Crystalline forms of (R)-2-(TERT-butylamino)-1-(5-fluoropyridin-3-yl)-ethan-1-ol hemitartrate for the treatment of hyperglycemia and type 2 diabetes

Abstract

The present invention discloses a crystalline form of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethanol (formula (I)) hemi-(2R,3R)-tartrate salt, characterized by a melting point of 211° C. and the XRPD pattern of FIG. 1. The present invention also relates to said hemitartrate salt for use in the treatment of hyperglycemia and type 2 diabetes by activation of beta 2-adrenergic receptors. Importantly, such salts do not exert their effect via significant cAMP release and are therefore believed to have a beneficial side effect profile. [Formula 1] TIFF2024544698000021.tif42125

Description

[Technical field]

[0001] The present invention relates to novel salts and compositions and their use in the treatment of hyperglycemia and disorders characterized by hyperglycemia, such as type 2 diabetes. In particular, the present invention relates to novel salts and compositions comprising β 2 The present invention relates to novel salts, compositions and methods for treating conditions such as type 2 diabetes mellitus via activation of -adrenergic receptors. Importantly, such salts do not exert their effect via significant cAMP release and are therefore believed to have a beneficial side effect profile. [Background technology]

[0002] The listing or discussion of a 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.

[0003] Hyperglycemia, or hyperglycemia, is a condition in which an excessive amount of glucose circulates in the blood plasma. If left untreated, hyperglycemia can become a serious problem and can develop into life-threatening conditions such as ketoacidosis. For example, chronic hyperglycemia can cause damage to the heart and is strongly associated with heart attacks and death in subjects without a history of coronary heart disease or heart failure. The causes of hyperglycemia are manifold, including diabetes and severe insulin resistance.

[0004] Severe insulin resistance (SIR) is a condition in which patents suffer from a very low level (or, in extreme cases, insignificant) response to insulin. There are several syndromes characterized by SIR, including Rabson-Mendenhall syndrome, Donahue syndrome (leprechaunism), types A and B syndromes of insulin resistance, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy. The majority of these conditions have a genetic cause, such as a mutation in the insulin receptor gene. The prevalence of Donahue syndrome, Rabson-Mendenhall syndrome, and type A syndrome of insulin resistance has been reported to vary from approximately 50 reported cases to 1 in 100,000 cases. However, because some of the diseases are severe and extremely rare, it is likely that many patients will not be diagnosed before death, especially in developing regions of the world. Therefore, it is difficult to assess the exact number of patients with these syndromes.

[0005] The current standard for treating hyperglycemia in patients with SIR is a restricted diet supplemented with drugs that affect insulin receptor sensitivity, such as metformin, or insulin supplementation. However, this treatment has proven to be ineffective and ultimately unsuccessful, especially for disorders caused by mutations in the insulin receptor gene.

[0006] Diabetes mellitus comprises two distinct diseases, namely type 1 (or insulin-dependent diabetes) and type 2 (non-insulin-dependent diabetes), both of which involve dysfunction of glucose homeostasis. Type 2 diabetes affects more than 400 million people worldwide, and the number is rising rapidly. Complications of type 2 diabetes include severe cardiovascular disorders, renal failure, peripheral neuropathy, blindness, and even loss of limbs and ultimately death in the later stages of the disease. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and there is currently no definitive cure. Most treatments used today focus on improving dysfunctional insulin signaling or suppressing glucose output from the liver, but many of these treatments have several drawbacks and side effects. Therefore, there is great interest in identifying novel insulin-independent methods to treat type 2 diabetes.

[0007] In type 2 diabetes, the insulin signaling pathway becomes blunted in peripheral tissues such as adipose tissue and skeletal muscle. Methods for treating type 2 diabetes typically include lifestyle modifications and insulin injections or oral medications to regulate glucose homeostasis. People with type 2 diabetes in the later stages of the disease develop "beta cell failure," i.e., the inability of the pancreas to release insulin in response to high blood glucose levels. In the later stages of the disease, patients often require insulin injections in combination with oral medications to manage their diabetes. Furthermore, the most common drugs have side effects that include downregulation or desensitization of the insulin pathway and / or promotion of lipid uptake in adipose tissue, liver, and skeletal muscle. Thus, there is great interest in identifying novel methods for treating metabolic diseases, including type 2 diabetes, that do not include these side effects.

[0008] After a meal, the rise in blood glucose stimulates insulin release from the pancreas. Insulin mediates the normalization of blood glucose levels. The important effects of insulin on glucose metabolism include promoting glucose uptake into skeletal muscle and adipocytes, and increasing glycogen storage in the liver. Skeletal muscle and adipocytes are responsible for insulin-mediated glucose uptake and utilization in the fed state, making them very important sites for glucose metabolism.

[0009] The signaling pathway downstream of the insulin receptor has been difficult to understand in detail. In summary, the control of glucose uptake by insulin involves the activation of the insulin receptor (IR), insulin receptor substrates (IRS), phosphoinositide 3-kinase (PI3K), and thus the stimulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), mammalian target of rapamycin (also called mechanistic target of rapamycin, mTOR), Akt / PKB (Akt), and TBC1D4 (AS160), resulting in the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Akt activation is considered to be necessary for GLUT4 translocation.

[0010] It should be noted that skeletal muscle constitutes the majority of mammalian body mass and plays a key role in regulating whole-body glucose metabolism, responsible for up to 85% of whole-body glucose disposal. Glucose uptake in skeletal muscle is regulated by several intracellular and extracellular signals. Insulin is the best-studied mediator, but others exist. For example, AMP-activated kinase (AMPK) functions as an energy sensor within the cell and can increase glucose uptake and fatty acid oxidation. Due to the major impact skeletal muscle has on glucose homeostasis, additional mechanisms are likely to exist. In light of the increasing prevalence of type 2 diabetes, there is great interest in finding and characterizing novel insulin-independent mechanisms to increase glucose uptake in muscle cells.

[0011] Blood glucose levels can be regulated by both insulin and catecholamines, which are released in the body in response to different stimuli. Insulin is released in response to an increase in blood glucose levels (e.g., after a meal), whereas epinephrine and norepinephrine are released in response to various internal and external stimuli, such as exercise, emotion, and stress, as well as for the maintenance of tissue homeostasis. Insulin is an anabolic hormone that stimulates many processes involved in growth, including glucose uptake, glycogen, and triglyceride formation, while catecholamines are primarily catabolic.

