oil, or cherry. In the case of capsules, tablets, and pills, the dosage form may also contain buffers. When the dosage form is a capsule, it may contain liquid carriers, such as fatty oils, in addition to the materials of the types described above. Many other materials may be used as coatings or in physical forms to change the dosage unit. Tablets and pills may also be additionally prepared with enteric coating, and tablets may be coated with shellac, sugar coating, or both. Tablets may include, but are not limited to, matrix tablets, film-coated tablets, permeable tablets, multilayer tablets (e.g., bilayer or triplelayer tablets), conventional tablets, etc.

[0216] Similar solid compositions can be used as fillers in soft and / or hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation field. They may optionally contain light-blocking agents, and their composition may allow them to release the provided composition only at a specific site in the intestine or targeting a specific site in the intestine, optionally in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0217] In some respects, the capsule may contain an excipient formulation comprising one or more of hydroxypropyl methylcellulose (HPMC), gelatin, meglumine, and fish gelatin. In some respects, the capsule may contain a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and in certain specific respects. The capsule optionally further contains one or more of lycopene, ellagic acid (polyphenol), curcumin, piperine, calcein, resveratrol, isothiocyanates (such as sulforaphane), capsaicin, and piperazine.

[0218] When used in the form of microparticles or nanoparticles, the compounds of the present invention can achieve higher blood drug concentrations. The present invention includes microparticles and / or nanoparticles of the disclosed compounds in tablet form or encapsulated in capsules.

[0219] Orally administered liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, self-microemulsifying drug delivery systems (SMEDDS), liposomes, syrups, and elixirs containing inert diluents commonly used in the art, such as water. In addition to such inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, as well as sweeteners, flavoring agents and aroma agents, oils, surfactants, and co-surfactants. Syrups or elixirs may contain active compounds, sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavoring agents, such as cherry or orange flavorings.

[0220] Formulations in the form of orally administered SMEDDS will improve the bioavailability and pharmacokinetics of GAL475 and / or the second agent. These formulations typically comprise an emulsion containing oil or lipid materials, surfactants, and hydrophilic co-surfactants. Emulsifying a poorly water-soluble drug or drug formulation into a self-microemulsifying excipient formulation improves the in vivo bioavailability of that drug or drug formulation. Furthermore, poorly water-soluble drugs can be used in combination with GAL475.

[0221] The SMEDDS pharmaceutical compositions of the present invention can be formulated for oral administration of GAL475, for example, in the form of emulsions, aqueous or oily suspensions, filled hard or soft capsules, syrups, prepared powders or granules, lozenges, tablets, or lozenges. Acceptable carriers or additives in the formulation include binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; and glidants such as magnesium stearate, calcium stearate, or sodium stearoyl fumarate.

[0222] The formulations of this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. According to conventional pharmaceutical practice, sterile injectable compositions can be formulated by dissolving or suspending the active substance in a solvent, such as water for injection, natural vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty solvents such as ethyl oleate. Buffers, preservatives, antioxidants, etc., may be added as needed. Examples of non-aqueous solvents or carriers include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil and corn oil), gelatin, and injectable organic esters (e.g., ethyl oleate). Such dosage forms may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. They can be sterilized, for example, by filtering through a bacterial trap, incorporating a sterilizing agent into the composition, irradiating the composition, or heating the composition. They can also be formulated as sterile solid compositions that are immediately dissolved in sterile water or other sterile injectable media before use.

[0223] The dosage of the active agent in the compositions of this invention can be varied as long as a therapeutic dose is achieved. Preferably, the active agent is administered to a patient (human or animal) requiring such treatment at a dose that provides optimal efficacy. The selected dose depends on the nature and severity of the disease or condition to be treated, the desired therapeutic effect, the route of administration, and the duration of administration. The dose may also be adjusted based on the patient's weight and other factors. For example, the dose of GAL475 used to reduce weight may differ from the dose required to alleviate diabetes. The dose will vary from patient to patient, depending on the nature and severity of the disease, the patient's weight, the patient's current specific diet, concomitant medications, the bioavailability of the compound after administration, and other factors that will be recognized by those skilled in the art.

