Phragmalin-derived compounds for use in the treatment and / or prevention of a metabolic disease and / or disorder

Abstract

The disclosure provides a compound of Formula (I), or a stereoisomer or hydrate thereof, for use in the treatment and / or prevention of a metabolic disease or disorder. There is also provided a non-therapeutic method of weight management, blood glucose management, blood lipid management and / or appetite regulation in a subject comprising administering the compound of Formula (I), or a stereoisomer or hydrate thereof to the subject. The disclosure also provides a dietary supplement comprising the compound of Formula (I), or a stereoisomer or hydrate thereof.

Description

[0001] PHRAGMALIN-DERIVED COMPOUNDS FOR USE IN THE TREATMENT AND / OR PREVENTION OF A METABOLIC DISEASE AND / OR DISORDER

[0002] Technical field

[0003] The present disclosure concerns a new use of phragmalin-derived compounds. More specifically, the disclosure provides a compound derived from phragmalin, or a stereoisomer or hydrate thereof, for use in the treatment and / or prevention of a metabolic disease or disorder. There is also provided a non-therapeutic method of weight management, blood glucose management, blood lipid management and / or appetite regulation in a subject comprising administering the compound derived from phragmalin, or a stereoisomer or hydrate thereof, to the subject. The disclosure also provides a dietary supplement comprising the compound derived from phragmalin or a stereoisomer or hydrate thereof.

[0004] Background

[0005] The listing or discussion of any prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0006] Metabolism refers to the sum of all energetic processes in the body, including the breakdown of nutrients and the synthesis of necessary compounds. Metabolic disorders disrupt normal metabolic processes. These disorders can affect the body's ability to break down amino acids, carbohydrates, or lipids. They can also impact the parts of the cell responsible for energy production (e.g., mitochondrial diseases). Metabolic disorders may be caused by changes in specific genes that affect metabolism (i.e. inherited metabolic disorders) or caused by lifestyle and environmental factors.

[0007] Metabolic disorders, which include metabolic syndrome, obesity, diabetes, prediabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease (MASLD), dyslipidemia and gout, are often interconnected, with one condition exacerbating the others.

[0008] Metabolic syndrome is a medical term that defines a clustering of at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides and low high-density lipoprotein (HDL) levels. Metabolic syndrome is indicative of an increased risk of cardiovascular diseases and type 2 diabetes. Insulin resistance, metabolic syndrome, and prediabetes are closely related to one another and have overlapping aspects. Metabolic syndrome has been defined in several ways over the years. The World Health Organization (WHO) first developed a definition in 1998, which mandates evidence of insulin resistance and two additional criteria selected from obesity, dyslipidemia, hypertension, and microalbuminuria (Alberti K.G., Zimmet P.Z. (1998), Diabet. Med., 15, 539-553).

[0009] In 1999, the European Group for the Study of Insulin Resistance (EGIR) modified the WHO definition. This definition maintains the requirement for insulin resistance together with two additional criteria selected from obesity, hypertension, and dyslipidemia, thereby removing microalbuminuria as a diagnostic criterion (Balkau B., Charles M.A. (1999), Diabet. Med., 16, 442-443).

[0010] The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) introduced a definition in 2001, which was then updated by the American Heart Association and the National Heart Lung and Blood Institute in 2005. This definition identifies metabolic syndrome if three or more of the following five criteria are met: waist circumference over 40 inches (men) or 35 inches (women), blood pressure over 130 / 85 mm Hg, fasting triglyceride (TG) level over 150 mg / dl, fasting HDL cholesterol level less than 40 mg / dl (men) or 50 mg / dl (women), and fasting blood sugar over 100 mg / dl (NCEPNE Panel (2002), Circulation, 106, 3143-3421; Grundy S.M. et al. (2005), Circulation, 112, 2735-2752).

[0011] In 2005, the International Diabetes Foundation (IDF) published new criteria for metabolic syndrome, necessitating the presence of obesity, but not necessarily insulin resistance. The obesity requirement is met by population-specific thresholds, thereby acknowledging that different populations, ethnicities, and nationalities have different norms for body weight and waist circumference (Zimmet P. et al. (2005), J Atheroscler Thromb, 12, 295-300).

[0012] Obesity is characterised by abnormal or excessive fat accumulation that can potentially have negative effects on health. Obesity occurs when, over time, the body takes in more calories than it burns and is often caused by a combination of excessive food intake and lack of physical activity, although genetic susceptibility may also play a role. Obesity increases the risk of developing a number of chronic diseases, including insulin resistance, type 2 diabetes, prediabetes, high blood pressure, high cholesterol, stroke, heart attacks, sleep apnea, congestive heart failure, osteoarthritis and cancer. Pathological glucose levels refer to blood sugar concentrations that fall outside the normal physiological range, indicating an underlying health issue. In healthy individuals, fasting blood glucose typically ranges between 70-99 mg / dL (3.9-5.5 mmol / L). After meals, levels may rise but generally stay below 140 mg / dL (7.8 mmol / L). When glucose levels deviate significantly from these norms, they are considered pathological.

[0013] Hyperglycaemia (i.e. high blood glucose) occurs when the body either doesn't produce enough insulin or cannot use it effectively. Persistent hyperglycaemia can damage blood vessels and organs, increasing the risk of heart disease, kidney failure, nerve damage, and vision loss.

[0014] Hypoglycaemia i.e. (low blood glucose) can result from excessive insulin use, prolonged fasting, or certain endocrine disorders. Chronic or severe hypoglycaemia can be life-threatening if not promptly treated.

[0015] Diabetes is the most common metabolic disease and is characterised by high blood sugar levels over a prolonged period. It is classified into two main types: type 1, where the body does not produce insulin, and type 2, where the body does not use insulin properly. Both types result from a combination of genetic and environmental factors, though type 2 diabetes is strongly linked to being overweight.

[0016] More specifically, type 1 diabetes mellitus (also known as type 1 diabetes) is an autoimmune disorder characterized by the destruction of pancreatic beta cells, which are responsible for producing insulin. This destruction leads to an absolute deficiency of insulin, which is essential for the uptake of glucose by cells for energy production. Consequently, insulin deficiency results in hyperglycemia (i.e. elevated blood glucose levels), which can cause acute complications like diabetic ketoacidosis and chronic complications affecting the cardiovascular system, kidneys, nerves and eyes. Management of type 1 diabetes requires lifelong insulin replacement therapy, which can be administered via subcutaneous injections or continuous subcutaneous insulin infusion using e.g. an insulin pump.

[0017] Type 2 diabetes mellitus (also known as type 2 diabetes) is primarily caused by insulin resistance, where peripheral tissues such as muscle and adipose tissue exhibit a diminished response to insulin. Over time, pancreatic beta cells may also exhibit dysfunction, leading to relative insulin deficiency. Risk factors include obesity, sedentary lifestyle, and dietary habits. Insulin resistance and beta-cell dysfunction result in chronic hyperglycemia. The gradual onset of hyperglycemia can lead to microvascular complications (e.g., retinopathy, nephropathy, neuropathy) and macrovascular complications (e.g., coronary artery disease, cerebrovascular disease). Management of type 2 diabetes typically begins with lifestyle modifications, including dietary changes, increased physical activity, and weight management. Pharmacological interventions may include oral hypoglycemic agents (e.g., metformin, sulfonylureas) and injectable medications (e.g., GLP-1 receptor agonists, insulin). Regular monitoring of blood glucose levels and management of comorbid conditions are also essential.

[0018] Glycated hemoglobin (HbAlc) levels provide a reliable measure of long-term glucose control, reflecting average blood glucose concentrations over the preceding two to three months. A subject with an HbAlc level of greater than or equal to 6.5% is considered to meet the diagnostic criteria for diabetes mellitus. This threshold is widely accepted in clinical practice for the diagnosis of both type 1 and type 2 diabetes.

[0019] Estimated average glucose (eAG), which is mathematically derived from HbAlc values, may also be used to assess glycemic status. An eAG of approximately 140 mg / dL corresponds to an HbAlc of 6.5%, and thus serves as an equivalent diagnostic marker for diabetes 1.

[0020] Before developing type 2 diabetes, patients suffer from a medical condition called prediabetes. Prediabetes is characterised by blood sugar levels elevated above what is considered normal but not high enough to be classified as type 2 diabetes. It is characterized by insulin resistance, with lifestyle factors such as lack of exercise and poor diet often contributing to its development.

[0021] Cardiovascular disease is a general term for a group of conditions that involve narrowed or blocked blood vessels, leading to heart attacks, chest pain (angina) or stroke and include coronary heart disease, peripheral arterial disease, aortic disease, endothelial dysfunction and hypertension. Cardiovascular disease is often associated with conditions such as high blood pressure, high cholesterol, diabetes, dyslipidemia and obesity.

[0022] Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is characterised by the accumulation of fat in the liver, which is unrelated to alcohol use. It is often linked to obesity, metabolic syndrome, type 2 diabetes and insulin resistance. Dyslipidemia is characterised by an abnormal amount of lipids (e.g., cholesterol and / or fat, e.g. triglycerides) in the blood. This condition can involve high levels of low-density lipoprotein (LDL) cholesterol (often called "bad" cholesterol), low levels of high-density lipoprotein (HDL) cholesterol ("good" cholesterol), or high levels of triglycerides. Dyslipidemia is often linked to diet and lifestyle but may be caused by genetic factors and is a risk factor for the development of cardiovascular diseases.

[0023] There are two main types of dyslipidemia: primary, which is inherited and often due to genetic disorders like familial hypercholesterolemia, and secondary, which results from lifestyle factors or other medical conditions. Common causes of secondary dyslipidemia include obesity, diabetes, hypothyroidism, excessive alcohol consumption, and diets high in saturated fats and sugars.

[0024] Often, dyslipidemia does not present any symptoms and is only discovered through routine blood tests. In rare cases, especially in inherited forms, physical signs such as fatty deposits under the skin (xanthomas) may appear. Diagnosis is typically made using a lipid panel, a blood test that measures total cholesterol, LDL, HDL, and triglycerides.

[0025] Gout is a form of inflammatory arthritis characterised by recurrent attacks of severe pain and swelling in the joints. It is caused by the crystallisation of uric acid in joints, tendons, and surrounding tissues. While not directly causing gout, high levels of cholesterol and triglycerides are known to increase the risk of developing gout.

[0026] The prevalence of metabolic diseases is on the rise worldwide. According to the World Health Organization, the number of people with diabetes rose from 108 million in 1980 to 422 million in 2014. According to a study by Chew et. al. (Cell Metabolism, 2023, 35, pg. 414-428), from 2000 to 2019, prevalence rates increased for all metabolic diseases, with the most pronounced increase in high socio-demographic index (SDI) countries. Results from the same study indicated that the prevalence of metabolic diseases has been rising at a stable rate over the last two decades.

[0027] WO 2007 / 031830 Al discloses a bioactive fraction obtained from Xylocarpus (belonging to the Meliaceae family), a process for the preparation of such and its use for the treatment of diabetes and dyslipidemia. Phragmalin diacetate is reported to be found in the chloroform fractions extracted during the processes for the preparation of the bioactive fraction. The chloroform-soluble fraction showed antihyperglycemic activity in streptozotocin (STZ)-induced diabetic rats (Example 8) and antidyslipidemic activity (lowering triglycerides and total cholesterol) in a dyslipidemic hamster model (Example 9).

[0028] Peng J. et al., molecules 2016, 21, 58; doi: 10.3390 / molecules21010058 discloses the isolation, structural elucidation and the a-glucosidase inhibitory evaluation of eleven limonoids from Chukrasia tabula s (Meliaceae). Bioactivity screening indicated that the EtOAc-soluble extract of the stems of C. tabularis showed significant a-glucosidase inhibitory activity. Compounds 2 (shown below), 3, 4, 5, and 8 showed inhibitory activities against a-glucosidase. It is stated that structure-activity relationship analysis revealed that the furanyl ring and the C-16 / 17 6-lactone ring (labelled below) in these phragmalin limonoids are important for the a-glucosidase inhibitory activity. In contrast, compounds 9-11 (shown below) did not show inhibitory activities against a- glucosidase.

[0029] Compound 2 Compounds 9-11 CN 108 210 600 A describes a method for preparing a limonoid extract from Melia azedarach leaves, Clausena lansium leaves, and Toona sinensis leaves and its application in the preparation of diabetes treatment drugs. Examples 1 to 3 describe the preparation of the limonoid extracts, which, in Example 4, are determined to contain clauemargine B, libiguin A, libiguin B, and aphanamixoid F in varying weight ratios. In a hypoglycemic effect study (Experimental Example 1), the establishment of a mouse experimental diabetes model is described, wherein normal Kunming mice were intravenously injected with alloxan. The effect of the limonoid extract of Examples 1 to 3 on fasting blood glucose in diabetic mice is then described. It is stated that, after 1 to 4 weeks of treatment, the blood glucose levels of animals in the limonoid extract group from Example 1 were significantly lower than those in the model group. In a study on the effect of the limonoid extract on glucose tolerance in diabetic mice, it is further stated that, after intragastric administration of glucose, the limonoid extracts all significantly inhibited the increase in postprandial blood glucose levels and effectively restored glucose tolerance.

[0030] As described herein, type 1 diabetes is an autoimmune disease characterized by the destruction of pancreatic beta cells, resulting in an absolute deficiency of insulin. Alloxan is a cytotoxin glucose analogue that selectively destroys the insulin-producing beta cells in the pancreas and is commonly used to induce type 1 diabetes in animal models, particularly in rodents such as rats and mice.

[0031] In contrast, type 2 diabetes is primarily caused by insulin resistance and subsequent beta-cell dysfunction, leading to a relative insulin deficiency.

[0032] WO 2008 / 145996 Al discloses extracts and pharmaceuticals from Neobeguea mahafalenstis (Meliaceae), the procedures for their preparation, and their use for eliciting a sexual enhancing effect and the treatment of sexual dysfunction. The document describes that species of the genus Entandophragma are useful sources as raw materials in the synthesis of the compounds described in that document. It is stated that Entandophragma caudatum is a rich source of phragmalin which can be used as a precursor in the semisynthesis of the compound with the structure R306. The document describes that the compound R306AB may be hydrolyzed to provide the compound R306.

[0033]

[0034] WO 2024 / 072288 Al describes a process for obtaining phragmalin derivatives from Entandrophragma caudatum seed extracts and producing therapeutically active limonoids and limonoid-type compounds therefrom in a multi-step synthesis.

[0035] WO 2013 / 110744 A2 describes chemical compounds, methods for synthesis of such compounds, and the use of these compounds in the synthesis of other chemical compounds that may be used in the treatment of sexual dysfunction, and for eliciting enhancing effects on sexual behavior.

[0036] Fossen T. et al., Planta Medica 2016, 82, 1087-1095, doi: 10.1055 / S-0042-108741 describes polyfunctional phragmalin limonoids from Neobeguea mahafalensis.

[0037] Grigorjeva L. et al., The Journal of Organic Chemistry 2014, 79, 4148-4153, doi: 10.1021 / jo500318w describes the semisynthesis of libiguin A and its analogues by trans-lactonization of phragmalin.

[0038] Ono E. et al., Biochemical and Biophysical Research Communications 2011, 410, 3, 677-681, doi: 10.1016 / J.BBRC.2011.06.055 discloses limonoids extracted from citrus seeds having anti-obesity and anti-hyperglycemic effects. Compounds of Formula I as described in the present document are not disclosed.

[0039] Given the increasing prevalence of metabolic diseases, there is an urgent, pressing need for new and effective treatments. Thus, there is a need for compounds for use in the treatment and / or prevention of a metabolic disease or disorder. Further, there is a need for compounds, products and methods such as therapeutic or non-therapeutic methods allowing for a healthy life and / or prevention of diseases or disorders such as a metabolic disease or disorder.