[0012] Although insulin and catecholamines usually have opposite effects, they have been shown to have similar actions on glucose uptake in skeletal muscle (Nevzorova et al., Br. J. Pharmacol, 137, 9, (2002)). In particular, it has been reported that catecholamines stimulate glucose uptake via adrenergic receptors (Nevzorova et al., Br. J. Pharmacol, 147, 446, (2006); Hutchinson, Bengtsson Endocrinology 146, 901, (2005)) to provide muscle cells with an energy-rich substrate. Thus, in mammals, including humans, it is likely that the adrenergic and insulin systems can act independently to regulate the energy needs of skeletal muscle in different situations. Since insulin also stimulates many anabolic processes, including some that promote undesirable effects such as the stimulation of lipid uptake into tissues, leading to obesity, it would be beneficial to be able to stimulate glucose uptake by other means, for example, by stimulation of adrenergic receptors (AR).

[0013] All ARs are G protein-coupled receptors (GPCRs) located in the plasma membrane and characterized by an extracellular N-terminus followed by seven transmembrane α-helices (TM-1 to TM-7) connecting three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. There are three distinct classes of ARs with distinct expression patterns and pharmacological profiles:1 -, α 2 -, and β-AR. 1 -AR is α 1A , α 1B , and α 1D Subtypes include α 2 -AR is α 2A , α 2B , and α 2C β-AR is also classified into subtype β 1 , β 2 , and β 3 Among these, β 2 -AR is the predominant isoform in skeletal muscle cells. AR is a G protein-coupled receptor (GPCR) that signals via classical second messengers such as cyclic adenosine monophosphate (cAMP) and phospholipase C (PLC).

[0014] Many downstream effects of AR in skeletal muscle are due to classical second messenger signaling, such as increasing cAMP levels, PLC activity, and calcium levels. Stimulation involving classical second messengers has many effects in different tissues. For example, the above stimulation increases heart rate, blood flow, air flow in the lungs, and glucose release from the liver, all of which may be harmful or may be considered as undesirable side effects if stimulation of AR is to be considered as a type 2 diabetes treatment. Adverse effects of classical AR agonists are, for example, tachycardia, palpitations, tremors, sweating, agitation, and increased glucose levels in the blood (glucose output from the liver). Therefore, it would be beneficial to activate AR without activating these classical second messengers such as cAMP to increase glucose uptake in peripheral tissues without stimulating undesirable side effects.

[0015] Glucose uptake is stimulated primarily through facilitative glucose transporters (GLUTs), which mediate glucose uptake into most cells. GLUTs are transporter proteins that mediate the transport of glucose and / or fructose across the cell membrane down a concentration gradient. There are 14 known members of the GLUT family, designated GLUT1-14, which are divided into three classes (class I, class II, and class III) depending on their substrate specificity and tissue expression. GLUT1 and GLUT4 are the most intensively studied isoforms and, together with GLUT2 and GLUT3, belong to class I, which primarily transports glucose (as opposed to class II, which also transports fructose). GLUT1 is expressed ubiquitously and is involved in basal glucose transport. GLUT4 is expressed only in peripheral tissues such as skeletal muscle, cardiac muscle, and adipose tissue. GLUT4 has also been reported to be expressed, for example, in the brain, kidney, and liver. GLUT4 is the major isoform involved in insulin-stimulated glucose uptake. The mechanism by which insulin signaling increases glucose uptake is primarily mediated by GLUT4 translocation from intracellular stores to the plasma membrane. 2 -It is known to be induced by stimulation of adrenergic receptors.

[0016] Thus, potential treatments for conditions involving dysregulation of glucose homeostasis or glucose uptake in mammals, such as type 2 diabetes, include the use of β-glucose agonists that lead to GLUT4 translocation to the cell membrane. 2 -adrenergic receptor activation and promotion of glucose uptake in skeletal muscle leading to normalization of whole body glucose homeostasis. In addition, it would be advantageous if the treatment did not involve cAMP signaling, leading to a favorable side effect profile.

[0017] (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol is disclosed in WO 2019 / 053427 and is 2-adrenergic receptors, which have been shown to increase glucose uptake in skeletal muscle but without resulting in significant release of cyclic adenosine monophosphate (cAMP).

[0018] There is still a need to improve the properties of active ingredients such as (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol to improve their ease of use, especially when used in the preparation of medicaments.In particular, there is still a need to provide active ingredients in a form that has improved ease of formulation, improved stability, improved bioavailability, improved taste, improved scale-up capability, and / or lower hygroscopicity.There is also still a need to be able to obtain active ingredients as crystalline solids with high yields and high purities (including, in some circumstances, high enantiomeric excess).

[0019] The listing or discussion of a 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. Summary of the Invention

[0020] The present inventors have surprisingly found that (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)-ethan-1-ol (i.e., the compound of formula I described below) can be prepared in a scalable manner with high yield as the hemitartrate salt with high purity and high enantiomeric excess.In contrast, many other salt forms of this compound are either not amenable to crystallization or can only be obtained in low yield and / or low purity, are found to be highly hygroscopic, are not suitable for pharmaceutical use (e.g., due to toxicity concerns), and / or are not suitable for scale-up production due to filtration problems.

[0021] (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (i.e., the compound of formula I) is a β 2 -adrenergic receptor agonists and have been found to increase glucose uptake in skeletal muscle.

[0022] In addition, this effect is not mediated through significant cAMP release and is not mediated through traditional β 2 It has been found that many of the commonly described side effects seen with adrenergic agonists (e.g., tachycardia, palpitations, tremors, sweating, agitation, etc.) can be reduced.

[0023] The use of such salt forms of the compounds described herein in medicine represents a promising strategy for the treatment of conditions characterized by high blood glucose levels (ie, hyperglycemia), such as type 2 diabetes.

[0024] Compounds of the Invention In a first aspect of the present invention, a compound of formula I:

[0025] [ka] is provided, which compound of formula I may be referred to herein as the "compound of the invention" and which hemitartrate salt may be referred to herein as the "salt of the invention."

[0026] For the avoidance of doubt, those skilled in the art will understand that reference herein to a salt of a particular aspect of the invention (such as the first aspect of the invention, e.g., the hemitartrate salt of the compound of formula I) includes reference to all embodiments and particular features thereof, and that the embodiments and particular features may be combined to form further embodiments.

[0027] For the avoidance of doubt, the compound of formula I is otherwise known by the IUPAC name (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol.