[0224] When treating conditions according to the present invention, a suitable daily dose level is generally about 2-1000 mg. This daily dose can be administered once daily or in multiple divided doses. Preferably, the dose level will be about 100-500 mg.

[0225] The alternative treatment regimens of the present invention may include administration regimens of twice daily, twice weekly, once weekly, once every two weeks, and once monthly.

[0226] The formulations of this invention can be in an immediate-release form, or in a prolonged-release or controlled-release form. Prolonged-release formulations include delayed-release, sustained-release, pulsatile-release, or controlled-release formulations. Suitable prolonged-release formulations for the purposes of this invention include those of the type described in U.S. Patent Nos. 6,106,864, 7,053,122, and 7,118,762, which are incorporated herein by reference. For example, details of other suitable release technologies (such as high-energy dispersions, permeable and coated particles) can be found in Verma, R. and S. Garg, Pharmaceutical Technology On - Line,25(2), 1-14 (2001), which is incorporated herein by reference.

[0227] The duration of compound release in extended-release formulations depends on the indication and the target therapeutic level. For example, in diabetes, it is desirable to limit the pharmacological effects of the compound on glucose bioavailability to within a few hours.

[0228] The present invention is illustrated by the following embodiments. These embodiments should be understood as illustrative only and are not intended to limit the scope of the invention in any way.

[0229] Example

[0230] The present invention will now be described with reference to the following embodiments. These embodiments are for illustrative purposes only, and the invention is not limited to these embodiments, but includes all variations that will be apparent from the teachings provided herein.

[0231] Example 1: GAL475 enhanced the binding of neurotensin to the NTSR1 receptor.

[0232] GAL475 (30 μmol) was tested in multiple receptor binding assays. Binding rates were calculated as the percentage of inhibition of binding to the specific radiolabeled ligand at each target site.

[0233] In the presence of 30 μmol GAL475, inhibition of the following receptor radioligands was observed to be greater than 50%: 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 GAL 475 on these receptors was less than 1 μmol and therefore not pharmacologically significant. However, an unexpected finding was that at a concentration of 30 μmol, GAL475 not only failed to inhibit NTS1(h) (agonist radioligand), but actually enhanced it by 32%, suggesting that it is a positive allosteric modulator (PAM).

[0234] Subsequently, the PAM activity of GAL475 on human NTS1 (FAST-0330I) and NTS2 (FAST-0331I) receptors was tested in the concentration range of 100–50,000 nanomolars. The agonistic activity of GAL475 was expressed as the percentage of activity of a reference agonist (neurotensin) at its EC100 (maximum response) concentration. The antagonistic activity of GAL475 was expressed as the percentage of inhibition of activity of a reference agonist at its EC80 (80% inhibition) concentration. The results are shown in Tables 1–3. The experiments were performed using recombinant cell lines. Receptor accession numbers, cell backgrounds, and reference compounds are shown in Table 1.

[0235] Table 1

[0236] GAL475 (100–50,000 nM) was tested for orthoallosteric modulator (PAM) activity on human NTS1 (FAST-0330I) and NTS2 (FAST-0331I) receptors (Tables 2 and 3). The results showed that GAL475 could bind to and activate the NTSR1 receptor, but not the NTSR2 receptor, with a half-maximal effective concentration of 355 nM.

[0237] Table 2: Allosteric binding of GAL475 and NTSR1

[0238] Table 3: Affinity of GAL475 to NTSR2

[0239] Example 2: GAL475 Effects of repeated oral administration of 2HCl for 28 days and a 14-day recovery period on weight gain in rats

[0240] One hundred and forty-two rats (71 of each sex) were randomly divided into four groups and administered Gal-475 at 20, 40, and 80 mg / kg / day, respectively, with the following treatments: 0.1 M phosphate buffer containing 2% (w / v) CMC-Na and 1% (v / v) Tween 80, pH 7.4±0.2. 2HCl was administered orally once daily for 28 days.