[0040] It is an object of the present disclosure to provide compound(s) for use in the treatment and / or prevention of a metabolic disease or disorder. It is also an object of the present disclosure to provide compound(s), product(s) and method(s) such as therapeutic or non-therapeutic method(s) allowing for a healthy life and / or prevention of disease(s) or disorder(s) such as a metabolic disease or disorder. Further, it is an object of the present disclosure to provide aspects and / or advantages not provided by hitherto know techniques.

[0041] Brief description of the drawings

[0042] Figure 1 shows levels of fasting glucose after subcutaneous administration for 28 days as described in Example 4A.

[0043] Figure 2 shows levels of cholesterol after subcutaneous administration for 28 days as described in Example 4A.

[0044] Figure 3 shows weight gain after subcutaneous administration for 28 days as described in Example 4A.

[0045] Figure 4 shows mean weekly food intake after subcutaneous administration for 28 days and during recovery weeks as described in Example 4A.

[0046] Figure 5 shows levels of cholesterol after subcutaneous administration for 14 days as described in Example 4B.

[0047] Figure 6 shows weight gain after subcutaneous administration for 14 days as described in Example 4B.

[0048] Figure 7 shows levels of fasting glucose after oral administration for 14 days as described in Example 5.

[0049] Figure 8 shows weight gain after oral administration for 14 days as described in Example 5. Figure 9 shows mean weekly food intake after oral administration for 14 days as described in Example 5.

[0050] Figure 10 shows the systolic blood pressure after oral administration for 3 consecutive days as described in Example 7.

[0051] Figure 11 shows the diastolic blood pressure after oral administration for 3 consecutive days as described in Example 7.

[0052] Figure 12A shows a decrease in the level of total cholesterol as described in Example 8.

[0053] Figure 12B shows a decrease in the level of HDL cholesterol as described in Example 8.

[0054] Figure 12C a reduction in the level of LDL cholesterol as described in Example 8.

[0055] Description

[0056] The present disclosure provides a compound of Formula I:

[0057] Formula I or a stereoisomer thereof, or a hydrate thereof wherein

[0058] R1is Ci-Cealkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, and R2and R3are independently

[0059] H, or

[0060] C(O)Ci-Cealkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, for use in the treatment and / or prevention of a metabolic disease or disorder. There is also provided the use of a compound of Formula I

[0061] Formula I or a stereoisomer thereof, or a hydrate thereof, wherein R1, R2and R3are as defined herein, for the manufacture of a medicament for the treatment and / or prevention of a metabolic disease or disorder.

[0062] Further, there is provided a method for the treatment and / or prevention of a metabolic disease or disorder, said method comprising administering to a patient, such as a human or animal in need thereof, an effective amount, such as a therapeutically effective amount, of a compound of Formula I

[0063] Formula I or a stereoisomer thereof, or a hydrate thereof, wherein R1, R2and R3are as defined herein.

[0064] The following definition applies throughout this document. The term "Ci-Cealkyl" denotes a straight or branched, saturated alkyl group of one to six carbon atoms. Examples of "Ci-Cealkyl" include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, / so-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl and neohexyl.

[0065] The values for R1, R2and R3for the compound of Formula I may be selected so that R1is methyl, R2is (CHs O) and R3is hydrogen, thereby providing a compound of Formula la:

[0066] Formula la

[0067] In a further example, the values for R1, R2and R3for the compound of Formula I may be selected so that R1is methyl and R2and R3are both hydrogen, thereby providing a compound of Formula lb:

[0068] The compound of Formula I may be provided as a stereoisomer of Formula II:

[0069] wherein R1, R2and R3are as defined herein.

[0070] For instance, the stereoisomer of Formula II may be a stereoisomer of Formula Ila or

[0071] Formula lib:

[0072] Additionally or alternatively, the compound of Formula I may be provided as a hydrate, i.e. a combination of the compound of Formula I and water. The hydrate of the compound of Formula I may be a combination of the compound of Formula I and water taken in a ratio, such as a molar ratio, of l:n where n is a number such as an integer from 1 to 10. It will be appreciated that hydrate(s) such as the monohydrate(s) described herein may allow for good solubility, chemical stability, chemical purity, chemical stability and / or good handling properties. For at least this reason, it may be desired to use the hydrate(s) such as the monohydrate(s) described herein in e.g. the pharmaceutical compositions described herein.

[0073] Thus, there is provided a hydrate of Formula III: said hydrate being a combination of a compound of Formula I and water:

[0074] Formula I water wherein R1, R2and R3are as defined herein in a ratio, such as a molar ratio, of l :n, wherein n is a number such as an integer from 1 to 10. For instance, the value of n may be 1 thereby providing a monohydrate of Formula

[0075] III1, i.e.,

[0076] wherein R1, R2and R3are as defined herein. In an example, there is provided a hydrate of Formula Illa: said hydrate being a combination of the compound of Formula la and water: in a ratio, such as a molar ratio, of l:n, wherein n is a number such as an integer from 1 to 10.

[0077] For instance, the value of n may be 1 thereby providing a monohydrate of Formula

[0078] Illal, i.e.,

[0079] Further, there is provided a hydrate Formula IV: said hydrate being a combination of a compound of Formula II and water taken in a ratio such as a molar ratio of l:n. In an example, n is one thereby providing a monohydrate of Formula IV1:

[0080] Formula IV1

[0081] The values for R1, R2and R3for the hydrate of Formula IV and the monohydrate of Formula IV1 may be as described herein. There is also provided a hydrate of Formula IVa: said hydrate being a combination of the compound of Formula Ila and water: in a ratio, such as a molar ratio, of l:n, wherein n is a number such as an integer from 1 to 10. The value of n may be 1 thereby providing a monohydrate of Formula IVal, i.e.

[0082] In a further example, there is provided a hydrate of Formula Illb. : said hydrate being a combination of a compound of Formula lb and water:

[0083] in a ratio, such as a molar ratio, of l:n, wherein n is a number such as an integer from 1 to 10.

[0084] The value of n may be 1 thereby providing a monohydrate of Formula Illbl, i.e.

[0085] Formula Illbl

[0086] The hydrate of Formula Illb may be provided as a stereoisomer of Formula IVb:

[0087] said hydrate being a combination of a compound of Formula lib and water: in a ratio, such as a molar ratio, of l:n, wherein n is a number such as an integer from 1 to 10.

[0088] The value of n may be 1 thereby providing a monohydrate of Formula IVbl, i.e.

[0089] Formula IVbl .

[0090] It will be appreciated that the compound of Formula la or the stereoisomer thereof, i.e., the compound of Formula Ila, may be denominated SAE5. Further, it will be appreciated that the monohydrate of Formula Illa 1 or the stereoisomer thereof, i.e. the monohydrate of Formula IVal, may be denominated LIB-01. Alternatively, it will be appreciated that the monohydrate of Formula Illa 1 or the stereoisomer thereof, i.e., the monohydrate of Formula IVal, may be denominated SAE5 monohydrate.

[0091] Further, it will be appreciated that the compound of Formula lb or the stereoisomer thereof, i.e. the compound of Formula lib, may be denominated SAE4A.

[0092] The compounds of the present disclosure may also be referred to by using their chemical names such a name based on IUPAC nomenclature.

[0093] The IUPAC name of the compound of Formula Ila has been found to be methyl (3aR,4R,6aS,8S,9aR,llR,12S,12aS,12bR,12cR,14S,15R)-4-(3- furanylcarbonyl)decahydro-12a-hydroxy-4,8,ll,15-tetramethyl-12-(2-methyl-l- oxopropoxy)-2-oxo-10 / 7-8,12c-epoxy-ll,6a,9a- ethanylylidenecyclopenta[t / ]pyrano[2,3,4-fij] [l,3]benzodioxocin-14-acetate.

[0094] Further, the IUPAC name of the monohydrate of Formula IVal has been found to be methyl (3aR,4R,6aS,8S,9aR,llR,12S,12aS,12bR,12cR,14S,15R)-4-(3- furanylcarbonyl)decahydro-12a-hydroxy-4,8,ll,15-tetramethyl-12-(2-methyl-l- oxopropoxy)-2-oxo-10 / 7-8,12c-epoxy-ll,6a,9a- ethanylylidenecyclopenta[t / ]pyrano[2,3,4-fij] [l,3]benzodioxocin-14-acetate monohydrate. Unexpectedly it has been found that the substance SAE5, or a stereoisomer and / or hydrate thereof, seems to be able to have an effect on several conditions and diseases that are commonly characterized by disturbances in the body's metabolism, including diseases such as obesity, insulin resistance (type 2 diabetes) and high blood pressure. Therefore, it has unexpectedly been found that the compound of Formula I, or a hydrate or stereoisomer thereof, as described herein is useful in the treatment and / or prevention of metabolic diseases or disorders.

[0095] The compound of Formula I is known in the context of treatment of erectile dysfunction. Although erectile dysfunction is often a symptom of underlying metabolic disease, that the compound of Formula I may have a direct positive effect on such metabolic disorders is indeed surprising.

[0096] The term "metabolic disease or disorder" will be understood by those skilled in the art to include any disease or disorder that serves to affect or disrupt normal metabolism, i.e. the process of converting food to energy in a measurable way, including the body's ability to break down amino acids, carbohydrates, or lipids; to affect, disrupt or impact in a measurable way whole cells of parts thereof that are responsible for energy production (i.e. mitochondrial diseases), which disease or disorder may be caused by changes in specific genes that affect metabolism (i.e. inherited metabolic disorders) or caused by lifestyle and environmental factors.

[0097] The term metabolic disease or disorder may thus include one or more of the following: metabolic syndrome, obesity, type 2 diabetes, prediabetes, cardiovascular disease, triglyceride disorder, cholesterol disorder, metabolic dysfunction-associated steatotic liver disease (MASLD), dyslipidemia, gout, body adipose tissue disorder.

[0098] Thus, the treatment and / or prevention of the metabolic disease or disorder described herein may comprise or consist of one or more of the following: the treatment and / or prevention of metabolic syndrome, the treatment and / or prevention of obesity, the treatment and / or prevention of type 2 diabetes, the treatment and / or prevention of prediabetes, the treatment and / or prevention of cardiovascular disease, the lowering of, or prevention of increase in, triglyceride and / or cholesterol levels, the treatment and / or prevention metabolic dysfunction-associated steatotic liver disease (MASLD), the treatment and / or prevention of dyslipidemia, the treatment and / or prevention of gout, the lowering of, or prevention of increase in, body adipose tissue.

[0099] For example, the treatment and / or prevention of the metabolic disease or disorder described herein may comprise or consist of one or more of the following: the treatment and / or prevention of metabolic syndrome, the treatment and / or prevention of obesity, the treatment and / or prevention of type 2 diabetes, the treatment and / or prevention of prediabetes, the treatment and / or prevention of cardiovascular disease, the treatment and / or prevention metabolic dysfunction-associated steatotic liver disease (MASLD), the treatment and / or prevention of dyslipidemia, the treatment and / or prevention of gout.

[0100] The metabolic disease or disorder may be associated with a pathological blood glucose level, i.e. blood sugar concentrations that fall outside the normal physiological range such as a fasting blood glucose between 70-99 mg / dL (3.9-5.5 mmol / L) and blood glucose remaining below 140 mg / dL (7.8 mmol / L) after a meal.

[0101] Further, it has unexpectedly been found that the compound of Formula I, or a hydrate or stereoisomer thereof, as described herein has been associated with decreased blood glucose levels such as decreasing fasting blood glucose levels.

[0102] Thus, the treatment and / or prevention of the metabolic disease or disorder described herein may involve blood glucose lowering.

[0103] The blood glucose lowering may comprise or consist of the lowering of fasting blood glucose, HbAlc and / or eAG levels.

[0104] The lowering of fasting blood glucose levels may involve lowering the glucose levels from diabetic levels (i.e. levels greater than or equal to about 126 mg / dL) to healthy levels (i.e. levels below about 100 mg / dL, such as below about 90 mg / dL), or from elevated levels (i.e. between about 110 mg / dL and about 125 mg / dL) to healthy levels, or from borderline elevated levels (i.e. between about 100 mg / dL and about 109 mg / dL) to healthy levels. The lowering of HbAlc levels may involve lowering the HbAlc from diabetic levels (i.e. levels greater than or equal to about 6.5%) to healthy levels (i.e. levels below about 5.7%, such as below about 5.5%), or from elevated levels (i.e. between about 6.0% and about 6.4%) to healthy levels, or from borderline elevated levels (i.e. between about 5.7% and about 5.9%) to healthy levels.

[0105] Similarly, the lowering of estimated average glucose (eAG) levels may involve lowering the eAG from diabetic levels (i.e. levels greater than or equal to about 140 mg / dL, which corresponds to an HbAlc of 6.5%) to healthy levels (i.e. levels below about 117 mg / dL, which corresponds to an HbAlc of 5.7%), or from elevated levels (i.e. between about 125 mg / dL and about 139 mg / dL) to healthy levels, or from borderline elevated levels (i.e. between about 117 mg / dL and about 124 mg / dL) to healthy levels.

[0106] Alternatively, the metabolic disease or disorder may not be associated with a pathological blood glucose level, i.e. blood sugar concentrations that fall outside the normal physiological range.

[0107] The present disclosure also provides treatment and / or prevention of a metabolic disease or disorder as described herein, wherein the metabolic disease or disorder is a metabolic disease or disorder that is not associated with pathological blood glucose level(s) as described herein and / or a metabolic disease or disorder that is associated with a pathological blood glucose level(s) as described herein.

[0108] The treatment and / or prevention of the metabolic disease or disorder may comprise or consist of treatment and / or prevention of metabolic syndrome. The metabolic syndrome may lack or involve insulin resistance and / or be as defined by one or more of the following organizations: The World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), National Cholesterol Education Program (NCEP).

[0109] Further, the treatment and / or prevention of the metabolic disease or disorder may comprise or consist of treatment and / or prevention of obesity, i.e. an accumulation of body fat that can potentially have a negative impact of a person's health. The obesity may be defined by a body mass index, commonly abbreviated BMI, and be greater than or equal to about 25, such as from about 25 to about 30, such as equal to or above about 30, such as from about 30 to about 35, such as equal to or above about 35, such as from about 35 to about 40, such as equal to or above about 40. BMI may be as defined in the art such as the ratio of body mass divided by the square of body height and measured in kilograms per square meter (kg / m2). Additionally or alternatively, the obesity may involve abdominal obesity such as abdominal obesity wherein the subject's waist circumference is 88 centimetres or more such as 102 cm or more.

[0110] The treatment and / or prevention of the metabolic disorder may also include the lowering of, or prevention of increase in, body adipose tissue.

[0111] In a further example, the treatment and / or prevention of the metabolic disorder may comprise or consist of type 2 diabetes. In still a further example, the treatment and / or prevention of the metabolic disorder may comprise or consist of prediabetes. The term 'type 2 diabetes' is defined in the art. For instance, the type 2 diabetes may comprise high blood sugar levels, insulin resistance and / or lack of insulin. The prediabetes may be as defined in the art and include higher than normal blood sugar levels.

[0112] It will be appreciated that the metabolic disease or disorder may not include type 1 diabetes. Thus, in an example, the treatment and / or prevention of a metabolic disease or disorder does not comprise the treatment and / or prevention of type 1 diabetes.

[0113] In yet a further example the treatment and / or prevention may comprise or consist of treatment and / or prevention of cardiovascular disease such as cardiovascular disease selected from the group consisting of coronary heart disease, stroke, peripheral arterial disease, aortic disease, endothelial dysfunction, elevated blood pressure and hypertension. For instance, the cardiovascular disease may comprise or consist of elevated blood pressure or hypertension. The elevated blood pressure may involve a blood pressure of 120-129 / 80 mm Hg. The hypertension may be as defined in the art such as a hypertension of 130-140 / 80-90 mm Hg, such as 130 / 80 mmHg or 140 / 90 mm Hg. In a further example, the cardiovascular disease may comprise or consist of coronary heart disease or stroke. In still a further example, the cardiovascular disease may comprise or consist of peripheral arterial disease or aortic disease. In a further example, the cardiovascular disease may comprise or consist of endothelial dysfunction.