[0028] Tartaric acid is also known as 2,3-dihydroxybutanedioic acid or 2,3-dihydroxy-succinic acid and its structure may be represented graphically as follows:

[0029] [ka]

[0030] Those skilled in the art will appreciate that tartaric acid can exist as three stereoisomers due to the two asymmetric carbon centers present in the molecule.

[0031] (R,R)-tartaric acid (also known as dextrotartaric acid, (2R,3R)-tartaric acid, L-(+)-tartaric acid, and L-tartaric acid) is one of a pair of enantiomers of tartaric acid and has the structure that may be represented graphically as follows:

[0032] [ka]

[0033] (S,S)-tartaric acid (also known as levotartaric acid, (2S,3S)-tartaric acid, D-(-)-tartaric acid, and D-tartaric acid) is the other of a pair of enantiomers of tartaric acid and has a structure that may be represented graphically as follows:

[0034] [ka]

[0035] (2R,3S)-tartaric acid (also known as mesotartaric acid) is a stereoisomer of tartaric acid and has a structure that can be represented graphically as follows:

[0036] [ka]

[0037] For the avoidance of doubt, all stereoisomers of tartaric acid and mixtures thereof (and thus tartrates) are included within the scope of the present invention.

[0038] The term "tartrate" refers to the anion of tartaric acid. Thus, the term "tartrate salt of the compound of formula I" will be understood to refer to a chemical compound consisting of an assembly of the anion of tartaric acid and the associated cation of the compound of formula I.

[0039] Tartaric acid can exist as a monoanion (also known as hydrogen tartrate or hemi-tartrate anion) or a dianion (also known as tartrate dianion). Thus, as used herein, the term "tartrate" is intended to include the tartrate monoanion, the tartrate dianion, and / or mixtures thereof necessary to provide the appropriate charge balance within the salt.

[0040] As used herein, the term "hemi" in "hemi-tartrate salt of the compound of formula I" means that the stoichiometry between the compound of formula I and the tartrate salt is 1:0.5 (i.e., equivalent to 2:1). Thus, the structure of the hemi-tartrate salt of the compound of formula I can be represented graphically, for example, as follows:

[0041] [ka]

[0042] For the avoidance of doubt, the salts of the first aspect of the invention are solid under ambient conditions and therefore the scope of the invention includes all amorphous, crystalline and partially crystalline forms thereof.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0044] All of the embodiments and specific features of the invention mentioned herein may be taken in isolation or in combination with any other embodiment and / or specific feature mentioned herein without departing from the disclosure of the present invention (and thus the more specific embodiments and specific features disclosed herein are set forth).

[0045] In certain embodiments of the first aspect of the invention, the tartrate (i.e., the tartrate counterion present in the compounds of the invention) comprises (2R,3R)-tartrate.

[0046] In a more particular embodiment, the tartrate salt is essentially composed of (2R,3R)-tartrate. By "essentially composed of", we mean that the tartrate salt comprises at least 90% of the relevant form, such as at least 95% or at least 98%, such as at least 99%, such as at least 99.9%. Alternatively, the relevant stereochemical configuration (i.e., that of tartaric acid) may be said to be present in an enantiomeric excess (ee) or diastereomeric excess (de) of at least 90% (at least 95%, at least 98%, or in particular at least 99% or at least 99.5%; such as at least 99.9%).

[0047] In certain embodiments of the first aspect of the invention, the tartrate component of the salt of the invention is (2R,3R)-tartrate.

[0048] Those of skill in the art will understand that reference to a particular stereoisomer of a compound of formula I (i.e., where the carbon replaced by the required -OH group is in the (R) configuration) can, in certain embodiments, refer to that particular stereoisomer in the substantial absence of the corresponding opposite stereoisomer (i.e., where the carbon replaced by the required -OH group is in the (S) configuration).

[0049] As used herein, reference to the substantial absence of the corresponding opposite stereoisomer refers to the desired stereoisomer being present in a purity of at least 80% (e.g., at least 90%, such as at least 95%) relative to the opposite stereoisomer. Alternatively, in such cases, the compound may be referred to as being present in the substantial absence of compounds in the other configuration (i.e., the (S) configuration), which may indicate that the compound in the relevant configuration is present in an enantiomeric excess (ee) of at least 90% (at least 95%, at least 98%, etc., or particularly at least 99% or at least 99.5%; e.g., at least 99.8%).

[0050] For the avoidance of doubt, reference to the enantiomeric excess (ee) of a salt of the present invention refers to the enantiomeric excess (ee) of a compound of formula I that constitutes a salt of the present invention.

[0051] In certain embodiments, the relevant salt form (i.e., the claimed salt form which is a combination of the compound of formula I with tartaric acid) has a purity of greater than about 80% or 90%, preferably greater than about 95% or greater than about 98%, more particularly greater than about 99% (which value can be expressed as a range, where appropriate, with the maximum achievable in the circumstances as the upper point, which can be 100%, or a value closer to 100%, such as 99.5% or 99.9%, or especially 99.99%).

[0052] In certain embodiments, the salt has a melting point at atmospheric pressure of about 209 to about 213° C. In more specific embodiments, the salt has a melting point of about 210 to about 212° C., such as about 211° C.

[0053] When used herein in relation to a particular value (such as an amount), the term "about" (or similar terms such as "approximately") is understood as indicating that such value may vary by up to 10% (particularly up to 5%, such as up to 1%) of the defined value. In each case, it is contemplated that such terms may be replaced with the notation "±10%" or the like (or by indicating a particular amount of variation calculated based on the relevant value). It is also contemplated that in each case, such terms may be deleted.

[0054] In certain embodiments, the salt is crystalline (ie, a crystalline solid; when observed at room temperature, eg, 20° C., and atmospheric pressure).

[0055] Those skilled in the art will understand that the compounds (salts) of the present invention are crystalline and therefore may exist in partially crystalline forms. Those skilled in the art are familiar with techniques that can be used to characterize such crystalline forms, such as X-ray powder diffraction (XRPD).

[0056] In certain embodiments, the salt is characterized by X-ray powder diffraction peaks at 2θ angles including peaks at 11.35, 17.24, and 18.19.

[0057] In a more specific embodiment, the salt is characterized by X-ray powder diffraction peaks at 2θ angles including peaks at 11.35, 17.24, 18.19, and 18.91.

[0058] In a more specific embodiment, the salt is characterized by X-ray powder diffraction peaks at 2θ angles including peaks at 11.35, 17.24, 18.19, 18.91, and 22.80.