[0241] At the end of the dosing phase, the average body weight of animals given ≥40 mg / kg / day was significantly lower than that of the control group (-7.35% in males and -4.70% in females). Figure 1However, when comparing data from day -1 to day 28, the overall weight gain of animals receiving the 80 mg / kg / day dose was significantly lower than that of the control group (71% in males and 79% in females). The reduced mean weight gain within the group was due to lower weight gain, which was associated with and attributed to reduced food intake. During the 2-week recovery period (during the period without Gal-475 administration), animals in the 80 mg / kg / day dose group showed comparable or greater weight gain compared to the control group at the same time point, suggesting that the effect of GAL475 on body weight is reversible.

[0242] During the dosing phase, compared with the control group mean, at doses >40 mg / kg / day, both sexes observed a significant reduction in mean food expenditure within the group, which resulted in lower weight gain. Figure 2 However, as the weight data shows, food intake reverses at the end of the recovery phase.

[0243] When administered orally to rats once daily for 28 days at doses of 20, 40, or 80 mg / kg / day, GAL475 was well tolerated. No adverse clinical signs, food consumption, clinicopathological, or pathological changes related to the test substance were observed.

[0244] Example 3: GAL475 Effects of repeated oral administration of 2HCl for 28 days and a 14-day recovery period on weight gain in broodstock dogs

[0245] Thirty-two dogs (16 of each sex) were randomly divided into four groups and administered Gal-475 orally once daily with a solvent (containing 2% (w / v) CMC-Na and 1% (v / v) Tween 80 dissolved in 0.1M phosphate buffer, pH 7.4) or 7.5, 15, or 30 mg / kg / day. 2HCl, administered continuously for up to 28 days.

[0246] Reduced weight gain was observed in all male and female test animals (≥7.5 mg / kg / day) during all dosing phases (up to 22.7% in males and 29.9% in females). Figure 3 This also resulted in reduced food intake (up to 81% in males and 98% in females). During the recovery period, weight gain and food consumption were comparable to the control group.

[0247] Example 4: Inhibition of acute gastric emptying in rats by GAL475

[0248] The effect of a single intravenous injection of 3 mg / kg GAL-475 on gastric emptying was evaluated using nascent male Sprague-Dawley rats (239–297 g).

[0249] Rats were fasted for 16-18 hours before the experiment and administered either a solvent (1% Tween-80 2% CMC) or GAL475 (3 mg / kg, intravenous injection) via a single bolus injection through the lateral tail vein. Five minutes after administration, the rats were gavaged with a charcoal suspension (5 ml / kg, 2.5% gum arabic solution containing 10% charcoal) and then returned to their cages. Twenty minutes after administration of the suspension, the rats were euthanized using CO2. The stomach was removed, weighed, emptied, washed, and weighed again. The stomach contents were calculated as the difference between the full weight and the empty weight. Increased stomach contents were interpreted as decreased gastric emptying (food retention).

[0250] The effects of GAL475 and solvents (25% DMA: 45% PEG300: 40% D5W) on gastric emptying in rats were presented. Figure 4 Compared with the solvent, GAL-475 significantly reduced the gastric emptying rate (p<0.05). After administration of GAL-475 (3 mg / kg intravenously), the amount of gastric contents retained was up to 105% higher than that in the solvent control group.

[0251] Example 5: Patients treated with a single oral dose of GAL475 experienced weight loss.

[0252] In a phase 1, randomized, placebo-controlled, double-blind, first-in-human single-dose escalation study, the effects of oral doses of GAL-475 (450 mg capsules) on 12 healthy male volunteers were tested.

[0253] The study drug (GAL475) or placebo was administered at doses of 50, 150, or 450 mg on the morning of Day 1. Subjects fasted for 8 hours before taking the study drug or placebo and for at least 4 hours after administration.

[0254] Subject weight was measured using a calibrated balance on day -1 and at follow-up (day 7). Weight was recorded to one decimal place. Treatment was well tolerated. Only on the day of capsule intake, 2 out of 6 subjects taking 50 mg GAL475 experienced mild headaches, none of the 6 subjects taking 150 mg GAL475 experienced headaches, 5 out of 6 subjects taking 450 mg GAL475 experienced headaches, and 1 out of 6 subjects taking a placebo experienced headaches.