[0114] Further, the treatment and / or prevention may comprise or consist of lowering of, or prevention of increase in triglyceride. In a further example, the treatment and / or prevention may comprise or consist of lowering of, or prevention of increase in cholesterol (such as LDL cholesterol) levels. This may result from treating and / or preventing dyslipidemia. As such, the treatment and / or prevention may comprise or consist of treatment and / or prevention of dyslipidemia. The lowering of triglyceride levels may involve lowering the triglyceride levels from very high levels (i.e. levels above about 500 mg / dL) to healthy levels (i.e. levels below about 150 mg / dL such as below about 90 mg / dL), or from high levels (i.e. between about 200 mg / dL and about 499 mg / dL) to healthy levels, or from borderline high levels (i.e. between about 150 mg and about 199 mg / dL) to healthy levels.

[0115] The lowering of LDL cholesterol levels may involve lowering the LDL cholesterol from very high levels (i.e. levels above about 190 mg / dL) to healthy levels (i.e. levels below about 100 mg / dL, such as below about 70 mg / dL), or from high levels (i.e. between about 160 mg / dL and about 189 mg / dL) to healthy levels, or from borderline high levels (i.e. between about 130 mg / dL and about 159 mg / dL) to healthy levels.

[0116] For instance, the treatment and / or prevention of the metabolic disorder may comprise or consist of the treatment and / or prevention of gout.

[0117] Moreover, the treatment and / or prevention of the metabolic disorder may comprise or consist of the treatment and / or prevention metabolic dysfunction-associated steatotic liver disease (MASLD).

[0118] Thus, the treatment and / or prevention of the metabolic disease or disorder described herein may comprise or consist of the treatment and / or prevention one or more of the following: metabolic syndrome, obesity, type 2 diabetes, prediabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular disease.

[0119] Additionally or alternatively, the treatment and / or prevention of the metabolic disease or disorder described herein may comprise or consist of one or more of the following: the lowering of, or prevention of increase in, triglyceride and / or cholesterol levels, and / or the lowering of, or prevention of increase in, body adipose tissue.

[0120] Further, it has unexpectedly been found that the compound of Formula I, or a hydrate and / or stereoisomer thereof, as described herein is associated with weight reduction.

[0121] Thus, the treatment and / or prevention may comprise or consist of weight reduction, for medical or cosmetic reasons. Additionally or alternatively, the treatment and / or prevention may comprise or consist of blood glucose lowering. While not wishing to be bound by any specific theory, weight reduction may be a result of reduced appetite as it has been found that administration of the compound of Formula I, or a stereoisomer and / or hydrate thereof as described herein, reduces food intake over time. Thus, the compound of Formula I, or a stereoisomer or hydrate thereof, may further be an appetite regulating agent, appetite suppressant and / or weight management agent. As such, the treatment and / or prevention may comprise or consist of appetite regulation. The appetite regulation may comprise of consist of appetite reduction and / or reduction of craving(s).

[0122] The appetite reduction may involve a decrease in caloric intake, such as a reduction of about 5% or more, such as about 10% or more, such as about 10% to about 30% relative to baseline intake (i.e., an intake of food in the absence of administration of the compounds described herein) . The craving reduction may involve a decrease in the frequency or intensity of cravings for specific food types (e.g., high-fat or high- sugar foods).

[0123] There is further provided the use of a compound of Formula I, or a hydrate or stereoisomer thereof as described herein for the manufacture of a medicament for the treatment and / or prevention of a metabolic disease or disorder, including one or more of: metabolic syndrome, obesity, type 2 diabetes, prediabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease (MASLD), dyslipidemia and / or gout, as well as for the lowering, or prevention of increase in, triglyceride and / or cholesterol levels, and / or body adipose tissue.

[0124] There is further provided a method for the treatment and / or prevention of metabolic disease or disorder, including one or more of: metabolic syndrome, obesity, type 2 diabetes, prediabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease (MASLD), dyslipidemia and / or gout, as well as for the lowering, or prevention of increase in, triglyceride and / or cholesterol levels, and / or body adipose tissue, which method comprises administering to a patient in need thereof a compound of Formula I, or a hydrate or stereoisomer thereof, as described herein.

[0125] As used herein, the term prevention includes references to the prophylaxis of (and, similarly, preventing) the disease or disorder (and vice-versa). In particular, the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).

[0126] Compounds of Formula I, hydrates or stereoisomers thereof may be used in human or veterinary medicine. "Patients" and / or "subjects" thus include avian, mammalian and, especially, human patients. In addition to therapeutic, symptomatic and palliative treatment, and prophylaxis / prevention of the relevant conditions, we also include the diagnosis of such conditions.

[0127] As used herein, the term treatment includes references to obtaining a desired pharmacological and physiological effect. The effect may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease.

[0128] The compound of Formula I described herein, or a stereoisomer or hydrate thereof, may be administered for (i) treating, (ii) preventing or (iii) treating and preventing a metabolic disease or disorder as described herein. Accordingly, there is provided a provided a compound of Formula I, or a stereoisomer or hydrate thereof, as described herein for use in the treatment of a metabolic disease or disorder as described herein. Further, there is provided a compound of Formula I, or a stereoisomer or hydrate thereof, as described herein for use in the prevention of a metabolic disease or disorder as described herein. It will be appreciated that the prevention of the metabolic disease or disorder may comprise or consist of weight management as described herein, such as weight reduction, and / or appetite regulation as described herein such as appetite reduction. Moreover, there is provided a compound of Formula I, or a stereoisomer or hydrate thereof, as described herein for use in the treatment and prevention of a metabolic disease or disorder as described herein.

[0129] The prevention of a metabolic disease or disorder may comprise administration of the compound to a subject at risk of developing a metabolic disorder. The subject may be a human. A subject at risk of developing a metabolic disease or disorder may meet one or more of the following criteria, each of which is independently associated with increased metabolic risk:

[0130] A subject at risk of developing a metabolic disorder may exhibit abdominal obesity, as determined by waist circumference. In men, a waist circumference of greater than or equal to 102 cm is considered elevated, while in women, the threshold is greater than or equal to 88 cm. In certain populations, such as individuals of Asian descent, lower thresholds may apply, including 90 cm for men and 80 cm for women.

[0131] A subject may also be considered at risk if they exhibit elevated triglyceride levels. A triglyceride level of greater than or equal to 150 mg / dL (1.7 mmol / L) is indicative of increased metabolic risk. Subjects currently receiving pharmacological or dietary treatment for hypertriglyceridemia are also considered at risk. Reduced levels of high-density lipoprotein (HDL) cholesterol are another indicator of metabolic risk. In men, HDL cholesterol levels equal to or lower than 40 mg / dL (1.0 mmol / L) are considered low, while in women, the threshold is equal to or lower than 50 mg / dL (1.3 mmol / L). Subjects undergoing treatment for low HDL cholesterol levels are also considered at risk.

[0132] Elevated blood pressure is a further criterion for identifying at-risk individuals. A systolic blood pressure of greater than or equal to 130 mmHg and / or a diastolic blood pressure of greater than or equal to 85 mmHg is indicative of increased risk. Subjects currently receiving antihypertensive therapy are also considered at risk.

[0133] A subject at risk of developing a metabolic disorder may also have an elevated fasting glucose level, such as a fasting glucose level of greater than or equal to 100 mg / dL (5.6 mmol / L). Subjects receiving treatment for elevated glucose levels are considered at risk.

[0134] A subject with an HbAlc level of greater than or equal to 5.7%, which corresponds to an eAG of greater than or equal to 117 mg / dL, is considered to be at risk of developing diabetes.

[0135] Body mass index (BMI) is another relevant factor. A BMI of 25 kg / m2or greater is considered overweight, while a BMI of 30 kg / m2or greater is classified as obese. Further classifications include Class I obesity (BMI >30), Class II obesity (BMI >35), and Class III obesity (BMI >40). As such, a subject at risk of developing a metabolic disorder may have a BMI greater than or equal to 25, such as from 25 to 30, such as equal to or above 30, such as from 30 to 35, such as equal to or above 35, such as from 35 to 40, such as equal to or above 40.

[0136] Further, a subject at risk of developing a metabolic disorder may have insulin resistance. Insulin resistance may be inferred from elevated fasting insulin levels or calculated using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), with values greater than 2.5 indicating insulin resistance.

[0137] A subject may be considered at risk based on family history. A family history of type 2 diabetes or cardiovascular disease, particularly in a first-degree relative, is a well- established risk factor. Cardiovascular events occurring in a male relative before the age of 55 or in a female relative before the age of 65 are particularly indicative of increased risk.

[0138] The compound of Formula I, or a stereoisomer or hydrate thereof, may be provided as a pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent. The pharmaceutical composition may be used in the treatment and / or prevention of a metabolic disease or disorder.

[0139] Accordingly, there is provided a pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, as defined herein in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent for use in the treatment and / or prevention of a metabolic disease or disorder as defined herein.

[0140] Further, there is provided the use of a pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, as defined herein in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent for the manufacture of a medicament for the treatment and / or prevention of a metabolic disease or disorder as defined herein.

[0141] There is also provided a method for the treatment and / or prevention of a metabolic disease or disorder as defined herein, said method comprising administering to a patient, such as a human or animal in need thereof, an effective amount, such as a therapeutically effective amount, of a pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, as defined herein in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent.

[0142] The pharmaceutical composition may be adapted for the intended type of administration such as oral administration or subcutaneous administration. Thus, the pharmaceutical composition may be an oral pharmaceutical composition or a subcutaneous pharmaceutical composition.

[0143] Advantageously, the pharmaceutical composition or the compound of Formula I, or stereoisomer or hydrate thereof, is administered to a patient such as a human or animal at risk of developing a metabolic disease or disorder such as a patient suffering from abdominal obesity and / or having a body mass index (BMI) equal to or above about 25, such as from about 25 to about 30, such as equal to or above about 30, such as from about 30 to about 35, such as equal to or above about 35, such as from about 35 to about 40.

[0144] Pharmaceutical compositions

[0145] The oral pharmaceutical composition described herein may be prepared as a liquid such as a syrup, suspension or solution, or as a solid such a powder, tablet, capsule or lozenge.

[0146] Advantageously, the solid oral pharmaceutical composition may be a spray-dried pharmaceutical composition as it has been found that the physico-chemical (e.g. dissolution) properties of compounds and hydrates described hereinbefore can be vastly improved by spray-drying along with a polymer or co-polymer that is capable of forming physico-chemical interactions with such compounds or hydrates.

[0147] Thus, there is provided a spray-dried composition comprising a compound of Formula I, or a stereoisomer or hydrate thereof as described herein and an excipient suitable for spray-drying. The excipient suitable for spray-drying may comprise a polymer or co-polymer capable of forming physico-chemical interactions with the compound of Formula I, or a hydrate or stereoisomer thereof as described herein.

[0148] For example, the excipient suitable for spray-drying may comprise one or more of a cellulose ester, N-vinylpyrrolidone-vinyl acetate co-polymer, polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft co-polymer and methacrylic acid-methyl methacrylate co-polymer.

[0149] Further, the excipient suitable for spray-drying may comprise a cellulose ester such as a non-ionic cellulose ester. The cellulose ester may comprise or consist of hydroxypropylmethyl cellulose (HPMC) or a derivative thereof. For instance, the derivative of HPMC may comprise or consist of hydroxypropylmethyl cellulose acetate succinate (HPMC-AS) and / or hydroxypropylmethyl cellulose phthalate (HPMC-P).

[0150] Additionally or alternatively, one or more of the following polymers may be used: Hypromellose phtalate, polyvinylpyrrolidone-vinyl acetate (i.,e. PVP-vinyl acetate), polymethacrylates, olyvinyl Caprolactam-Polyvinyl Acetate-Polyethylene Glycol Graft Co-Polymer. In still a further example, one or more of the following polymers may be used: PVP, PVP-vinylacetate, crospovidone, polyethylene glycol (PEG), methylcellulose, hydroxypropyl methyl cellulose. The ratio, such as a weight ratio, of the compound of Formula I, or a hydrate or stereoisomer thereof as described herein to the pharmaceutically acceptable, excipient, carrier and / or diluent as described herein may be from about 1: 10 to about 10: 1, such as about 1:5 to about 5: 1, such as about 1:4 to about 4: 1, about 1 :3 to about 3: 1, about 1 :2 to about 2: 1 or about 1: 1. For instance, the ratio, such as a weight ratio, of the compound of Formula I, or a hydrate or stereoisomer thereof as described herein to the pharmaceutically acceptable, excipient, carrier and / or diluent as described herein may be about 1 :3.

[0151] The spray-dried composition may comprise particles having a particle size distribution with a Dv90, also denominated D(v, 0.9), of 120 micrometer(s) or less, such as 100 micrometer(s) or less, such as from 10 micrometer(s) to 120 micrometer(s). As used herein, the terms ' Dv90 ' and ' D(v, 0.9) ' mean the size (or diameter) in a particle size distribution in which 90% of the total volume of the material is contained. Similarly, the terms "Dv50" and "D(v,0.5)" refer to the median particle size (or diameter), i.e., the particle size at which 50% of the total volume of particles are smaller and 50% are larger. This value represents the midpoint of the volume-based particle size distribution. The terms "DvlO" and "D(v,0.1)" refers to the particle size (or diameter) at which 10% of the total volume of particles are smaller than or equal to that size. The particle size distribution may be measured using methods used in the art. For example, the measurement may be performed using laser diffraction, dynamic light scattering, Scanning Electron Microscopy (SEM), sieve analysis and any combination thereof.

[0152] Further, the spray-dried composition may comprise or consist of a powder, granules, pellets and / or beads.

[0153] It will be appreciated that spray-drying will convert any hydrate of the compound of Formula I into the compound of Formula I as the spray-drying process conditions result in evaporation of the volatile spray-drying solvent (which may comprise one or more organic solvents, such as lower alkyl alcohols (e.g. methanol, isopropanol or, more especially, ethanol), hydrocarbons (e.g. C5-10 alkanes), haloalkanes (e.g. dichloromethane), dimethylformamide, dimethylsulfoxide, ethyl acetate, acetone, etc., or mixtures thereof or, more preferably aqueous solvents, such as water. Further, the spray drying conditions will provide the spray-dried pharmaceutical composition comprising the compound of Formula I, or a stereoisomer thereof, in a form that is wholly or predominantly amorphous. For example, more than about 50% by weight, such as more than about 75% by weight, such as more than about 90% by weight, such as more than about 95% by weight, including more than about 99% by weight of the spray-dried composition may be amorphous.

[0154] The pharmaceutical composition of may also be prepared in such a way that it allows for including a compound of Formula I, or a hydrate or stereoisomer thereof as described herein.

[0155] The term "therapeutically effective amount", as used herein, refers to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and / or feels an effect).

[0156] The amount of the compound of Formula I, or a hydrate or stereoisomer thereof as described herein, to be administered may vary depending on factors such as age, weight and the severity of the condition to be treated. In an example, the compound of Formula I, or a hydrate or stereoisomer thereof as described herein, may be administered in a dosage from about 1 microgram to about 500 milligrams per day. In a further example, a patient may be treated with a dosage of from about 1 mg to about 500 mg such as from about 1 mg to about 100 mg per day.

[0157] Thus, there is provided a pharmaceutical formulation comprising: a therapeutically effective amount of a compound of Formula I, or a hydrate or stereoisomer thereof, as described herein in admixture with a pharmaceutically acceptable excipient, carrier and / or diluent, or a spray-dried composition as described herein, said spray-dried composition comprising a therapeutically effective amount of a compound of Formula I as described herein in admixture with a pharmaceutically acceptable excipient, carrier and / or diluent.