[0059] In certain embodiments, the salts are characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from the peaks shown in Table A (below):

[0060] [Table 1]

[0061] In more particular embodiments, the salt is characterized as having at least 4, such as at least 5, including at least 6, 7, 8, or 9 (or particularly at least 10) X-ray powder diffraction peaks at 2θ angles selected from the peaks in Table A.

[0062] In an even more particular embodiment, the salt is characterized by having X-ray powder diffraction peaks at 2θ angles that include peaks that correspond (or substantially correspond) to those in Table A.

[0063] In certain embodiments, the salt is characterized by having an X-ray powder diffraction pattern substantially in accordance with the pattern shown in FIG.

[0064] In certain embodiments, the salt is a solvate. By "solvate," we mean that the salt contains molecules of a solvent inside the crystal structure, which may be the solvent used in its preparation (e.g., i-PrOH, EtOH, or a mixture of EtOH and water; see examples provided herein).

[0065] In a more particular embodiment, the salt is a hydrate. By "hydrate" we mean that the salt contains molecules of water inside the crystal structure.

[0066] In certain embodiments, the salt may be described as substantially non-hygroscopic or non-hygroscopic, as such terms are understood by those of skill in the art. In particular, the term substantially non-hygroscopic may be taken to mean that the salt absorbs 0.5% water by weight or less (such as less than 0.3% or 0.2% water by weight, more specifically 0.1% water by weight or less) after exposure to conditions of 40° C. and 75% relative humidity for 2 days.

[0067] medical use As provided herein, the compounds of the present invention, as well as compositions and kits comprising same, are useful as pharmaceuticals.

[0068] Thus, according to a second aspect of the invention, there is provided a salt of the first aspect of the invention as defined above (i.e. a salt as defined in the first aspect of the invention, including all embodiments and particular features thereof) for use as a medicament (or for use in medicine).

[0069] As provided herein, the salts of the invention may be particularly useful in the treatment of hyperglycemia or disorders characterized by hyperglycemia.

[0070] Thus, in a third aspect of the invention there is provided a salt of the first aspect of the invention as defined above for use in the treatment of hyperglycemia or a disorder characterised by hyperglycemia.

[0071] In an alternative third aspect of the invention there is provided the use of a salt of the first aspect of the invention in the manufacture of a medicament for use in the treatment of hyperglycemia or a disorder characterised by hyperglycemia.

[0072] In a further alternative third aspect of the invention there is provided a method of treating hyperglycemia or a disorder characterised by hyperglycemia comprising administering to a patient in need thereof a therapeutically effective amount of a salt of the first aspect of the invention.

[0073] For the avoidance of doubt, it will be understood by those skilled in the art that the term "hyperglycemia" as used herein refers to a condition in which an excessive amount of glucose circulates in the plasma of a subject suffering therefrom.In particular, the term may refer to a subject (e.g., a human subject) having a blood glucose level higher than about 10.0 mmol / L (e.g., higher than about 11.1 mmol / L, e.g., higher than about 15 mmol / L), but the term may also refer to a subject (e.g., a human subject) having a blood glucose level higher than about 7 mmol / L for an extended period of time (e.g., more than 24 hours, e.g., more than 48 hours, etc.).

[0074] Those skilled in the art will understand that references to "treatment" of a particular condition (or, equivalently, treating the condition) are their ordinary meaning in the pharmaceutical arts. In particular, the term may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition. For example, in the case of type 2 diabetes, the term may refer to achieving a reduction in blood glucose levels. In certain embodiments, when treating hyperglycemia or a condition characterized by hyperglycemia, the term may refer to achieving a reduction in blood glucose levels (e.g., to about 10.0 mmol / mL or less (e.g., to a level in the range of about 4.0 mmol / L to about 10.0 mmol / L), e.g., to about 7.5 mmol / mL or less (e.g., to a level in the range of about 4.0 mmol / L to about 7.5 mmol / L), or to about 6 mmol / mL or less (e.g., to a level in the range of about 4.0 mmol / L to about 6.0 mmol / L)).

[0075] As used herein, reference to a patient refers to the living body being treated, including a mammalian (e.g., human) patient. Thus, in certain embodiments of the first aspect of the invention, the treatment is performed in a mammalian (e.g., human) patient.

[0076] As used herein, the term therapeutically effective amount refers to that amount of salt that confers a therapeutic effect on the treated patient, which 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).

[0077] For the avoidance of doubt, the compounds of the first aspect of the invention are useful because they possess pharmacological activity and / or are metabolized in the body following oral or parenteral administration to form compounds that possess pharmacological activity. In particular, as described herein, the compounds of the first aspect of the invention are useful in the treatment of hyperglycemia or disorders characterized by hyperglycemia (such as type 2 diabetes), a term that will be readily understood by those of skill in the art (as described herein).

[0078] In certain embodiments, the treatment is treatment of a disorder (which may also be referred to as a condition or disease) characterized by hyperglycemia.

[0079] In certain embodiments, the salts of the invention (i.e., the hemitartrate salt of the compound of formula I, including all embodiments thereof) are for use in the treatment of type 2 diabetes (or are useful in the manufacture of a medicament for such treatment, or are useful in the methods for such treatment, as described herein).

[0080] In certain embodiments of the first aspect of the invention, the disorder is type 2 diabetes, e.g., a subtype of type 2 diabetes selected from the list consisting of maturity-onset diabetes of the young (MODY), ketosis-prone diabetes mellitus, latent autoimmune diabetes of adulthood (LADA), and gestational diabetes.

[0081] In a further particular embodiment, the treatment of type 2 diabetes is in a non-obese patient.

[0082] For the avoidance of doubt, those skilled in the art will understand that a patient with a body mass index (BMI) of greater than 30 is considered to be obese.

[0083] In certain embodiments, the treatment may be treatment of hyperglycemia in patients at risk of developing type 2 diabetes, a condition which may be defined as prediabetes. Thus, the salts of the invention may be useful in the prevention of type 2 diabetes (e.g. in patients suffering from prediabetes).

[0084] As used herein, the term prevention (and, similarly, preventing) includes a reference to prophylaxis of a disease or disorder (and vice versa). Thus, a reference to prevention can also be a reference to prophylaxis, and vice versa. In particular, the term may mean achieving a reduction (e.g., at least a 10% reduction, at least a 20%, 30%, or 40% reduction, e.g., at least a 50% reduction) in the likelihood that a patient (or healthy subject) will develop a condition.