[0255] like Figure 5As shown, a weight analysis of subjects treated with 450 mg GAL475 revealed a consistent weight loss in all subjects taking GAL-475 (mean -0.6 kg, range -0.1 to -1.6 kg), while no such weight loss was observed in subjects receiving placebo (mean -0.07 kg, range +1.4 kg to -0.8 kg). Weight loss was only observed one week after a single capsule administration in subjects taking 450 mg GAL-475 instead of placebo.

[0256] The effect of 450 mg GAL475 on weight loss was statistically significant compared with all other groups (P=0.006).

[0257] It should be understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications fall within the scope of the following claims.

[0258] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In case of any conflict, this specification (including definitions) shall prevail. Furthermore, section headings, materials, methods, and examples are illustrative only and are not intended to be limiting.

Claims

1. A method for the following: a) To treat subjects suffering from metabolic syndrome or disease; b) Reduce the weight of subjects who require it; c) Treating subjects who have diabetes or are at risk of developing diabetes; d) Treatment of subjects who are obese or overweight; e) Treating subjects with eating disorders; f) Treatment of subjects with polyphagia; g) Treatment of subjects with hyperlipidemia; or h) Treating subjects with insulin resistance, The method comprises administering a composition to the subject, the 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: (I), where in (I): Selected from Y 1 and Y 2 One of the substituents in the group is selected from -N(R) 1 )-LC(R 9 (R) 10 )OH、 and The group consists of another substituent, -N(R). 1 )R 2 ; R 1 R 5 and R 7 Independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups; R 2 It is selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted. R 6 and R 8 Independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted; R 9 and R 10 Independently selected from the group consisting of H and optionally substituted C1-C3 alkyl groups; or R 9 and R 10 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl group; R 11 Each instance is independently selected from H and optionally substituted C1-C3 alkyl groups; wherein the cyclo b -C(R) inside 11 )2-C(R 11 The 2-group is optionally combined with a ring. b Fused optional substituted 1,2-phenylene substitution; Each time it appears, the substituted C1-C3 alkylene group is independently selected; m and n are independently selected from the group consisting of 1, 2, 3 and 4, such that 2≤(m+n)≤4; p and q are independently selected from the group consisting of 0, 1, 2, 3 and 4, such that 2≤(p+q)≤4; The condition is that the alkyl group is not substituted with a hydroxyl group.

2. A method of treating a subject suffering from metabolic syndrome or disease, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-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 in need, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-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 of treating a subject who has diabetes or is at risk of developing diabetes, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-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 of treating a subject with obesity or overweight, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-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 of treating a subject suffering from an eating disorder, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-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 of treating a subject suffering from polyphagia, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-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 of treating a subject with hyperlipidemia, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-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 of treating a subject with insulin resistance, the method comprising administering to the subject a composition comprising GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

10. The method of any one of claims 1-9, wherein the composition is a controlled release composition.

11. The method of claim 10, wherein the release-modulating composition is an oral release-modulating composition.

12. The method of any one of claims 1-11, wherein the composition comprises an enteric coating.

13. The method of any one of claims 1-12, wherein the composition comprises a gelatin coating.

14. The method of any one of claims 1-13, wherein the composition comprises an excipient, wherein the excipient comprises a binder, a disintegrant, a diluent, a buffer, a lubricant, a flow aid, an antioxidant, an antimicrobial preservative, a colorant, or a flavoring agent.

15. The method of any one of claims 1-14, wherein the compound is coated onto matrix particles to form a core.

16. The method of claim 15, wherein the core is coated with an enteric coating to form an enteric-coated microsphere.

17. The method of any one of claims 1-16, wherein the dosage form is an oral dosage form.

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

19. The method of any one of claims 1-18, wherein the composition comprises 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 of the compound.

20. The method of any one of claims 1-19, wherein the composition is encapsulated in a capsule.

21. The method of claim 20, wherein the capsule contains particles or powder of the compound, or particles or powder comprising a mixture of the compound and the pharmaceutically acceptable carrier or excipient.

22. The method of claim 21, wherein the capsule is coated with an enteric coating, but the granules or powder are not coated with an enteric coating.

23. The method of claim 21, wherein at least a portion of the particles or powder is coated with an enteric coating.

24. The method of claim 23, wherein at least a portion of the particles or powder is coated with an enteric coating before being encapsulated.