[0158] The pharmaceutical formulation, such as the pharmaceutical composition comprising the spray-dried composition, may be formulated for oral administration. For instance, the pharmaceutical formulation may be provided as a tablet, capsule or lozenge. In a further example, the pharmaceutical formulation may be provided as a liquid such as a syrup, suspension or solution.

[0159] Compound(s) and / or spray-dried compositions as described herein may thus be presented following their preparation (e.g. by spray-drying) in the form of simple powder mixtures, powder microspheres, coated powder microspheres, a lyophilised liposomal dispersion, or a combination thereof.

[0160] Such pharmaceutical formulations and / or dosage forms may be provided in the form of a single unit dosage form, such as a pill, a capsule, a cake, a film (e.g. an intraoral film) or a tablet.

[0161] Capsules may be prepared by loading a compound or a spray-dried composition as described herein directly into a pharmaceutically-acceptable capsule made from an appropriate material designed for e.g. peroral delivery, or by mixing said compound or a spray-dried composition along with excipients prior to loading into such a capsule, which may involve a granulation step (as described below), prior to loading into a capsule for such delivery.

[0162] Compound and / or spray-dried compositions as described herein may in this respect be granulated into a pellet or a pill, but they may also be formulated (that is, provided for administration) in the form of a dry, free-flowing powder. By 'dry' we include essentially free of water and other liquid solvents, which includes that there is less than about 10%, such as less than about 6%, including less than about 5%, or less than about 4%, more preferably less than about 3%, such as less than about 2%, e.g. less than about 1% of the formulation is a liquid, such as water.

[0163] Flowability of powder compositions may be measured by standard techniques known to those skilled in the art including bulk density measurements, or measurements taken on a powder flow analyser (for example those sold by Stable Micro Systems or Meritics, both UK), including powder flow speed dependence tests, caking tests, cohesion tests, etc. A preferred measurement of flowability is the standard angle of repose, which may be carried out using a revolving cylinder, a fixed funnel or a tilting box.

[0164] In the context of the present disclosure, the term 'free-flowing' may include that the powder exhibits an angle of repose of no more than about 50°, such as no more than about 45°, including no more than about 40°, for example no more than about 35°, and more particularly no more than about 30°; a bulk density of no less than about 0.3 g / mL, for example no less than about 0.4 g / mL, such as no less than about 0.5 g / mL, and more particularly no less than about 0.6 g / mL; and / or a tap density of no less than about 0.5 g / mL, such as no less than about 0.6 g / mL, for example no less than about 0.7 g / mL, and in particular no less than about 0.8 g / mL. Appropriate techniques for making dosage forms comprising dry powders or granulates include simple dry mixing, granulation (including dry granulation, wet granulation, melt granulation, thermoplastic pelletising, spray granulation), extrusion / spheronisation or, more preferably, freeze-drying or spray-drying.

[0165] Compositions of the disclosure may in the alternative be provided in the form of a tablet for e.g. peroral use. Such tablets may be formed for example by direct compression / compaction of a composition of the disclosure, optionally following mixing it together with one or more appropriate excipients, such as a diluent, a disintegrant, a glidant and / or a lubricant, and may be achieved using techniques such as those described in, for example, Pharmaceutical Dosage Forms: Tablets. Volume 1, 3rdEdition, Augsburger et al (eds.), CRC Press (2008) and the documents cited therein. Suitable compacting equipment includes standard tabletting machines, such as the Kilian SP300 or the Korsch EKO, XP1, XL 100, and XL 200.

[0166] Suitable disintegrants (as defined in, for example, Rowe et al, Handbook of Pharmaceutical Excipients, 6thed. (2009)) that may be employed in tablets include cellulose derivatives such as hydroxypropyl cellulose (HPC), low substituted HPC, methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, modified cellulose gum; starch derivatives such as moderately cross-linked starch, modified starch, hydroxylpropyl starch and pregelatinized starch; and other disintegrants such as calcium alginate, sodium alginate, alginic acid, chitosan, colloidal silicon dioxide, docusate sodium, guar gum, magnesium aluminum silicate, polacrilin potassium and polyvinylpyrrolidone. Combinations of two or more disintegrants may be used.

[0167] Preferred disintegrants include so-called 'superdisintergrants' (as defined in, for example, Mohanachandran et al, International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)), such as cross-linked polyvinylpyrrolidone, sodium starch glycolate and croscarmellose sodium. Combinations of two or more superdisintegrants may be used.

[0168] When disintegrants and / or superdisintegrants are employed in tablets, they may be employed in an (e.g. total) amount of between 0.5 and 15% by weight based upon the total weight of a composition. A preferred range is from 1 to 8%, such as from about 2 to about 7% (e.g. about 5%, such as about 4%) by weight. If present, binder is preferably employed in an amount of between 0.5 and 20% by weight based upon the total weight of the tablet formulation. A preferred range is from 1.0 to 15%, such as from about 2.0 to about 12% (e.g. about 10%) by weight. Suitable binders include cellulose gum and microcrystalline cellulose.

[0169] The spray-dried pharmaceutical composition may further comprise an enteric substance, such as a coating, that serves to prevent release of the compound, hydrate or spray-dried composition in the stomach.

[0170] Alternatively, compounds or, especially, spray-dried pharmaceutical composition as described herein may be reconstituted with a liquid that is a vehicle for oral administration, such as an oil-based or water-based vehicle. The vehicle may comprise a cellulose-based agent, such as a non-ionic cellulose-based agent, such as carboxymethylcellulose (CMC), microcrystalline cellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), and / or hydroxyethyl methylcellulose (HEMC), or a derivative of any of the foregoing cellulose-based agents. In particular the cellulose-based agent may comprise or consist of HPMC, which may also be denominated hypromellose, or a derivative thereof. The HPMC may be HPMC-AS such as HPMC-AS of grade M (medium) or grade United States Pharmacopeia (USP) / National Formulary (NF). Additionally or alternatively, one or more of the following polymers may be used: Hypromellose phthalate, PVP-vinyl acetate, polymethacrylates, Polyvinyl Caprolactam-Polyvinyl Acetate-Polyethylene Glycol Graft Co-Polymer. In still a further example, one or more of the following polymers may be used: PVP (i.e. polyvinylpyrrolidone), PVP-vinylacetate, crospvoidone, PEG, methylcellulose, hydroxypropyl methyl cellulose.

[0171] The compound of Formula I, or a hydrate or stereoisomer thereof, or a pharmaceutical formulation or composition described herein may also be provided for parenteral administration such as intramuscular, intravenous, and intradermal administration. For example, the administration may be buccal, sublingual, rectal, intranasal, transdermal, vaginal or take place through inhalation. In such a situation, compounds or, especially, spray-dried pharmaceutical composition as described herein may also be reconstituted with a liquid that is a vehicle suitable for injection, such as an oil-based or water-based vehicle. Thus, there is provided a pharmaceutical composition as described herein which is in injectable form, i.e. an injectable pharmaceutical composition. Combinations

[0172] The compound of Formula I, or pharmaceutically acceptable salt thereof as described herein may be administered alone or in combination with a further pharmaceutical drug for treating a metabolic disease or disorder such as a metabolic disease or disorder as described herein. For instance, the further pharmaceutical drug may be one or more of the following: an anti-diabetic drug, an antihypertensive agent, a lipid lowering drug, a drug for treating Erectile Dysfunction such as an inhibitor of PDE5 (i.e. a phosphodiesterase type 5 inhibitor).

[0173] Non-therapeutic uses

[0174] The present disclosure also provides a non-therapeutic method of weight management such as weight reduction, weight stabilization and / or prevention of weight gain in a subject such as a human or an animal, said method comprising administering a compound of Formula I, or a stereoisomer or hydrate thereof, or a pharmaceutical composition comprising the compound of Formula I, as defined herein to the subject. For instance, the compound of Formula I may be a compound of Formula la or Formula lb, or a hydrate or stereoisomer thereof as described herein. In particular, the weight management may comprise or consist of weight reduction.

[0175] As such, the non-therapeutic method may not treat or prevent a disease in a subject such as a human or animal but may provide an increased well-being and / or improved physical or mental state in the subject. The non-therapeutic method may be a cosmetic method. For example, the subject may lose a small amount of weight such as about 5% or less, such as from about 1% to about 5%, such as about 4% or less, such as about 3% or less, such as about 2% or less, of his or her weight and / or experience a reduction in cravings. Additionally or alternatively, the subject such as a human may have a healthy body mass index (BMI) and / or waist circumference before and after being subjected to the non-therapeutic method. The healthy BMI may be from 18.5 to 24.9 before and after the subject is subjected to the non-therapeutic method. For women, the healthy waist circumference may be 88 centimenters or less, such as from about 65 centimeters to 88 centimeters, before and after the woman is subjected to the non-therapeutic method. For men, the healthy waist circumference may be 102 centimenters or less, such as from about 80 centimeters to 102 centimeters, before and after the woman is subjected to the non-therapeutic method.

[0176] There is further provided a non-therapeutic method of blood glucose stabilization or blood glucose lowering in a subject such as a human or an animal, said method comprising administering a compound of Formula I, or a stereoisomer or hydrate thereof, or a pharmaceutical composition comprising the compound of Formula I, as defined herein to the subject. For instance, the compound of Formula I may be a compound of Formula la or Formula lb, or a hydrate or stereoisomer thereof as described herein.

[0177] The blood glucose lowering may comprise or consist of the lowering of fasting blood glucose, HbAlc and / or eAG levels.

[0178] The lowering of fasting blood glucose levels may involve lowering the glucose levels from diabetic levels (i.e. levels greater than or equal to about 126 mg / dL) to healthy levels (i.e. levels below about 100 mg / dL, such as below about 90 mg / dL), or from elevated levels (i.e. between about 110 mg / dL and about 125 mg / dL) to healthy levels, or from borderline elevated levels (i.e. between about 100 mg / dL and about 109 mg / dL) to healthy levels.

[0179] The lowering of HbAlc levels may involve lowering the HbAlc from diabetic levels (i.e. levels greater than or equal to about 6.5%) to healthy levels (i.e. levels below about 5.7%, such as below about 5.5%), or from elevated levels (i.e. between about 6.0% and about 6.4%) to healthy levels, or from borderline elevated levels (i.e. between about 5.7% and about 5.9%) to healthy levels.

[0180] Similarly, the lowering of estimated average glucose (eAG) levels may involve lowering the eAG from diabetic levels (i.e. levels greater than or equal to about 140 mg / dL, which corresponds to an HbAlc of 6.5%) to healthy levels (i.e. levels below about 117 mg / dL, which corresponds to an HbAlc of 5.7%), or from elevated levels (i.e. between about 125 mg / dL and about 139 mg / dL) to healthy levels, or from borderline elevated levels (i.e. between about 117 mg / dL and about 124 mg / dL) to healthy levels.

[0181] The present disclosure also provides a non-therapeutic method of blood lipid management such as blood triglyceride lowering and / or blood cholesterol (such as LDL cholesterol) lowering in a subject such as a human or an animal, said method comprising administering a compound of Formula I, or a stereoisomer or hydrate thereof, or a pharmaceutical composition comprising the compound of Formula I, as defined herein to the subject. For instance, the compound of Formula I may be a compound of Formula la or Formula lb, or a hydrate or stereoisomer thereof as described herein. In particular, the blood lipid management may comprise or consist of blood cholesterol lowering. The lowering of triglyceride levels may involve lowering fasting triglyceride levels from very high levels (i.e. levels above about 500 mg / dL) to healthy levels (i.e. levels below about 150 mg / dL such as below about 90 mg / dL), or from high levels (i.e. between about 200 mg / dL and about 499 mg / dL) to healthy levels, or from borderline high levels (i.e. between about 150 mg and about 199 mg / dL) to healthy levels.

[0182] The lowering of LDL cholesterol levels may involve lowering the LDL cholesterol from very high levels (i.e. levels above about 190 mg / dL) to healthy levels (i.e. levels below about 100 mg / dL, such as below about 70 mg / dL), or from high levels (i.e. between about 160 mg / dL and about 189 mg / dL) to healthy levels, or from borderline high levels (i.e. between about 130 mg / dL and about 159 mg / dL) to healthy levels.

[0183] The present disclosure also provides a non-therapeutic method of appetite regulation in a subject such as a human or an animal, said method comprising administering a compound of Formula I, or a stereoisomer or hydrate thereof, or a pharmaceutical composition comprising the compound of Formula I, as defined herein to the subject. For instance, the compound of Formula I may be a compound of Formula la or Formula lb, or a hydrate or stereoisomer thereof as described herein. In particular, the appetite regulation may comprise or consist of appetite reduction and / or reduction of craving(s).

[0184] The appetite reduction may involve a decrease in caloric intake, such as a reduction of about 5% or more, such as about 10% to about 30% relative to baseline intake (i.e., an intake of food in the absence of administration of the compounds described herein). The craving reduction may involve a decrease in the frequency or intensity of cravings for specific food types (e.g., high-fat or high-sugar foods).

[0185] The non-therapeutic method may involve administration of the compound of Formula I, or a hydrate or stereoisomer thereof, provided as a dietary supplement. The dietary supplement may comprise or consist of the compound of Formula I, or a hydrate or stereoisomer thereof, and optionally one or more dietary ingredients such as vitamin(s), mineral(s), herb(s), amino acid(s), enzyme(s), preservative(s), sweetener(s), flavouring(s), fragrance(s) and / or colorant(s).

[0186] The dietary supplement may provided in a form suitable for the intended use. For instance the dietary supplement may be provided for oral consumption, i.e. the dietary supplement may be an oral dietary supplement. In an example, the dietary supplement may be provided as a powder, pill, capsule, tablet or a liquid preparation such as a syrup, suspension or solution. Further, the dietary supplement may be administered separately from or together with food, feed or beverage. In the latter case, the dietary supplement may be administered before or after intake of the food, feed or beverage. Alternatively, it may be administered together with the food, feed or beverage. For example, the dietary supplement may be mixed with the food, feed or beverage.

[0187] The dietary supplement may be provided with instructions for use to inform the consumer of e.g. different and suitable ways of administration. Further, the dietary supplement may be provided as a kit of parts comprising: (i) the dietary supplement, (ii) food, feed or a beverage and (iii) optionally instructions for use such as instructions relating to separate, sequential or simultaneous administration of the dietary supplement and the food, feed or beverage. It will be appreciated that (i) and (ii) may be provided as separate entities, or as a single composition comprising a mixture of (i) and (ii). The single composition may be considered to be functional food, functional feed or functional beverage.

[0188] Methods of preparation

[0189] The compounds of the present disclosure may be prepared as described in this document and / or using methods known in the art. For instance, the compounds may be prepared as described in WO 2008 / 145996 A2 or WO 2024 / 072288 Al such as shown in Figures 4-5. Scheme 1 below illustrates a synthesis of the compound of Formula la and the monohydrate of Formula Illal starting from a mixture of the phragmalin diesters phragmalin-3,30-di-isobutyrate and phragmalin-3-isobutyrate- 30-proprionate, which may be obtained from extraction of seeds from Entandrophragma caudatum.

[0190]

[0191] It will be appreciated that the compounds of the present disclosure may be depicted in different ways and these representations may be used interchangeably, as shown in Table 1. It will that the stereoisomers such as the stereoisomers of Formula II, Formula Ila, Formula lib, Formula IV, Formula IV1, Formula IVa, Formula IVal, Formula IVb and / or Formula IVbl may be exchanged for the corresponding prime or bis stereoisomer. Moreover, for the avoidance of doubt, the skilled person will appreciate that compounds of the present disclosure include those that are obtainable, i.e. those that may be prepared in a stable form. That is, compounds of the disclosure include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity. Table 1 Aspects

[0192] The present disclosure also provides the following aspects.