[0085] In a more particular embodiment, type 2 diabetes is characterized by patients exhibiting severe insulin resistance (SIR).

[0086] In a further embodiment, the treatment may be treatment of hyperglycemia in a patient with type 1 diabetes. Thus, the salts of the invention may be useful in treating hyperglycemia in type 1 diabetes.

[0087] Those skilled in the art will appreciate that the salts of the invention may be useful for treating hyperglycemia in patients with impaired insulin production, such as those with cystic fibrosis. Thus, in a further embodiment, the disorder characterized by hyperglycemia is cystic fibrosis-related diabetes.

[0088] In certain embodiments that may be mentioned, the disorder characterized by hyperglycemia is (or is characterized by) severe insulin resistance (SIR), and it can be understood by those skilled in the art that it typically refers to a disorder in which the subject has normal insulin production, or in some cases, increased insulin production, but significantly reduced insulin sensitivity. In certain cases, such patients may be non-obese (e.g., those with a healthy weight). Thus, in certain embodiments, such treatment is performed in patients who are not defined as obese (e.g., those who are defined as having a healthy weight).

[0089] For example, the SIR may be determined for a patient based on the patient having fasting insulin of greater than 150 pmol / L and / or peak insulin in a glucose tolerance test of greater than 1,500 pmol / L, particularly for a patient with a fasting insulin level of 30 kg / m 2 In individuals with a BMI below 18.5, who may alternatively have normal glucose tolerance, the patient may be identified.

[0090] More specifically, SIR can be characterized as a patient having no significant response to the presence of insulin, which may be due to a defect (eg, a genetic defect) in the function of the insulin receptor.

[0091] Specific disorders that may be characterized by SIR include Rabson-Mendenhall syndrome, Donahue syndrome (leprechaunism), insulin resistance types A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.

[0092] More specific disorders which may be characterized by SIR include Donahue syndrome and Type A syndrome of insulin resistance, and even more specifically, Rabson-Mendenhall syndrome.

[0093] Those skilled in the art will appreciate that treatment with a salt of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatments for the same condition. In particular, treatment with a compound of the invention may be combined with other measures for the treatment of type 2 diabetes, such as treatment with one or more other therapeutic agents useful in the treatment of type 2 diabetes known to those skilled in the art, for example a therapy involving requiring the patient to change their diet and / or undertake a course of exercise, and / or a surgical procedure designed to promote weight loss (e.g. gastric band surgery).

[0094] In particular, treatment with a salt of the invention may be carried out in combination (e.g. in a patient being treated) with one or more (e.g. one) further compounds (i.e. therapeutic agents), the combined salt being (i) capable of lowering blood glucose levels; and / or (ii) is an insulin sensitizer; and / or (iii) enhances insulin release; All of these are described below.

[0095] In an alternative embodiment, the salts of the first aspect of the invention (ie the salts of the invention) may be useful in the treatment of non-alcoholic fatty liver disease (NAFLD).

[0096] Nonalcoholic fatty liver disease (NAFLD) is defined by excess fat accumulation (steatosis) in the form of triglycerides in the liver (histologically designated as accumulation in more than 5% of liver cells). It is the most common liver disorder in developed countries (e.g., about 30% of adults in the United States are affected), and most patients are asymptomatic. If left untreated, the condition can gradually worsen and eventually cause cirrhosis. NAFLD is particularly common in obese patients, with about 80% believed to have the disease.

[0097] A subgroup of NAFLD patients (e.g., 2-5% of adults in the United States) exhibits hepatocellular injury and inflammation in addition to excess fat accumulation. This condition, designated nonalcoholic steatohepatitis (NASH), is virtually histologically indistinguishable from alcoholic steatohepatitis. Although the simple steatosis seen in NAFLD does not directly correlate with increased short-term morbidity or mortality, progression of this condition to NASH dramatically increases the risk of cirrhosis, liver failure, and hepatocellular carcinoma. Indeed, NASH is now believed to be one of the leading causes of cirrhosis (including cryptogenic cirrhosis) in developed countries.

[0098] The exact cause of NASH has yet to be elucidated and is almost certainly not the same in all patients. It is most closely associated with insulin resistance, obesity, and metabolic syndrome, including diseases associated with type 2 diabetes, insulin resistance, central (Torn) obesity, hyperlipidemia, low high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and hypertension. However, not all patients with these conditions have NASH, and not all patients with NASH suffer from one of these conditions. Nevertheless, given that NASH is a potentially fatal condition that can lead to cirrhosis, liver failure, and hepatocellular carcinoma, there is a clear need for effective treatment.

[0099] In certain embodiments, there is provided salts of the invention (i.e., hemi-tatrate salts of compounds of formula I, including all embodiments) for use in the treatment of non-alcoholic fatty liver disease (or for use in the manufacture of a medicament for such treatment).

[0100] Alternatively, there is provided a method of treating non-alcoholic fatty liver disease, comprising administering to a patient in need thereof a therapeutically effective amount of a salt of the invention (i.e., the hemitartrate salt of the compound of formula I, including all of its embodiments).

[0101] The process of triglyceride fat accumulating in liver cells is called steatosis (i.e. fatty liver).Those skilled in the art will understand that the term "steatosis" includes the abnormal retention of fat (i.e. lipid) in cells.Therefore, in certain embodiments of the first aspect of the present invention, treatment or prevention is treatment or prevention of fatty liver disease characterized by steatosis.

[0102] During steatosis, excess lipids accumulate in vesicles that displace the cytoplasm of cells. Over time, vesicles may grow large enough to distort the nucleus, a condition known as macrovesicular steatosis. Otherwise, the condition may be called microvesicular steatosis. Steatosis is mostly harmless in mild cases. However, large amounts of fat accumulated in the liver can cause serious health problems. Risk factors associated with steatosis include diabetes mellitus, protein malnutrition, hypertension, obesity, anoxia, sleep apnea, and the presence of toxins in cells.

[0103] As described herein, fatty liver disease is most commonly associated with alcohol or metabolic syndrome (e.g., diabetes, hypertension, obesity, or dyslipidemia).Accordingly, depending on the underlying cause, fatty liver disease can be diagnosed as alcohol-related fatty liver disease or non-alcoholic fatty liver disease (NAFLD).

[0104] Specific diseases or conditions associated with non-alcohol-related fatty liver disease include metabolic conditions such as diabetes, hypertension, obesity, dyslipidemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, acute fatty liver of pregnancy, and lipodystrophy. Other non-alcohol-related factors associated with fatty liver disease include malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunal bypass, gastric bypass, polycystic ovary syndrome, and diverticulosis.