25. The method of claim 23 or claim 24, comprising the particles or powder of a first sub-part coated with an enteric coating, and the particles or powder of at least a second sub-part coated with a different enteric coating, wherein the release region of the first sub-part in the intestine of the subject is different from that of the second sub-part.

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

27. The method of claim 26, wherein the capsule is coated with an enteric coating, and wherein the liquid formulation in the capsule does not contain an enteric coating.

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

29. The method of any one of claims 1-27, 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. The method of any one of claims 28 and 29, comprising administering the composition or capsule separately from the at least one pharmaceutical agent.

31. The method of any one of claims 28 and 29, comprising co-administering the composition or capsule with the at least one pharmaceutical agent.

32. The method of any one of claims 28 and 29, wherein the compound is physically mixed with the at least one additional agent in the composition.

33. The method of any one of claims 28 and 29, wherein the compound and the at least one additional agent are configured in the composition as physically separated structures.

34. The method of any one of claims 1-33, wherein the subject is a mammal or a bird.

35. The method of any one of claims 1-33, wherein the subject is a human.

36. The method of any one of claims 1-9, wherein the administration is carried out via at least one route selected from the group consisting of: nasal, inhalation, local, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, intrathecal, and intravenous.

37. The method of any one of claims 1-36, 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, galactopyric acid, and galacturonic acid, or combinations thereof.

38. Use of GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers or isotopic variants thereof in the preparation of a medicament for the inhibition or treatment of metabolic syndrome or disease in a subject of need.

39. Use of GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers or isotopic variants thereof in the preparation of a medicament for inducing weight loss in subjects in need.

40. Use of GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers or isotopic variants thereof in the preparation of a medicament for the treatment or prevention of diabetes in a subject of need.

41. Use of GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers or isotopic variants thereof in the preparation of a medicament for treating eating disorders in subjects in need.

42. Use of GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers or isotopic variants thereof in the preparation of a medicament for treating polyphagia in subjects in need.

43. Use of GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers or isotopic variants thereof in the preparation of a medicament for treating hyperlipidemia in subjects of need.

44. Use of GAL475 (l-(2,6-bis-methylamino-8-propylamino-pyrimidino[5,4-d]pyrimidin-4-ylamino)-2-methylprop-2-ol) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, tautomers or isotopic variants thereof in the preparation of a medicament for treating insulin resistance in subjects of need.

45. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, stereoisomer, tautomer or isotopic variant thereof in the preparation of a medicament: (I), where in (I): Selected from Y 1 and Y 2 One of the substituents in the group is selected from -N(R) 1 )-LC(R 9 (R) 10 )OH、 and The group consists of another substituent, -N(R). 1 )R 2 ; R 1 R 5 and R 7 Independently selected from the group consisting of hydrogen and optionally substituted C1-C3 alkyl groups; R 2 It is selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted. R 6 and R 8 Independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, ynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl, or heteroaryl is independently optionally substituted; R 9 and R 10 Independently selected from the group consisting of H and optionally substituted C1-C3 alkyl groups; or R 9 and R 10 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl group; R 11 Each instance is independently selected from H and optionally substituted C1-C3 alkyl groups; wherein the cyclo b -C(R) inside 11 )2-C(R 11 The 2-group is optionally combined with a ring. b Fused optional substituted 1,2-phenylene substitution; Each time it appears, the substituted C1-C3 alkylene group is independently selected; m and n are independently selected from the group consisting of 1, 2, 3 and 4, such that 2≤(m+n)≤4; p and q are independently selected from the group consisting of 0, 1, 2, 3 and 4, such that 2≤(p+q)≤4; The condition is that the alkyl group is not substituted with a hydroxyl group; the drug is used for: a) To treat subjects suffering from metabolic syndrome or disease; b) Reduce the weight of subjects who require it; c) Treating subjects who have diabetes or are at risk of developing diabetes; d) Treatment of subjects who are obese or overweight; e) Treating subjects with eating disorders; f) Treatment of subjects with polyphagia; g) Treatment of subjects with hyperlipidemia; or h) Treatment of subjects with insulin resistance.

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