[0193] Aspect 1

[0194] A compound of Formula I:

[0195] Formula I or a stereoisomer thereof, or a hydrate thereof wherein

[0196] R1is Ci-Cealkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, and R2and R3are independently

[0197] H, or

[0198] C(O)Ci-C6alkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, for use in the treatment and / or prevention of a metabolic disease or disorder.

[0199] Aspect 2

[0200] The compound for use according to aspect 1, or a stereoisomer or hydrate thereof, wherein R1is methyl, R2is isopropyl and R3is hydrogen thereby providing a compound of Formula la:

[0201]

[0202] Formula la

[0203] Aspect 3 The compound for use according to aspect 1, or a stereoisomer or hydrate thereof, wherein R1is methyl, and R2and R3are both hydrogen thereby providing a compound of Formula lb:

[0204] Formula lb Aspect 4

[0205] The compound for use according to any one of aspects 1-3, wherein the compound of Formula I is provided as a stereoisomer of Formula II:

[0206] Formula II or a hydrate thereof.

[0207] Aspect 5

[0208] The compound for use according to any one of aspects 1-4, wherein the compound of Formula I or stereoisomer thereof is provided as a hydrate of Formula III:

[0209] Formula III said hydrate being a combination of a compound of Formula I and water: r in a ratio of l:n, wherein n is a number such as an integer from 1 to 10.

[0210] Aspect 6

[0211] The compound for use according to any one of aspects 1-5, or a stereoisomer or hydrate thereof, wherein the treatment and / or prevention of a metabolic disease or disorder is one or more of the following: the treatment and / or prevention of metabolic syndrome, the treatment and / or prevention of obesity, the treatment and / or prevention of type 2 diabetes, the treatment and / or prevention of prediabetes, the treatment and / or prevention of cardiovascular disease, the lowering of, or prevention of increase in, triglyceride and / or cholesterol levels, the treatment and / or prevention of metabolic dysfunction-associated steatotic liver disease (MASLD), the treatment and / or prevention of dyslipidemia, the treatment and / or prevention of gout, the lowering of, or prevention of increase in, body adipose tissue.

[0212] Aspect 7

[0213] The compound for use according to aspect 6, or a stereoisomer or hydrate thereof, wherein the cardiovascular disease is selected from the group consisting of coronary heart disease, stroke, peripheral arterial disease, aortic disease, endothelial dysfunction and hypertension.

[0214] Aspect 8

[0215] The compound for use according to any one of the preceding aspects, or a stereoisomer or hydrate thereof, wherein the treatment and / or prevention of a metabolic disease or disorder comprises weight reduction.

[0216] Aspect 9

[0217] The compound for use according to any one of the preceding aspects, or a stereoisomer or hydrate thereof, wherein the treatment and / or prevention of a metabolic disease or disorder comprises blood glucose lowering.

[0218] Aspect 10

[0219] A pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, as defined in any one of aspects 1-5 in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent for use in the treatment and / or prevention as defined in any one of aspects 1 or 6-9.

[0220] Aspect 11

[0221] The pharmaceutical composition for use according to aspect 10, wherein the composition is formulated for subcutaneous administration.

[0222] Aspect 12

[0223] The pharmaceutical composition for use according to aspect 10, wherein the composition is formulated for oral administration. Aspect 13

[0224] The compound for use according to any one of aspects 1-9, or a stereoisomer or hydrate thereof, or the pharmaceutical composition for use according to any one of aspects 10-12 wherein the compound or pharmaceutical composition is administered to a patient suffering from abdominal obesity and / or having a body mass index (BMI) equal to or above 25 such as equal to or above 30.

[0225] Aspect 14

[0226] A non-therapeutic method of weight reduction and / or blood glucose lowering in a subject, said method comprising administering a compound of Formula I as defined in any one of aspects 1-5, or a stereoisomer or hydrate thereof, or a pharmaceutical composition as defined in any one of aspects 10-12 to the subject.

[0227] Aspect 15

[0228] A dietary supplement comprising a compound of Formula I, or a stereoisomer or hydrate thereof, as defined in any one of aspects 1-5.

[0229] References

[0230] 1. Alberti K.G., Zimmet P.Z. (1998), Diabet. Med., 15, 539-553

[0231] 2. Balkau B., Charles M.A. (1999), Diabet. Med., 16, 442-443

[0232] 3. NCEPNE Panel (2002), Circulation, 106, 3143-3421

[0233] 4. Grundy S.M. et al. (2005), Circulation, 112, 2735-2752

[0234] 5. Zimmet P. et al. (2005), J Atheroscler Thromb, 12, 295-300

[0235] 6. Chew et. al. (cell metabolism, 2023, 35, pg. 414-428)

[0236] 7. WO 2007 / 031830 Al

[0237] 8. Peng J. et al., molecules 2016, 21, 58; doi: 10.3390

[0238] 9. CN 108 210 600 A

[0239] 10. WO 2008 / 145996 Al

[0240] 11. WO 2024 / 072288 Al

[0241] 12. WO 2013 / 110744 A2

[0242] 13. Fossen T. et al., Planta Medica 2016, 82, 1087-1095

[0243] 14. Grigorjeva L. et al., The Journal of Organic Chemistry 2014, 79, 4148-4153

[0244] 15. Ono E. et al., Biochemical and Biophysical Research Communications 2011, 410, 3, 677-681

[0245] 16. Pharmaceutical Dosage Forms: Tablets. Volume 1, 3rdEdition, Augsburger et al (eds.), CRC Press (2008)

[0246] 17. Rowe et al, Handbook of Pharmaceutical Excipients, 6thed. (2009))

[0247] 18. Mohanachandran et al, International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)

[0248] 19. European pharmacopeia standard: PhEur 2.4.24

[0249] The disclosure is illustrated by the following non-limitative examples.

[0250] EXAMPLES

[0251] In this document, unless otherwise stated, the drawing of the chemical compounds have been made using the software package ChemDraw Ultra 12.0. If the drawing and naming are inconsistent, the drawing of the chemical structure shall be considered to be correct.

[0252] Abbreviations

[0253] API Active Pharmaceutical Ingredient

[0254] ASTM American Society for testing and Materials

[0255] AUC area under curve

[0256] BID bis in die, i.e. twice a day

[0257] BMI body mass index b.w. body weight

[0258] Cmax maximum concentration

[0259] CMC carboxymethylcellulose

[0260] DBP diastolic blood pressure

[0261] DCM methylene chloride

[0262] DIPEA diisopropylethylamine

[0263] DMAP / V, / V-dimethylaminopyridine

[0264] DMF dimethyl formamide dL deciliter eAG estimated average glucose

[0265] ECG electrocardiogram

[0266] EDC / V-(3-dimethylaminopropyl)- / V'-ethylcarbodiimide

[0267] EGIR European Group for the Study of Insulin Resistance eq equivalents

[0268] EtOAc ethyl acetate g gram(s)

[0269] GCP good clinical practice h hour(s)

[0270] HbAlc glycated hemoglobin

[0271] HDL high-density lipoprotein

[0272] HEC hydroxyethyl cellulose HEMC hydroxyethyl methylcellulose

[0273] HLD hyperlipidemia

[0274] HPC hydroxypropyl cellulose

[0275] HPLC high-performance liquid chromatography

[0276] HPMC hydroxypropyl methylcellulose

[0277] HPMC AS- MG hydroxypropyl methylcellulose acetate succinate - medium grade

[0278] HPMCAS- 'I hydroxypropyl methylcellulose acetate succinate - medium grade

[0279] ICH international conference on harmonization

[0280] IDF International Diabetes Foundation

[0281] I PA isopropyl alcohol

[0282] IU International Unit

[0283] K2 EDTA ethylenediaminetetraacetic acid dipotassium salt kg kilogram(s)

[0284] KMnO4potassium permanganate

[0285] L liter(s)

[0286] LDPE low density polyethylene

[0287] LOD loss of drying

[0288] MAD multiple ascending dosing

[0289] MASLD metabolic dysfunction-associated steatotic liver disease

[0290] MC microcrystalline cellulose

[0291] MeOH methanol min minute(s) mg milligram(s) mL milliliter(s) mm millimeter(s)

[0292] NAFLD non-alcoholic fatty liver disease

[0293] NCEP National Cholesterol Education Program

[0294] NF National Formulary

[0295] NLT not less than

[0296] NMR Nuclear magnetic resonance

[0297] OD once daily

[0298] PD pharmacodynamic

[0299] PK pharmacokinetic

[0300] PPm part per million psi pound per square inch

[0301] PVP polyvinylpyrrolidone rpm revolutions per minute s second(s) SAD single ascending dosing

[0302] SBP systolic blood pressure

[0303] SD Sprague Dawley

[0304] SDI socio-demographic index

[0305] SEM Scanning Electron Microscopy

[0306] STZ streptozotocin

[0307] TG triglyceride

[0308] TLC thin-layer chromatography

[0309] TPEG Trimethylolpropane ethoxylate pm micrometer(s)

[0310] USP United States Pharmacopeia

[0311] V volume w / v weight by volume w / w weight by weight

[0312] WHO World Health Organization

[0313] Materials

[0314] Seeds of Entandrophragma caudatum were purchased from Parceval Ltd, Wellington, South Africa. The seeds were processed and converted to compounds of Formula I, or a hydrate thereof, as described in WO 2024 / 072288 Al. See, for instance, Figures 4 and 5 in WO 2024 / 072288 Al.

[0315] The monohydrate of Formula Illal, i.e., the LIB-01, was prepared following the procedure outlined below and / or as shown in Scheme 1.

[0316] Example 1: Preparation of extract composition from seeds of Entandrophragma caudatum

[0317] Step 1: Preparation of a methanol extract from seeds of Entandrophragma caudatum

[0318] Methanol (ca 800 L) was added to a nitrogen filled glass reactor and stirred. Ground seeds of Entandrophragma caudatum (ca 100 kg) were then added and the reactor was evacuated and refilled with nitrogen. The temperature of the reactor was set to 40 °C and the contents stirred for at least 15-20 h. The mixture was then filtered through a polyamide filter cloth (having a mesh size of 25 pm) by applying pressurized nitrogen atmosphere and the filtrate was collected in a vessel. Methanol was added to the feeding vessel (100 L). From the feeding vessel methanol was passed through the filter bypassing the glass reactor (twice, 50 L each time) and the filtrate was collected into a vessel The mixture was then filtered again through the polyamide filter cloth by repeating the procedure. The resulting filter cake was then dried under vacuum for at least 1 h. The filtrate was then added to the glass reactor (ca 800 L in total) and the contents stirred. The methanol solvent was distilled off under vacuum at a jacket temperature of 40-70 °C (internal temperature during distillation was approx. 21-29 °C). The distillation was continued until approximately 200 L was left in the glass vessel. Care was taken to not distill off too much methanol, as the remaining content would be too sticky to be removed from the glass vessel. The jacket temperature was then adjusted to approximately 20-25 °C and the concentrated methanol extract was collected.

[0319] Step 2: Preparation of the extract composition of Entandrophragma caudatum in ethyl acetate

[0320] Concentrated methanol extract as prepared in Step 1 above (ca 400 L, i.e. two batches of step 1) was added to a nitrogen filled glass reactor. The temperature of the reactor was adjusted to 75 °C and stirring was started. The methanol was distilled off under vacuum to obtain a dry mixture and, thereafter, the temperature was adjusted to 20 °C. Ethyl acetate (EtOAc) (ca 400 L) was then added to the dry mixture in the reactor followed by water (ca 170 L). The temperature of the reactor was set to 40 °C and the contents of the reactor were stirred for ca 30 min. while maintaining the temperature at 40 °C. The stirring was then stopped and the two phases were allowed to separate for 30 to 60 min. The aqueous layer was then discarded. The temperature of the reactor was adjusted to 55-75 °C and the mixture remaining after water removal was concentrated under vacuum until the volume had been reduced to ca 50 L (i.e., when ca 350 L of distillate had been distilled off and collected). The resulting extract composition of Entandrophragma eaudatum in EtOAc was then collected as a dark yellow solution and stored at 5 °C ± 3 °C before further use.

[0321] The thus obtained extract composition of Entandrophragma caudatum contained a mixture of phragmalin-3,30-di-isobutyrate, phragmalin-3-isobutyrate-30-proprionate, phragmalin-3-nicotinate-30-isobutyrate, and a precursor to the compound of Formula lb. The chemical structure of the precursor was not established. Example 2: Synthesis of the compound of Formula la

[0322] Formula la

[0323] Step 1: Synthesis of the compound of Formula lai and the compound of Formula lb:

[0324] Formula lai Formula lb

[0325] The extract composition of Entandrophragma caudatum in EtOAc from Example 1 (138 kg) was dissolved in methanol (690 L, 5 vol) and distilled until no distillate was observed. Methanol (690 L, 5 vol) was added to reaction which was then further distilled at 45 °C until no distillate was observed to distill off thereby affording a solvent free extract residual as a brown syrup (105 kg).

[0326] The extract residual (105 kg, 1.0 eq) was dissolved in methanol (1050 L, 10.0 V) and cooled to 15 °C ± 5°C. Sodium methoxide (15. 75 kg, 0.15 % w / w) was added in four equal amounts in time intervals of 10 min at temperature below 30 °C (an exotherm of 5-10 °C was observed during addition of sodium methoxide). The reaction mixture was then stirred for 40 h at 45 °C ± 5 °C. Work up:

[0327] The pH of the reaction mixture was adjusted to 6.0 to 7.0 using aqueous acetic acid (ca 15.75 kg, ca 0.15 % w / w) at 15 °C ± 5 °C and purified water (315 L, 3.0 V) was added at a temperature below 30 °C. The reaction mixture was concentrated under reduced pressure at a temperature of less than 45 °C to remove the methanol. The residue was diluted with EtOAc (1050 L, 10.0 V). Purified water (420 L, 4.0 V) was then added followed by sodium chloride (21 kg, 0.2 % w / w) and stirred for 15 min. The biphasic medium was then separated and the aqueous phase was reextracted with EtOAc (735 L, 7 .0 V). The combined organic layer was washed with 10% sodium chloride solution (735 L, 7.0 V), separated, and dried over anhydrous sodium sulfate (ca 21 kg, 0.2 % w / w). The organic layer was concentrated under reduced pressure at a temperature of less than 45 °C to afford a crude mixture of compounds of Formula lai and lb.

[0328] Hexane slurry followed by column purification:

[0329] Hexane (1050 L, 10.0 V) was added to the crude mixture which was then heated to 40 °C ± 5°C and stirred for 2 h. The mixture was then cooled to 25°C ± 5 °C and stirred for 8 h. The precipitate was collected by filtration and washed with hexane (210 L, 2.0 V) to afford a crude mixture of compounds of Formula lai and lb as a pale yellow solid (ca 13.36 kg) (all non-polar impurities were washed out with hexane purification). The compounds of Formula lai and lb were separated from the crude mixture by column chromatography on silica gel to afford the compound of Formula lai (ca 4.17 kg) and the compound of Formula lb (ca 2.94 kg).

[0330] Purification of the compound of Formula lai :

[0331] The crude compound of Formula lai (4.17 kg) was stirred with isopropyl alcohol (IPA) (8.3 L, 2.0 V) at 50 °C ± 5 °C for 1 h. The temperature was then slowly reduced (for not less than (NLT) 1 hour) to 25 °C ± 5 ° and the crude compound was left to stir for 6 h. The solid was collected by filtration and washed with IPA (2.1 L, 0.5 V). The wet solid (2.32 kg) was dried under vacuum at 40 °C ± 5 °C to afford the compound of Formula lai (ca 2.13 kg) as a solid.

[0332] Analytical data: Purity (HPLC): 98.4 %.

[0333] Purification of a compound of Formula lb:

[0334] The crude compound of Formula lb (2.94 kg) was stirred with IPA (8.8 L, 3.0 V) at 50°C ± 5 °C for 1 h. The temperature was then slowly reduced (for NLT 1 hour) to 25 °C ± 5 ° and the crude compound was left to stir for 6 h. The solid was collected by filtration and washed with IPA (2.9 L, 1.0 V).