[0105] The salt of the present invention is found to be particularly useful for treating or preventing NAFLD, which may be called non-alcohol-related fatty liver disease."Non-alcohol-related" fatty liver disease may be diagnosed when the patient's alcohol intake is not considered to be the main causative factor.The typical threshold for diagnosing "non-alcohol-related" fatty liver disease is less than 20g per day for female subjects and less than 30g per day for male subjects.

[0106] If left untreated, subjects suffering from fatty liver disease may begin to suffer from liver inflammation (hepatitis).It is hypothesized that one of the possible causes of this inflammation may be lipid peroxidation damage to the membrane of liver cells.Since fatty liver inflammation can lead to many serious conditions, it is desirable to treat or prevent fatty liver disease before inflammation occurs.Therefore, in certain embodiments of the first aspect of the present invention, the treatment or prevention is the treatment or prevention of NAFLD associated with inflammation.

[0107] Nonalcoholic steatohepatitis (NASH) is the most aggressive form of NAFLD, a condition in which excess fat accumulation (steatosis) is accompanied by inflammation of the liver. In progression, NASH can cause the development of scar tissue in the liver (fibrosis) and ultimately cause cirrhosis. As mentioned above, the compounds of the present invention have been found to be useful for treating or preventing NAFLD, especially when accompanied by inflammation of the liver. Thus, the salts of the present invention are also useful for treating or preventing NASH. Thus, in a further embodiment of the first aspect of the present invention, the treatment or prevention is the treatment or prevention of nonalcoholic steatohepatitis (NASH).

[0108] Those skilled in the art will appreciate that treatment with the salt of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatments for the same condition. In particular, treatment with the salt of the invention may be combined with other measures for the treatment of fatty liver disease as described herein, such as treatment with one or more other therapeutic agents useful for the treatment of fatty liver disease known to those skilled in the art; for example, a therapy that includes a requirement that the patient undergo a change in diet and / or embark on an exercise regimen and / or a surgical procedure designed to promote weight loss (e.g. gastric band surgery).

[0109] In particular, treatment with a salt of the invention may be carried out in combination with one or more (e.g., one) further compounds (i.e., therapeutic agents) capable of lowering liver fat (e.g., triglyceride) levels (e.g., in a patient also being treated).

[0110] Reference to treating fatty liver disease refers to achieving a therapeutically significant reduction in fat (e.g., triglyceride levels) in liver cells (e.g., a reduction of at least 5% by weight, such as at least 10%, or at least 20%, or even 25% reduction).

[0111] Pharmaceutical Compositions As described herein, the salts of the first aspect of the invention are useful as pharmaceuticals. Such salts may be administered alone or via known pharmaceutical compositions / formulations.

[0112] In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a salt as defined in the first aspect of the invention (i.e. a salt of the invention), and optionally one or more pharma- ceutically acceptable adjuvants, diluents and / or carriers.

[0113] Those skilled in the art will understand that references herein to salts of the first aspect of the invention that are for particular uses (and similarly, uses and methods of use relating to salts of the invention) may also apply to pharmaceutical compositions comprising salts of the invention as described herein.

[0114] In a fifth aspect of the invention, there is provided a pharmaceutical composition for use in the treatment of hyperglycemia or a disorder characterised by hyperglycemia (such as type 2 diabetes, as defined herein) comprising a salt as defined in the first aspect of the invention and optionally one or more pharma- ceutically acceptable adjuvants, diluents and / or carriers.

[0115] In an alternative fifth aspect of the present invention there is provided a pharmaceutical composition for use in the treatment or prevention of non-alcoholic fatty liver disease as defined herein.

[0116] Those skilled in the art will appreciate that the salts of the first (and thus the second and third) aspects of the invention may act systemically and / or locally (ie at a specific site).

[0117] Those skilled in the art will appreciate that the salts and compositions described in the first to fifth aspects of the invention will typically be administered in a pharma- ceutically acceptable form, such as orally, intravenously, subcutaneously, bucally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, other parenteral routes, or via inhalation. Pharmaceutical compositions described herein include compositions in the form of tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Alternatively, pharmaceutical compositions may be formulated for topical administration, particularly where such salts of the invention act locally.

[0118] Thus, in certain embodiments of the fourth and fifth aspects of the invention, the pharmaceutical formulation is provided in a pharma- ceutically acceptable dosage form, including tablets or capsules, liquid forms taken orally or by injection, suppositories, creams, gels, foams, inhalants, intranasal dosage forms, or forms suitable for topical administration. For the avoidance of doubt, in such embodiments the salts of the invention may be present in solid (e.g. solid dispersions), liquid (e.g. in solution), or other forms such as in micellar form.

[0119] For example, in preparing pharmaceutical formulations for oral administration, the salts can be mixed with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol waxes. The mixture can then be processed into granules or compressed into tablets.

[0120] Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g., salts of the first aspect of the invention, therefore, and salts of the second and third aspects, and optionally additional therapeutic agents) together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Similarly, hard gelatin capsules may contain such compounds in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.

[0121] Dosage units for rectal administration may be prepared in the form of (i) suppositories containing the compound mixed with a neutral lipid base; (ii) gelatin rectal capsules containing the active substance in a mixture with vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) ready-made microenemas; or (iv) dry microenema preparations to be reconstituted in a suitable solvent immediately prior to administration.

[0122] Liquid preparations for oral administration may be prepared in the form of a syrup or suspension, for example, a solution or suspension, containing the compound and the remainder of the formulation consisting of sugar or sugar alcohol, as well as a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin, and carboxymethylcellulose, or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder that is reconstituted with a suitable solvent before use.

[0123] Solutions for parenteral administration can be prepared as solutions of compounds in pharma- ceutically acceptable solvents.These solutions can also contain stabilizing and / or buffering components and are dispensed in unit doses in the form of ampoules or vials.Solutions for parenteral administration can also be prepared as dry preparations that are reconstituted extemporaneously with suitable solvents before use.