[0335] The wet solid (1.53 kg (after loss of drying (LOD) correction)) was stirred with EtOAc (4.6 L, 3.0 V) at 50 °C ± 5 °C for 1 h. The temperature was then slowly reduced to 25 °C ± 5 ° and left to stir for 6 h. The solid was collected by filtration and washed with EtOAc (1.5 L, 1.0 V).

[0336] The wet solid (1.07 kg) was stirred with EtOAc ( 4.6 L, 3.0 V) at 50 °C ± 5 °C for 1 h. The temperature was then slowly reduced to 25 °C ± 5 °C and left to stir for 6 h. The solid was collected by filtration and washed with EtOAc (1.5 L, 1.0 V).

[0337] The wet solid (0.85 kg) was stirred with EtOAc (1.7 L, 2.0 V) at 50 °C ± 5 °C for 1 h. The temperature was then slowly reduced to 25 °C ± 5 ° and left to stir for 6 h. The solid was collected by filtration and washed with EtOAc (0.4 L, 0.5 V).

[0338] The wet solid (0.58 kg) was dried under vacuum at 40 °C ± 5 °C to afford the compound of Formula lb (ca 0.335 kg) as a solid.

[0339] Analytical data: Purity (HPLC): 99.5 %.

[0340] Step 2: Three step synthesis for the conversion of the compound of Formula lai to the compound of Formula lb

[0341] Step 2(a): Ring opening of lactone ring: Conversion of the compound of Formula lai

[0342] A suspension of barium hydroxide octahydrate (1.16 kg, 1.0 eq) in methanol (10.3 L, 5.0 V) was cooled to 0-5 °C and the compound of Formula lai (2.06 kg, 1.0 eq) was added in four equal amounts over 15 min at 0-5°C. The resulting reaction mixture was stirred at 0-10 °C for 2 h (the reaction mixture became homogenous as the reaction progressed). The progress of the reaction was monitored by thin-layer chromatography (TLC) (60 % EtOAc / hexane, for starting material consumption and 10 % methanol / methylene chloride (MeOH / DCM) for product elution; visualization : potassium permanganate (KMnO4) stain).

[0343] Work up:

[0344] After complete consumption of the starting material, the reaction mixture was acidified to pH 5-6 using 10 % aqueous acetic acid (~8.24 L, 4.0 V) and concentrated at a temperature below 40 °C to remove the methanol. The residue was extracted twice with (10.3 L *2, 5 V*2). The combined organic layer was washed with brine solution (8.2 L, 4.0 V), dried over anhydrous sodium sulfate and filtered.

[0345] Analytical data: Purity (HPLC): 99.5 %.

[0346] Step 2(b): Oxidation: Conversion of the compound of Formula V to the compound of Formula VI

[0347] A suspension of Dess-Martin periodinane (1.72 kg, 1.1 eq) in DCM (16.5 L, 8 V) was added to the organic layer of Step 2(a) (i.e. the compound of Formula III1) at 0-5 °C whilst stirring. The resulting reaction mixture (white suspension) was stirred at 10-15 °C for 3 h. The progress of the reaction was monitored by TLC (5 % MeOH / DCM + a drop of acetic acid; visualization: KMnO4 stain).

[0348] Work up:

[0349] After complete consumption of the compound of Formula V, the reaction mixture was quenched with 20 % sodium thiosulfate solution (20.6 L, 10 V) in purified water and stirred for 30 min (the reaction mixture became clear and a clear separation of the organic and aqueous layers was observed). The layers were separated, and the aqueous layer was extracted with DCM (10.3 L, 5.0 V). The combined organic layer was washed with brine solution (10.3 L, 5.0 V), dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated to 10.0 volume level with regards to the compound of Formula lai at below 40 °C.

[0350] Step 2(c): Ring formation: Conversion of the compound of Formula VI to the compound of Formula lb

[0351] To the organic layer of Step 2(b) (i.e. the compound of Formula IV1) was added N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC x HCI) (0. 702 kg, 1.0 eq.) followed by diisopropylethylamine (DIPEA) (0.957 L, 1.5 eq) at 10 °C ± 5 °C over a period of 30 min whilst stirring. The resulting reaction mixture was stirred at 10 °C ± 5 °C for 2 h. The progress of the reaction was monitored by TLC (10 % MeOH / DCM for starting material consumption and 80 % EtOAc / hexane for product elution; visualization: KMnO4 stain).

[0352] Work up:

[0353] After complete consumption of the compound of Formula VI, the reaction mixture was quenched with water (20.6 L, 10.0 V). The layers were separated, and the aqueous layer was extracted with DCM (10.3 L, 5.0 V). The organic layer was washed with brine solution (10.3 L, 5.0 V). The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and filtered. The combined organic layer was concentrated under reduced pressure at 40 °C until no distillate was observed.

[0354] Purification of the compound of Formula lb:

[0355] The crude product of the compound of Formula lb was charged with EtOAc (12.3 L, 6.0 V) at a temperature below 40 °C, concentrated to 3.0 vol level with regards to compound of Formula lb and stirred at 50 °C ± 5 °C for 1 h. The reaction mixture was gradually cooled to 25 °C ± 5 °C over 1 h and left to stir at 25 °C ± 5 °C for 6 h. The solid was collected by filtration and washed with EtOAc (2.1 L, 1.0 V) to obtain the wet solid of the compound of Formula lb (1.1 kg). The wet solid was dried under vacuum at 40°C ± 5 °C to afford the compound of Formula lb (0.85 kg) as a solid.

[0356] Analytical data: Purity (HPLC): 95.4 %.

[0357] Step 3: Synthesis of the compound of Formula la

[0358] Formula la

[0359] To a solution of the compound of Formula lb (obtained from both Steps 1 and 2 above) (322 g, 1.0 eq.) in dry dimethyl formamide (DMF) (1.6 L, 5.0 V) was added 4-N,N- dimethylaminopyridine hydrochloride (DMAP x HCI) (91 g) followed by isobutyryl chloride (92 g, 1.5 eq.) at 25 °C ± 5 °C. The reaction was heated to 60 °C ± 5 °C and stirred for 6 h. DMAP x HCI (45.6 g) was then added to the reaction followed by isobutyryl chloride (61.2 g, 1.0 eq.), and the reaction was continued for a further 4 h and monitored by HPLC.

[0360] Work up:

[0361] Once the reaction was complete, the reaction mixture was cooled to 25 °C ± 5 °C, filtered through a celite bed and washed with DMF (320 ml, 1.0 V). The filtrate was passed through a 0.2 pm cartridge and washed with DMF (320 ml, 1.0 V). Purified water (8.0 L, 25.0 V) was added to another reaction vessel and cooled to 15 °C ± 5 °C. The filtrate was then added slowly over a period of 1 h at 15 °C ± 5 °C (reverse quench). The reaction contents were allowed to attain a temperature of 25 °C ± 5 °C and left stirred for 4 h at the same temperature. The solid was collected by filtration and washed with purified water (0.65 L, 2.0 V). The wet solid was stirred with purified water (1.6 L, 5 V) at 40 °C ± 5 °C for 2 h then collected by filtration and washed with purified water (0.65 L, 2 V). The wet solid was dried under reduced pressure at 40 °C ± 5 °C for 12 h to afford the crude product of the compound of Formula la (456 g).

[0362] Analytical data: Purity (HPLC): 79.97 %.

[0363] Ethyl acetate purification:

[0364] Ethyl acetate slurry-1 : The crude product (456 g) was stirred with EtOAc (1.36 L, 3.0 V) at 50 °C ± 5 °C for 1 h. The reaction was gradually cooled to 25 °C ± 5 °C over 1 h and left to stir at 25 °C ± 5 °C for 4 h. The solid was collected by filtration and washed with EtOAc (0.45 L, 1.0 V).

[0365] Wet solid weight: 295 g, after LOD correction: 249 g (LOD: 15.6 % w / w). Purity by HPLC: 97.7% and impurities: RRT 0.68: 1.38%.

[0366] Ethyl acetate slurry-2: The crude product (249 g) was stirred with EtOAc (373 ml, 1.5 V) at 50 °C ± 5 °C for 1 h. The reaction was gradually cooled to 25 °C ± 5 °C over 1 h and left to stir at 25 °C ± 5 °C for 4 h. The solid was collected by filtration and washed with EtOAc (0.45 L, 1.0 V).

[0367] Wet solid weight: 236.6 g, after LOD correction : 230 g (LOD: 2.6 % w / w). Purity by HPLC: 98.68% and impurities: RRT 0.68: 1.38%.

[0368] Ethyl acetate slurry-3: The crude product (230 g) was stirred with EtOAc (460 ml, 2.0 V) at 50 °C ± 5 °C for 1 h. The reaction was gradually cooled to 25 °C ± 5 °C over 1 h and left to stir at 25 °C ± 5 °C for 4 h. The solid was collected by filtration and washed with EtOAc (115 ml, 1.0 V).

[0369] Wet solid weight: 191.6 g. Purity by HPLC: 99.8% and impurities: RRT 0.68: 0.12%.

[0370] The wet solids were dried under reduced pressure at 40 °C ± 5 °C for NLT 10 hours to afford the crude product of the compound of Formula la (185.4 g). Example 3: Synthesis of the monohydrate of Formula Illal

[0371] In this example, acetone / purified water purification took place in order to obtain the desired monohydrate form :

[0372] The crude product of the compound of Formula la (181.4 g) was stirred with acetone (1.3 L, 7.0 V) at 45 °C ± 5 °C for 30 min. to obtain a clear solution. Purified water (2.8 L, 15.0 V) was added to the reaction over 1 h and stirred for additional 1 h at 45 °C ± 5 °C. The reaction was gradually cooled (for NLT 1 h) to 25 °C ± 5 °C and stirred for 6 h. The solid was collected by filtration and washed with acetone / purified water (278 ml, 1.0 V) to afford the wet product of the monohydrate of the compound of Formula la, i.e., the monohydrate of Formula Illal (188 g). The wet solid was dried under reduced pressure at 40 °C ± 5 °C for NLT 16 h and sieved to afford of the monohydrate of Formula Illal (179 g).

[0373] Analytical data: Purity (HPLC): 99.9 %.

[0374] Specific optical rotation: -49. 8 °.

[0375] NMR data for the monohydrate of Formula Illal:

[0376] 1H-NMR (DMSO, 400 MHz): 8 8.64 (s, 1 H), 7.78 (s, 1 H), 6.75 (dd, 1 H), 5.09 (s, 1 H), 4.69 (s, 1 H), 3.92 (s, 1 H), 3.41 (s, 3H), 2.68 (m, 3 H), 2.35 (m, 2H), 2.24 (m, 3 5 H), 1.95 (m, 2 H), 1.67 (m, 1 H), 1.55 (d, 4 H), 1.42 (s, 3 H), 1.26 (d, 6 H), 1.18 (m, 1H), 1.04 (s, 1H), 0.76 (s, 3H) LCMS: 629.4 [M + H], HPLC purity: 98.50 %.

[0377] Co-micronization

[0378] In order to obtain a reasonable homogeneity of the feed material to the mill, it was pre-mixed manually prior to adding to the mill for the micronization process. The entire process consisted of several steps:

[0379] • 1 gram (g) Active Pharmaceutical Ingredient (API) and 4 g Lactose (Respitose SV003) were pre-mixed by first adding half the amount of Lactose, then the API and then the final amount of Lactose in a small stainless bowl.

[0380] • After careful mechanical mixing using a spoon, the material was sieved through a 1 mm mesh sieve twice and collected for further processing.

[0381] • To prevent a massive loss of material inside the mill, 1 g of pure Lactose was micronized using identical settings as below for the micronization pressures prior to micronization of the mixture. Thus, internal surfaces were "saturated" by micronized material whilst excluding a major loss of active ingredient.

[0382] • The outlet parts of the mill were then carefully mechanically cleaned from excess Lactose particles.

[0383] • The actual micronization of the mixed material, API:Lactose, (1 :4), was performed with a fluidized jet mill (2.5" radius Titanium nitride coated jet mill; Airfilco Jet Mill). Approximately 5g of substance mixture were fed into the milling chamber by use of a vibrating chute and using an ejector pressure of 4 Bar (Nz(g)) . Inside the chamber a similar gas flow (nitrogen) of 2 Bar (milling pressure) caused the particles to collide with each other and the walls, producing particle fragments and then resulting in overall smaller particles. Once the particles had obtained a sufficiently small particle size, they were able to pass through the classifier and were then collected in a glass jar. A feeding rate of 0.85 g / min was used and the yield was 90%, which is considered very high. Hence, about 4.5g of co-micronized API and Lactose was obtained and collected.

[0384] The co-micronized material was characterized by means of laser diffraction. A Malvern Mastersizer 3000 instrument, with a 300mm reverse Fourier lens and Hydro MV sample dispersion unit was used. The micronized material was introduced directly into the Hydro MV unit. The sample dispersion medium was deionized water. As lactose dissolved in the dispersion unit and obscuration stabilized, measurements were taken until a stable reading was obtained. A few drops of Polysorbate 20 were added, which shifted the distribution towards lower values. Sonication decreased this reading further. After sonication a tendency towards reagglomeration was noticed but this dispersed again when sonicated again reaching the same value as before. The measurements were done using the following settings; Background measurement time: 20s, Sample measurement time: 20s, Dispersant refractive index: 1.33, Analysis model: General purpose, Particle refractive index: N / A (Fraunhofer), Absorption : N / A (Fraunhofer), Stirrer speed: 2500 rpm, Sonication: 20% power for 1 minute. The results show that the percentiles of the volume-based distribution were as follows after co-micronization, D(v, 0.1) =0.8pm means that 10% of the size distribution based on volume has a diameter of 0.8 pm or less. In the same way D(v, 0.5)= 2.4pm means that 50% of the size distribution based on volume has a diameter of 2.4 pm or less. And D(v, 0.9) = 6.5 pm means that 90% of the size distribution based on volume has a diameter of 6.5 pm or less.

[0385] D(v, 0.1) / pm D(v, 0.5) / pm D(v, 0.9) / pm

[0386] 0.8 2.4 6.5

[0387] The co-micronization thus resulted in particles of API / lactose of micrometer scale. The API for the co-micronization was the compound SAE5, i.e. the compound of Formula la as defined herein.

[0388] Spray-drying

[0389] For spray-drying a Niro Mobile Minor Spray Dryer w / chamber extensions with Spraying Systems 40100 / 120 two-fluid nozzle was used together with a Budzar Chiller. An amount of 0.147 kg API was slowly added to 1kg methanol during gentle vortexing. When no particles were visible, 0.42kg HPMC AS-M was added and gently vortexed until no particles were visible (3 hours 29 min). The obtained mixture was then spray- dried at a target feed rate of 6 kg / hour, a drying gas flow rate of 80 kg / hour and an atomization pressure of 28 Psi. The target inlet temperature was 93°C while the target outlet temperature was 40°C. The material was collected in low-density polyethylene (LDPE) bags and transferred to line tray drier trays where the material was evenly distributed on trays with a depth not exceeding 2.5 cm. The tray was then dried at 40°C for at least 8 hours until the levels of residual solvents were acceptable. The limit was < 600 ppm for dichloromethane and < 3000 ppm for methanol, according to a method using gas chromatography with static headspace as per European pharmacopeia standard: PhEur 2.4.24. The material was subsequently dispensed into LDPE bags. The API for spray-drying was the monohydrate denominated LIB-01, i.e. the monohydrate of Formula Illa 1 as described herein.