[0124] Those skilled in the art will appreciate that the salts of the invention can be administered in a variety of doses (e.g., as formulations described herein above), and suitable doses can be readily determined by those of skill in the art. Oral, pulmonary, and topical dosages (and subcutaneous dosages, although these dosages may be relatively small) may range from about 0.01 μg / kg / day per kg body weight (μg / kg / day) to about 20 mg / kg / day per kg body weight (mg / kg / day), preferably from about 0.1 μg / kg / day to about 5 mg / kg / day, and more preferably from about 1 μg / kg / day to about 2 mg / kg / day (e.g., from about 10 μg / kg / day to about 1 mg / kg / day). For example, when administered orally, treatment with such salts may typically involve administration of a formulation containing about 1 μg to about 2000 mg, e.g., about 10 μg to about 500 mg, or 100 μg to about 200 mg (e.g., about 1 mg to about 100 mg) of active ingredient. When administered intravenously, the most preferred doses will be in the range of about 0.001 to about 10 μg / kg / hour during a constant rate infusion. Advantageously, treatment may involve administration of such salts and compositions in a single daily dose, or the total daily dosage may be administered in divided doses two, three or four times daily (e.g., twice daily for doses described herein, such as 10 mg, 20 mg, 30 mg or 40 mg twice daily, or 10 μg, 20 μg, 30 mg or 40 μg twice daily).

[0125] In any event, one of skill in the art (e.g., a physician) can determine the actual dosage that will be most suitable for an individual patient, which will likely vary with the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function and response of the particular patient being treated. The above dosages are exemplary of the average case, and there can, of course, be individual instances in which higher or lower dosage ranges are merited, and these are within the scope of the invention.

[0126] As described herein above, the skilled artisan will appreciate that treatment with a salt of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional / other) treatments for the same condition. In particular, treatment with a salt of the invention may be combined with other measures for the treatment of hyperglycemia or a disorder characterized by hyperglycemia (such as type 2 diabetes, as defined herein), for example treatment with one or more other therapeutic agents useful in the treatment of hyperglycemia or a disorder characterized by hyperglycemia (such as type 2 diabetes, as defined herein).

[0127] In certain embodiments of the fourth and fifth aspects of the invention, the pharmaceutical composition may further comprise one or more additional (ie other) therapeutic agents.

[0128] In more specific embodiments, the one or more additional therapeutic agents are metformin, a sulfonylurea (e.g., carbamide, acetohexamide, chlorpropamide, tolbutamide, glipizide (Glucotol), gliclazide, glibenclamide, glyburide (Micronase), glibornuride, gliquidone, glisoxepide, glycopyramide, glimepride (Amaryl), glimiprim, JB253, or JB558), a thiazolidinedione (e.g., pioglitazone, rosiglitazone (Avandia), lobeglitazone (Duvie), and troglitazone (Rezulin)), a dipeptide, and agents for the treatment of type 2 diabetes known to those skilled in the art, such as leupeptidase-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin, and omarigliptin), SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, and ertugliflozin), and glucagon-like peptide-1 (GLP-1) analogues.

[0129] Those skilled in the art will appreciate that combinations of therapeutic agents may also be described as combination products and / or provided as a kit of parts.

[0130] In a sixth aspect of the present invention, (A) a salt as defined in the first aspect of the invention; (B) one or more additional therapeutic agents, Combination products are provided in which each of components (A) and (B) is formulated, optionally in admixture with one or more pharma- ceutically acceptable adjuvants, diluents, or carriers.

[0131] In a seventh aspect of the present invention, (a) a salt as defined in the first (or second and / or third) aspect of the invention (or a pharmaceutical composition comprising same) or a pharmaceutical composition as defined in the fourth or fifth aspect of the invention, (b) one or more other therapeutic agents, optionally in admixture with one or more pharma- ceutically acceptable adjuvants, diluents, or carriers; A kit-of-parts is provided in which components (a) and (b) are each provided in a form suitable for administration in conjunction with the other.

[0132] In certain embodiments (e.g., of the sixth and seventh aspects of the invention), the additional therapeutic agent is a therapeutic agent useful for the treatment of hyperglycemia or a disorder characterized by hyperglycemia (e.g., type 2 diabetes), as known to those of skill in the art (e.g., as described herein).

[0133] For example, in certain embodiments of the fourth to fifth aspects of the invention, the additional therapeutic agent is: (i) capable of lowering blood glucose levels; and / or (ii) is an insulin sensitizer; and / or (iii) a drug capable of enhancing insulin release; Such agents are readily identifiable by one of skill in the art and specifically include such therapeutic agents that are commercially available (e.g., agents that are the subject of marketing authorization in one or more regions, such as marketing authorization in Europe or the United States).

[0134] Those skilled in the art will understand that reference to a therapeutic agent capable of lowering blood glucose levels may mean a compound that can lower the blood levels by at least 10% (e.g., at least 20%, at least 30%, or at least 40%, e.g., at least 50%, at least 60%, at least 70%, or at least 80%, e.g., at least 90%) compared to the blood glucose levels prior to treatment with the relevant compound.

[0135] In alternative embodiments of the sixth and seventh aspects of the invention, the additional therapeutic agent is an agent for the treatment or prevention of non-alcoholic fatty liver disease (such as NASH) (e.g., an agent that is subject to marketing approval in one or more regions, such as a marketing approval in Europe or the United States), which may be readily identified by a person skilled in the art, and which particularly includes such therapeutic agents that are commercially available.

[0136] Preparation of Salts / Compositions The pharmaceutical compositions / formulations, combination products and kits described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0137] Thus, in a further aspect of the invention there is provided a process for preparing a pharmaceutical composition / formulation as defined above, which process comprises bringing into association a salt of the invention as defined above with one or more pharma- ceutically acceptable adjuvants, diluents or carriers.

[0138] In a further aspect of the present invention, there is provided a process for preparing a combination product or kit-of-parts as defined herein above, which process comprises associating a salt of the invention as defined herein above, another therapeutic agent useful in the treatment of hyperglycemia or a disorder characterised by hyperglycemia (e.g. type 2 diabetes), and at least one pharma- ceutically acceptable adjuvant, diluent or carrier.

[0139] As used herein, reference to associating means rendering two components suitable for administration in conjunction with one another.

[0140] Thus, by "associating" two components with each other, with respect to the process for preparing a kit of parts as defined hereinabove, we mean that the two components of the kit of parts are (i) may be provided as separate formulations (i.e., independent of each other) which are then combined for use in conjunction with each other in a combination therapy; or (ii) It is contemplated that they may be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

[0141] Preparation of Compounds and Salts The compounds defined in the first (and therefore second and third) aspects of the present invention (i.e., compounds of formula I) can be prepared according to techniques well known to those skilled in the art, such as those described in the Examples provided herein below. For example, compounds of formula I can be made according to the techniques described in International Patent Application No. 2019 / 053427, the contents of which (particularly the Examples) are incorporated herein by reference.