[0390] Subcutaneous suspension:

[0391] The procedure described below was followed to prepare the test item suspension using 19.2% API co-micronized with lactose. All procedures were performed in a biosafety cabinet. Test item, 3.125 g of API co-micronized with lactose, was added to 150 mL sterile vehicle (1% HPMC and 0.1% Trimethylolpropane ethoxylate (TPEG)) in an ambercoloured sterile container during stirring until no visible lumps were observed. The resulting stock formulation had a concentration of 4 mg / mL of SAE5 and was used without dilution or was diluted to 2.5 mg / mL or 1.5 mg / mL of SAE5 by addition of sterile vehicle to achieve the required concentration. The API was the compound SAE5, i.e. the compound of Formula la as described herein.

[0392] Oral suspension:

[0393] Procedure A: The API for this procedure was the monohydrate denominated LIB-01, i.e. the monohydrate of Formula Illal as described herein. Vehicle (0.1% w / v HPMC) was prepared by adding ultrapure water type-1 (as defined by the American Society for testing and Materials (ASTM)), 1000 mL, to a schott bottle equipped with a stir bar and heated to 65 ± 5 °C on a magnetic stirrer plate. 1.0000 g of HPMC (Methocel™ Hydroxypropyl methylcellulose K100 Premium LV) was added gradually while stirring to prepare a 0.1% (w / v) solution. The powder was dispersed within a few minutes. The solution was then removed from heating and kept refrigerated for at least overnight without stirring, resulting in fully dissolved HPMC. Test item (25% API on HMPC AS-M prepared by spray drying as described above) was weighed and transferred to an adequately sized mortar [1016.25 mg, 2032.50 mg and 4878.00 mg for low dose, mid dose and high dose separately]. Vehicle (0.1% w / v of HPMC) was slowly added in a dropwise manner under thorough mixing using a pestle to form a wet paste, until 50-70% of the total volume was reached. The remaining volume of vehicle was added slowly with thorough pestle mixing until the paste formed a suspension. Any powder collected on the pestle was scraped off and rinsed with suspension vehicle into the mortar to obtain a homogenous suspension. Vehicle as added to a total volume of 25 mL and dose formulation strengths of 10 mg / mL (Low dose), 20 mg / mL (Mid dose) and 48 mg / mL (High dose) of API. The suspension was transferred to an appropriately sized glass container with a stir bar and placed on a stirrer plate for the duration of the administration.

[0394] Procedure B: The API for this procedure was the monohydrate denominated LIB-01, i.e. the monohydrate of Formula Illa 1. SyrSpend® SF PH4 was poured into a medicine cup (30 ml). With a 20 ml syringe, 25 ml of SyrSpend® SF PH4 (draw 2 times) was added to the bottle containing powder for suspension (25% API in HMPC AS-M or 100% HMPC AS-M) and the mixture was stirred for 30 seconds using a medicine spoon. The bottle was closed with a cap and shaken for 30 seconds. The content was visually checked to confirm that the preparation was homogeneous, there should be no lumps in it. If it was not mixed properly, it was shaken again. The final suspension was used within 2 hours.

[0395] The study drug was an oral suspension composed of LIB-01 powder for oral suspension (25% of API in HPMC AS-M) and vehicle: SyrSpend® SF PH4. The study drug was supplied in bottles containing 100 mg powder for suspension, corresponding to 25 mg API. The placebo oral suspension was composed of placebo powder for oral suspension (100% HPMC AS-M) and vehicle: SyrSpend® SF PH4 (a commercially available cellulose-based vehicle for reconstitution of powders). Placebo was supplied in bottles containing 100 mg HPMCAS-M powder for suspension.

[0396] Nonclinical in vivo studies

[0397] The formulation comprising co-micronized API (for subcutaneous administration) or spray-dried API on HMPC (for oral administration), as described above, was administered to male Sprague-Dawley rats (strain CD (SD) IGS), aged 6-7 weeks at the initiation of the study. The animals were housed in standard laboratory conditions, fed ad libitum throughout the acclimatization and experimental period (except for a period of fasting at the end of the study). Water was provided ad libitum throughout the acclimatization and experimental period. Randomization was performed based on stratified body weights. Dose volume was calculated based on the most recent nonfasted body weight. The animals were administered a dose volume of 10 mL / kg body weight (subcutaneous route) or 5 mL / kg / body weight (oral route). Control group animals were administered only vehicle at the corresponding volume.

[0398] The test item was administered by subcutaneous or oral route for a period of 28 or 14 days, including groups with withdrawal of the test item during a recovery period of 14 days (subcutaneous route) or 5 weeks (oral route). The animals were observed daily for signs of toxicity, and at the end of the in-life phase the animals were euthanized and necropsied.

[0399] Body Weights

[0400] Non-fasted body weight was recorded on the last day of acclimatization, first day of treatment prior to dosing (day 1), and weekly thereafter. Fasted body weight was recorded on the last day of the study. It will be appreciated that, since the rats were only 6-7 weeks old at the initiation of the study, a progressive increase in body weight was expected over the course of the study due to normal growth and development associated with their age. Feed Consumption

[0401] Feed consumption was recorded. Feed input (offered) and feed leftover (output) were recorded each time feed was offered except on day 1 and the last day of the study period. The cage wise weekly average feed intake (g / animal / day) was calculated.

[0402] Haematology and clinical chemistry

[0403] Blood samples were collected for hematology and clinical chemistry and evaluation. Blood was collected from retro-orbital plexus with a fine capillary tube under mild isoflurane anesthesia. About 1 mL of blood was collected into tubes containing K2EDTA solution (~2 mg / mL of blood) for hematology analysis and about 2.0 mL of blood into tubes containing lithium heparin (~20 lU / mL blood) for clinical chemistry parameter analysis. Blood (hematology) and plasma (clinical chemistry) samples were stored in crushed ice until analysis. Plasma samples were harvested by centrifuging the blood samples at 4000 rpm for 10 minutes at 4±2°C. Hematology parameters were analyzed using ADVIA 2120 (Siemens Limited) Hematology analyzer. Clinical chemistry parameters were analyzed using Dimension Xpand Plus clinical chemistry analyzer.

[0404] Example 4A: Subcutaneous administration for 28 consecutive days

[0405] The formulation was the suspension of co-micronized API described above. The formulation was administered to six groups of male Sprague-Dawley rats in dose levels of 15, 25 and 40 mg / kg body weight (b.w.) as shown in Table 2. The dose level refers to mg of API per kilo body weight of the rat (i.e. mg / kg b.w.). The volume being injected (i.e. the dose volume) was 10 mL. The formulation was administered by subcutaneous route once a day for 28 consecutive days. For the recovery groups, G1R and G4R, the administration of the formulation was withdrawn from day 28 to day 42 and monitoring was continued during this time.

[0406] Table 2: Subcutaneous administration for 28 consecutive days The results are shown in Figures 1-4. Figure 1 shows that the subcutaneous administration for 28 days resulted in a dose dependent decrease in fasting glucose on day 28. Figure 2 shows that subcutaneous administration resulted in a dose dependent decrease in cholesterol levels on day 28. Figure 3 shows that subcutaneous administration for 28 days resulted in a dose dependent attenuation in weight gain for the rats treated with API. This attenuation in weight gain indicates a weight loss as the rats in the absence of API were expected to increase more in body weight over the course of the study due to their normal growth and development. Figure 4 shows that food intake was reduced in rats exposed to API and that the effect remained during the recovery period. The rats who were exposed to API also continued to show a lower food intake during the recovery period when compared to vehicle treated control rats. The reduction in food intake indicates that the API provides appetite regulation allowing for reduction of the appetite.

[0407] Example 4B. Subcutaneous administration for 14 consecutive days

[0408] This experiment was performed in the same way as described for Example 4A. However, the suspension was administered for 14 consecutive days instead of 28 consecutive days.

[0409] Table 3: Subcutaneous administration for 14 consecutive days

[0410] The results are shown in Figures 5 and 6. As shown in Figure 5, subcutaneous administration for 14 consecutive days resulted in a decrease in cholesterol at the highest dose (40 mg / kg b.w.). Figure 6 shows that subcutaneous administration for 14 days resulted in an attenuation in weight gain for the rats treated with API compared to rats treated with vehicle. This attenuation in weight gain indicates a weight loss as the rats in the absence of API were expected to increase more in body weight over the course of the study due to their normal growth and development. Example 5: Oral administration for 14 consecutive days

[0411] The oral formulation was prepared as described in procedure A above and administered to six groups of male Sprague-Dawley rats, as shown in Table 4, in dose levels of 50, 100 and 240 mg / kg b.w. BID. The dose volume being provided to the animals was 5 mL / kg b.w. of oral suspension. The oral suspension was administered by oral gavage twice a day for 14 consecutive days. The oral formulation was withdrawn from day 15 to day 49 in the recovery groups G1R and G4R, and monitoring continued during this time.

[0412] Table 4: Oral administration for 14 consecutive days

[0413] The results are shown in Figures 7-9. Figure 7 shows that oral administration in norma SD rats for 14 days resulted in a decrease in fasting glucose on day 14, which was significant for two of the three dose levels (2x50 mg / kg and 2x240 mg / kg) when compared to control rats. Figure 8 shows that the rats treated with API for 14 days followed by a treatment-free recovery period of 35 days (49 days in total) gained less weight than the rats who had received vehicle. The difference was statistically significant (p<0.05) at all timepoints. This attenuation in weight gain indicates a weight loss as the rats in the absence of API were expected to increase more in body weight over the course of the study due to their normal growth and development Figure 9 shows that food intake was reduced in rats exposed to API and that the effect remained during the recovery period. The rats who were exposed to API also continued to show a reduced food intake during the recovery period, when compared to control rats. The reduction in food intake indicates that the API provides appetite regulation allowing for reduction of the appetite.

[0414] Example 6: Clinical trial

[0415] Part II of a first-in-human clinical trial explored multiple ascending dosing (MAD) of API. The initial dose, dose escalation and dosing schedule was based on emerging knowledge of safety, tolerability and PK of API observed in the single ascending dosing (SAD) part of the trial (Part I). The starting dose was 25 mg once daily (OD) for 3 days.

[0416] The study drug was administered once daily for 3 days. Each dose level during the Part II was selected such that the predicted maximum exposure at steady state (in terms of maximum observed concentration [Cmax] and area under the curve over the dosing interval [AUCtau]) would not exceed the maximum exposure (in terms of Cmax and AUC from 0 to infinity [AUCinf]) established as safe and tolerable in previously evaluated single dosing cohorts.

[0417] The study drug was administered in 3 sequential cohorts of 8 participants each. Within each cohort, participants were randomised in a 3: 1 ratio to receive either API (n = 6) or a matching placebo (n = 2). The participants were men aged 18-65 with BMI 20-30, who experienced erectile dysfunction, and were medically healthy without abnormal clinically significant medical history, physical findings, vital signs, electrocardiogram (ECG) or laboratory values.

[0418] The participants attended 6 visits to the trial site. Screening (Visit 1) took place from Day -28 to Day -1.

[0419] At Visit 2, participants were admitted to the site on Day -1 and remained at the trial site until Day 4 for multiple dose administrations, safety, pharmacokinetic (PK), pharmacodynamic (PD) and exploratory safety and efficacy assessments. The participants fasted for at least 10 hours before the dosing on Days 1 and 3, and 1 hour on Day 2. Water, but no other drinks, were allowed as desired except for 1 hour before and 1 hour after dosing. Participants were served standardised meals while they were in the trial site.

[0420] The first 2 participants in each cohort were dosed in a sentinel fashion (i.e. sequentially within the period of observation); 1 participant received API and the other received placebo as randomised. The participants were carefully monitored by clinical staff during and after dosing. Vital signs and ECG were checked at regular intervals. There was at least 48 hours until dosing of the next group of participants. The remaining 6 participants in the cohort were dosed in groups of 3 (at least 10 minutes apart) with at least 24 hours between the groups. The participants left the site after completion of all 24-hour post last dose assessments in the morning of Day 4.

[0421] In all cohorts, safety, tolerability, PK and PD were assessed before and after dose.

[0422] At Visits 3, 4 and 5 (Days 7, 14 and 21), the participants returned to the trial site for follow-up assessments of safety, tolerability and PD. A final end-of-trial visit (Visit 6) took place on Day 28. The final end-of-trial visit included follow-up assessments of safety, tolerability, PD and exploratory efficacy.

[0423] Example 7: Oral administration for 3 consecutive days

[0424] The oral suspension was prepared as described in procedure B above and administered to male subjects, participating in the above clinical trial, at dose levels of 25 mg once daily (OD), 25 mg twice daily (BID), 50 mg OD of API, or corresponding placebo, for three consecutive days (Day 1-3). The subjects were followed and monitored for safety (adverse events, vital signs, clinical chemistry, haematology, ECG) during 28 days from the first dose.

[0425] Table 5: Oral administration for 3 consecutive days

[0426] The results are shown in Figures 10-11. Figure 10 shows that oral administration of API at 25 mg once daily for three consecutive days resulted in reduced systolic blood pressure (SBP) up to 21 days from the first dose. The last dose of API was administered on day 3, whereas the decreased SBP continued for 18 days post last dose. The decrease in SBP was significant (using Student's t-test [2-tailed]) on days 7 (p<0.005) and 21 (p<0.05) when compared to placebo. Figure 11 shows that administration of API at 25 mg once daily resulted in decreased diastolic blood pressure (DBP) up to 21 days from the first dose and 18 days post last dose. In contrast to SBP, the decrease in DBP was not significant during this period. On day 28, both SBP and DBP had returned to the predose values. It was concluded that administration of the compound of Formula I, or a stereoisomer or hydrate thereof, allows for reducing the blood pressure such as the systolic blood pressure.

[0427] Example 8: Impact on cholesterol

[0428] Preparation of sterile vehicle

[0429] 1% Hydroxypropyl methylcellulose (HPMC) + 0.1% a-Tocopherol-Polyethylene glycol- Succinate (T-PEG)

[0430] The preparation was performed as follows:

[0431] 1. 1 g of T-PEG was dissolved in 600 ml of water 2. 10 g of HPMC was added slowly during intense stirring so that formation of lumps was avoided.

[0432] 3. When the HPMC had become finely dispersed : water was added to result in a final volume of 1 liter.

[0433] 4. Stirring was continued at a temperature of 2-8 °C for at least 16 hours to provide a crude vehicle preparation.

[0434] 5. The crude vehicle preparation was subjected to sterile filtering using a 0.2 pm sterile filter to provide the vehicle in a sterile container.

[0435] Preparation of LIB-01 microsuspension

[0436] LIB-01 formulated in microsuspension at 4 mg / ml was prepared according to the procedure below, using 19.2% co-micronized LIB-01 with lactose, and prepared as described herein. X stands for the volume of the microsuspension being prepared.

[0437] 1. Weigh in X*20.8 mg of LIB-01 co-micronized with lactose

[0438] 2. X ml of the sterile vehicle was added to a sterile container.

[0439] 3. The LIB-01 co-micronized with lactose was added to the vehicle during stirring without introducing air (to avoid foaming) into the suspension, until no visible lumps were observed in the resulting microsuspension.

[0440] 4. Aliquots of the microsuspension were dispensed into amber sterile containers.

[0441] The LIB-01 microsuspension having a concentration of 4 mg / ml was prepared at the beginning of the study, dispensed in aliquots for one week's use each and subsequently stored at -20°C. Upon use, the vial was defrosted in a fridge at 5°C. Once defrosted, the vial was inverted 10 times or more until no sediment could be observed at the bottom of the vial and an even microsuspension obtained. No ultrasonic or vortex mixer were applied, to avoid the surfactant vehicle components to foam. The content of the defrosted vial was dispensed in aliquots for each dosing day and re-freezed at -20°C.

[0442] The volume of administration used was 4 ml / kg, in line with good practice for subcutaneous administration volume in rat (<5ml / kg), depending on the dose as follows:

[0443] 8 mg / kg dose: LIB-01 suspension of 4 mg / ml was diluted to 2 mg / ml and administered at 4 ml / kg.

[0444] The vehicle was administered at 4 ml / kg.

[0445] Experiment

[0446] The experiment was conducted in normal Wistar rats and Goto-Kakizaki (GK) rats. The GK rat is a model for type 2 diabetes, with a genetic predisposition for dyslipidemia. The Wistar rats were used as a control animals. Adult male Wistar rats (Elevage Janvier, Le Genest-St-Isle, France, 18-week-old) and age-matched male GK rats (Metabrain, Maisons-Alfort, France, 17-22 week-old) were housed at least 10 days prior to the beginning of the experiments with free access to appropriate diet and water and maintained on an inversed 12 hour dark / light cycle (7:00 / 19:00). All procedures were performed in accordance with the legislation on the use of laboratory animals .

[0447] Rats were weighed and randomized into study groups for comparable mean body weight between study groups. There were 12 rats in each group.

[0448] GK rats received subcutaneous administration of the microsuspension of LIB-01 at 8 mg / kg / day or vehicle for 3 consecutive days, or LIB-01 at 8 mg / kg / day for 7 consecutive days. Wistar rats received subcutaneous administration of vehicle for 3 consecutive days.

[0449] After the treatment period, blood collection from the rats took place and the blood was analysed with respect to cholesterol (including total cholesterol, low-density cholesterol (LDL), and high-density cholesterol (HDL)). A reduction in all cholesterol parameters was observed at 24 hours post last administration in GK rats treated with LIB-01 at 8 mg / kg for 3 or 7 days, when compared to GK rats treated with vehicle as shown in Figures 12A, 12B and 12C. Figure 12A shows that the total cholesterol level (i.e. the cholesterol level including both HDL and LDL cholesterol) decreased after 3 days and 7 days of treatment. Figure 12B shows that the level of HDL cholesterol decreased after 3 days and 7 days of treatment. Figure 12C shows that the level of LDL cholesterol was reduced after 3 days and 7 days of treatment. In the 7-day treatment groups, a statistically significant reduction in total cholesterol (p=0.001) and high- density cholesterol (p=0.007) was found, when compared to vehicle treated GK rats. Data from normal Wistar rats was included for reference, representing non- dyslipidemic animals.

[0450] In conclusion, administration of LIB-01 allowed for reducing the blood level of total cholesterol. Further, lowering of HDL cholesterol was also observed.

Claims

Claims1. A compound of Formula I:or a stereoisomer thereof, or a hydrate thereof whereinR1is Ci-Cealkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, and R2and R3are independentlyH, orC(O)Ci-C6alkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, for use in the treatment and / or prevention of a metabolic disease or disorder.

2. Use of a compound of Formula I:or a stereoisomer thereof,or a hydrate thereof whereinR1is Ci-Cealkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, andR2and R3are independentlyH, orC(O)Ci-C6alkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, for the manufacture of a medicament for the treatment and / or prevention of a metabolic disease or disorder.

3. A method for the treatment and / or prevention of a metabolic disease or disorder, said method comprising administering to a patient, such as a human or animal, in need thereof, an effective amount, such as a therapeutically effective amount, of a compound of Formula I:or a stereoisomer thereof, or a hydrate thereof, whereinR1is Ci-Cealkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I, andR2and R3are independentlyH, orC(O)Ci-Cealkyl optionally substituted with one or more substituents selected from the group consisting of OH, Cl, Br, F and I.

4. The compound for use according to claim 1, or the use according to claim 2, orthe method according to claim 3 wherein R1is methyl, R2is isopropyl and R3is hydrogen thereby providing a compound of Formula la:Formula la or a stereoisomer thereof, or a hydrate thereof.

5. The compound for use according to claim 1, the use according to claim 2, or the method according to claim 3 wherein R1is methyl, and R2and R3are both hydrogen thereby providing a compound of Formula lb:Formula lb or a stereoisomer thereof, or a hydrate thereof.

6. The compound for use according to claim 1, 4 or 5, or the use according to claim 2, 4, or 5, or the method according to claim 3, 4 or 5 wherein the compound of Formula I, or stereoisomer thereof, is provided as a hydrate of Formula III:Formula III said hydrate being a combination of a compound of Formula I and water:wherein R1, R2and R3are as defined in any one of claims 1-5 in a molar ratio of l:n, wherein n is a number such as an integer from 1 to 10.

7. The compound for use according to claim 6, or the use according to claim 6, or the method according to claim 6 wherein n is 1 thereby providing a monohydrate of Formula III1 :Formula III1 said monohydrate being a combination of a compound of Formula I and waterwherein R1, R2and R3are as defined in any one of claims 1-6, taken in a molar ratio of 1 : 1.

8. The compound for use according to any one of claims 1 or 4-7, or the use according to any one of claims 2 or 4-7, or the method according to any one of claims 3-7 wherein the compound of Formula I is provided as a stereoisomer of Formula II or Formula II prime:Formula II Formula II prime wherein R1, R2and R3are as defined in any one of claims 1-7.

9. The compound for use according to any one of claims 1 or 4-8, the use according to any one of claims 2 or 4-8, or the method according to any one of claims 3-8 wherein the treatment and / or prevention of a metabolic disease or disorder is one or more of the following : the treatment and / or prevention of metabolic syndrome, the treatment and / or prevention of obesity, the treatment and / or prevention of type 2 diabetes, the treatment and / or prevention of prediabetes, the treatment and / or prevention of cardiovascular disease, the lowering of, or prevention of increase in, triglyceride and / or cholesterol levels, the treatment and / or prevention metabolic dysfunction-associated steatotic liver disease (MASLD), the treatment and / or prevention of dyslipidemia, the treatment and / or prevention of gout, the lowering of, or prevention of increase in, body adipose tissue.

10. The compound for use according to any one of claims 1 or 4-9, the use according to any one of claims 2 or 4-9, or the method according to any one of claims 3-9 wherein the treatment and / or prevention of a metabolic disease or disorder is one or more of the following: the treatment and / or prevention of metabolic syndrome, the treatment and / or prevention of obesity, the treatment and / or prevention of type 2 diabetes, the treatment and / or prevention of prediabetes,the treatment and / or prevention of cardiovascular disease, the treatment and / or prevention metabolic dysfunction-associated steatotic liver disease (MASLD), the treatment and / or prevention of dyslipidemia, the treatment and / or prevention of gout.

11. The compound for use according to any one of claims 1 or 4-10, the use or any one of claims 2 or 4-10, or the method according to any one of claims 3-10 wherein the metabolic disease or disorder is associated with a pathological blood glucose level.

12. The compound for use according to any one of claims 1 or 4-11, the use according to any one of claims 2 or 4-11, or the method according to any one of claims 3-11, wherein the treatment and / or prevention of the metabolic disease or disorder involves blood glucose lowering.

13. The compound for use according to claim 11 or 12, the use according to claim 11 or 12, or the method according to claim 11 or 12 wherein the metabolic disease is one or more of the following: metabolic syndrome, obesity, type 2 diabetes, prediabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular disease.

14. The compound for use according to any one of claims 1 or 4-13, the use according to any one of claims 2 or 4-13, or the method according to any one of claims 3-13 wherein the metabolic disease or disorder is metabolic syndrome.

15. The compound for use according to any one of claims 1 or 4-13, the use according to any one of claims 2 or 4-13, or the method according to any one of claims 3-13 wherein the metabolic disease or disorder is obesity.

16. The compound for use according to any one of claims 1 or 4-13, the use according to any one of claims 2 or 4-13, or the method according to any one of claims 3-13wherein the metabolic disease or disorder is type 2 diabetes.

17. The compound for use according to any one of claims 1 or 4-13, the use according to any one of claims 2 or 4-13, or the method according to any one of claims 3-13 wherein the metabolic disease or disorder is prediabetes.

18. The compound for use according to any one of claims 1 or 4-13, the use according to any one of claims 2 or 4-13, or the method according to any one of claims 3-13 wherein the metabolic disease or disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

19. The compound for use according to any one of claims 1 or 4-13, the use according to any one of claims 2 or 4-13, or the method according to any one of claims 3-13 wherein the metabolic disease or disorder is cardiovascular disease.

20. The compound for use according to claim 19, the use according to claim 19, or the method according to claim 19 wherein the cardiovascular disease is selected from the group consisting of coronary heart disease, stroke, peripheral arterial disease, aortic disease, endothelial dysfunction and hypertension.

21. The compound for use according to any one of claims 1 or 4-10, the use according to any one of claims 2 or 4-10, or the method according to any one of claims 3-10 wherein the metabolic disease or disorder is not associated with a pathological blood glucose level.

22. The compound for use according to any one of claims 1, 4-10 or 21, the use according to any one of claims 2, 4-10 or 21, or the method according to any one of claims 3-10 or 21 wherein the treatment and / or prevention of the metabolic disease or disorder comprises or consists of the lowering of, or prevention of increase in, triglyceride and / or cholesterol levels, and / or the lowering of, or prevention of increase in, body adipose tissue.

23. The compound for use according to claim 21 or 22, the use according to claim 21 or 22, or the method according to claim 21 or 22, wherein the treatment and / or prevention of a metabolic disease or disorder is the lowering of, or prevention of increase in, triglyceride levels.

24. The compound for use according to claim 21 or 22, the use according to claim 21 or 22, or the method according to claim 21 or 22 wherein the treatment and / or prevention of a metabolic disease or disorder is the lowering of, or prevention of increase in, cholesterol levels.

25. The compound for use according to any one of claims 1, 4-10 or 21, the use according to claims 2, 4-10 or 21, or the method according to claims 3-10 or 21 wherein the metabolic disease or disorder is dyslipidemia.

26. The compound for use according to 1, 4-10 or 21, the use according to claims 2, 4-10 or 21, or the method according to claims 3-10 or 21 wherein the metabolic disease or disorder is gout.

27. The compound for use according to claim 21 or 22, the use according to any one of claim 21 or 22, or the method according to any one of claim 21 or 22 wherein the treatment and / or prevention of the metabolic disease or disorder is the lowering of, or prevention of increase in, body adipose tissue.

28. The compound for use according to any one of claims 1 or 4-27, the use according to any one of claims 2 or 4-27, or the method according to any one of claims 3-27, wherein the treatment and / or prevention of the metabolic disease or disorder comprises or consists of weight reduction.

29. The compound for use according to any one of claims 1 or 4-28, the use according to any one of claims 2 or 4-28, or the method according to any one of claims 3-28wherein the treatment and / or prevention of a metabolic disease or disorder comprises or consists of appetite regulation.

30. The compound for use according to any one of claims 1 or 4-29, the use according to any one of claims 2 or 4-29, or the method according to any one of claims 3-29 wherein the metabolic disease or disorder does not comprise type 1 diabetes.

31. The compound for use according to any one of claims 1 or 4-30, the use according to any one of claims 2 or 4-30, or the method according to any one of claims 3-30 wherein the compound is administered to a human.

32. The compound for use according to any one of claims 1 or 4-31, the use according to any one of claims 2 or 4-31, or the method according to any one of claims 4-31 wherein the compound is administered to a patient such as a human suffering from obesity and / or having a body mass index (BMI) equal to or above 25, such as from 25 to 30, such as equal to or above 30, such as from 30 to 35, such as equal to or above 35, such as from 35 to 40.

33. The compound for use according to any one of claims 1 or 4-32, the use according to any one of claims 2 or 4-32, or the method according to any one of claims 4-32 for use in the treatment of a metabolic disease or disorder.

34. The compound for use according to any one of claims 1 or 4-32, the use according to any one of claims 2 or 4-32, or the method according to any one of claims 4-32 for use in the treatment and prevention of a metabolic disease or disorder.

35. The compound for use according to any one of claims 1 or 4-32, the use according to any one of claims 2 or 4-32, or the method according to any one of claims 4-32 for use in the prevention of a metabolic disease or disorder.

36. The compound for use according to claim 34 or 35, the use according to claim 34 or 35, or the method according to claim 34 or 35 wherein the compound is administered to a subject such as a human at risk of developing a metabolic disorder.

37. A pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, as defined in any one of claims 1-8 in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent for use in the treatment and / or prevention of a metabolic disease or disorder as defined in any one of the preceding claims.

38. Use of a pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, as defined in any one of claims 1-8 in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent for the manufacture of a medicament for the treatment and / or prevention of a metabolic disease or disorder as defined in any one the preceding claims.

39. A method for the treatment and / or prevention of a metabolic disease or disorder as defined in any one of the preceding claims, said method comprising administering to a patient, such as a human or animal in need thereof, an effective amount, such as a therapeutically effective amount, of a pharmaceutical composition comprising the compound of Formula I, or a stereoisomer or hydrate thereof, as defined in any one of claims 1-8 in admixture with a pharmaceutically acceptable, excipient, carrier and / or diluent.

40. The pharmaceutical composition for use according to claim 37, the use according to claim 38, or the method according to claim 39 wherein the composition is formulated for subcutaneous administration.

41. The pharmaceutical composition for use according to claim 37, the use according to claim 38, or the method according to claim 39 wherein the composition is formulated for oral administration.

42. The pharmaceutical composition for use according to any one of claims 37, 40 or41, the use according to any one of claims 38, 40 or 41, or the method according to any one of claims 39-41 wherein the pharmaceutical composition is administered to a human.

43. The pharmaceutical composition for use according to any one of claims 38 or 41-42,the use according to any one of claims 39 or 41-42, or the method according to any one of claims 40-42 wherein the pharmaceutical composition is administered to a patient suffering from obesity and / or having a body mass index (BMI) equal to or above 25, such as from 25 to 30, such as equal to or above 30, such as from 30 to 35, such as equal to or above 35, such as from 35 to 40.

44. A dietary supplement for oral consumption comprising the compound of Formula I as defined in any one of claims 1-8 and optionally one or more of the following: vitamin(s), mineral(s), herb(s), amino acid(s), enzyme(s), preservative(s), sweetener(s), flavouring(s), fragrance(s) and / or colorant(s).

45. The dietary supplement according to claim 44, which is provided as one or more of the following: powder, pill, capsule, tablet, a gel, a liquid preparation such as a syrup, suspension or solution.

46. The dietary supplement according to claim 44 or 45 provided together with food, feed or beverage.

47. The dietary supplement according to claim 46, which is provided as a kit of parts comprising:(i) the dietary supplement,(ii) food, feed or beverage, and(iii) optionally instructions for use such as instructions for mixing (i) and (ii).

48. The dietary supplement according to claim 47, which is provided as food, feed or beverage comprising the dietary supplement.

49. A non-therapeutic method for weight management such as weight reduction, weight stabilization and / or prevention of weight gain in a subject, said method comprising administering a compound of Formula I as defined in any one of claims 1-8, a pharmaceutical composition as defined in any one of claims 37, 40 or 41, or a dietary supplement according to any one of claims 44-46 to the subject.

50. The non-therapeutic method according to claim 49, wherein the weight management is weight reduction.

51. A non-therapeutic method of blood glucose management such as blood glucose stabilization or blood glucose lowering in a subject, said method comprising administering a compound of Formula I as defined in any one of claims 1-8, a pharmaceutical composition as defined in any one of claims 37, 40 or 41, or a dietary supplement according to any one of claims 44-46 to the subject.

52. A non-therapeutic method of blood lipid management such as blood triglyceride lowering or blood cholesterol lowering in a subject, said method comprising administering a compound of Formula I as defined in any one of claims 1-8, a pharmaceutical composition as defined in any one of claims 37, 40 or 41, or a dietary supplement according to any one of claims 44-46 to the subject.

53. The non-therapeutic method according to claim 52, wherein the blood lipid management is blood cholesterol lowering.

54. A non-therapeutic method of appetite regulation, said method comprising administering a compound of Formula I as defined in any one of claims 1-8, a pharmaceutical composition as defined in any one of claims 37, 40 or 41, or a dietary supplement according to any one of claims 44-46 to the subject.

55. The non-therapeutic method according to claim 53, wherein the appetite regulation is appetite reduction and / or reduction of craving(s).

56. The non-therapeutic method according to any one of claims 49-55, wherein the subject is a human or animal.

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