[0142] The salts defined in the first (and therefore second and third) aspects of the present invention (i.e., the salts of the present invention) can be prepared according to techniques well known to those skilled in the art, such as those described in the examples provided herein below. For example, a compound of formula I may be reacted with tartaric acid or a solution of tartaric acid (or vice versa). Salt switching techniques can also be used to convert one salt into another salt.

[0143] In certain embodiments, salts of the present invention are prepared by reacting a compound of formula I with a solution of tartaric acid (or vice versa).

[0144] In a particular embodiment that may be mentioned, the solvent in the solution is ethanol or an ethanol-water mixture.The use of ethanol or an ethanol-water mixture as the solvent allows the scale-up of the production of the hemitartrate salt of the compound of formula I with high yield, high purity, and high enantiomeric purity.

[0145] The salts described herein (particularly those defined in the first, and by extension the second and third aspects of the invention), whether for use in the aforementioned conditions or not, may have the advantage that they are more effective, less toxic, longer acting, more potent, have fewer side effects, are more easily absorbed and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance) and / or have other useful pharmacological, physical or chemical properties than compounds known in the prior art. In particular, such salts may have the advantage that they are more effective and / or exhibit advantageous properties in vivo.

[0146] Without wishing to be bound by theory, the compounds of the present invention have the ability to inhibit β-glucose uptake in skeletal muscle cells, which allows for increased glucose uptake in skeletal muscle cells. 2 The compounds of the present invention are also believed to provide a suitable level of metabolic stability.

[0147] In addition, the salts as described herein increase β-glucose uptake without inducing cAMP production (or with only a relatively minimal effect, such as a relatively small effect (when compared to the effect of inducing increased glucose uptake)). 2 -adrenergic receptor agonists, which are believed to allow increased glucose uptake in skeletal muscle cells with lower levels of side effects than may be produced by other treatments.Furthermore, it is believed that combining the salts described herein with therapeutic agents capable of reducing blood glucose levels provides an effective combination therapy.

[0148] Furthermore, the salts and compositions of the present invention may have several advantages over the corresponding free bases (i.e., the free bases of the compounds of formula I). ​​For example, the salts and compositions of the present invention may have improved ease of formulation, improved stability, improved purity, improved bioavailability, improved taste, improved ability to be scaled up in manufacturing processes, and / or reduced hygroscopicity compared to the corresponding free bases. Such salts also ideally have low toxicity and are therefore suitable for use in medicines (i.e., pharma- ceutical acceptable).

[0149] More specifically, the free base of the compound of formula I is difficult to prepare as a solid, and is obtained in low yields, either as an oil or as a solid. Other salts of the compound of formula I either could not be crystallized, could only be crystallized in low yields and / or low purity, or formed small crystals that were difficult to filter, isolate, and subsequently scale up the synthesis. In contrast, it is surprising to find that the hemitartrate salt of the compound of formula I may be easily obtained as a crystalline solid in a form that demonstrates high yield, high purity (and high enantiomeric excess), and low hygroscopicity. [Brief description of the drawings]

[0150] [Figure 1]1 shows an XRPD analysis of the hemitartrate salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol. EXAMPLES

[0151] The invention is illustrated by the following examples.

[0152] Chemicals and reagents were obtained from commercial suppliers and used as received unless otherwise noted. All reactions involving moisture sensitive reagents were carried out in oven- or flame-dried glassware under a positive pressure of nitrogen or argon.

[0153] Abbreviation The abbreviations used herein will be known to those of skill in the art. In particular, the following abbreviations may be used herein:

[0154] [Table 2]

[0155] Exemplary Compounds and Salts In case of discrepancies between the nomenclature and the structures of compounds shown in the figures, the latter shall prevail (unless contradicted by any experimental details which may be given and / or clear from the context).

[0156] Example compound: (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol

[0157] [ka]

[0158] (a) 2-Chloro-1-(5-fluoropyridin-3-yl)ethan-1-one

[0159] [ka]

[0160] Isopropylmagnesium chloride (2M in THF, 10.47 mL, 20.94 mmol) was added to a solution of LiCl (887.69 mg, 20.94 mmol) in THF (8 mL) at room temperature. After 15 min at room temperature, 3-bromo-5-fluoropyridine (3.35 g, 19.04 mmol) in THF (30 mL) was added dropwise at 0° C. The mixture was stirred at room temperature for 2 h and cooled in an ice bath. A solution of 2-chloro-N-methoxy-N-methylacetamide (2.62 g, 19.04 mmol) in THF (30 mL) was added dropwise and the mixture was stirred at room temperature for 2 h. NH 4 Cl (aq, 10%) was added and the mixture was diluted with Et 2 The combined extracts were washed with brine and dried (Na 2 SO 4 ) and concentrated. The residue was purified by chromatography to give the subtitle compound (1.52 g, 20.94 mmol, 46%).

[0161] (b) (R)-2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-one

[0162] [ka]

[0163] iPrOAc (250 mL, 10 volumes), pentamethylcyclopentadienylrhodium(III) chloride dimer (74 mg, 0.001 equiv.), (1S,2S)-(+)-Np-tosyl-1,2-diphenylethylenediamine (87 mg, 0.002 equiv.), and NEt 3 (66 μL, 0.004 equiv.) was stirred at room temperature for 1 h 20 min, followed by addition of 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-one hydrochloride (25 g, 1.00 equiv.). The mixture was cooled to 7° C. and diluted with NEt 3(83 mL, 5.00 equiv.) was added followed by HCOOH (9 mL, 2.00 equiv.). The mixture was stirred at room temperature for 1 h, then diluted with 0.5 M aqueous HCl, extracted with iPrOAc, and 2 The residue was diluted with iPrOH, cooled to 0° C., and then 5.56 M HCl in iPrOH (22 mL, 1.00 equiv.) was added. The solid was collected to give the subtitle compound (18.08 g, 72%, ee=98.7%).

[0164] (c) (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol

[0165] [ka]

[0166] tert-Butylamine (11.37 mL, 108.21 mmol) was added followed by NaOH (476.08 mg, 11.90 mmol) to a mixture of 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-ol (1.90 g, 10.82 mmol) and iPrOH (1.66 mL, 21.64 mmol) at room temperature. The mixture was heated at 75° C. for 4 h, allowed to cool, diluted with EtOAc, and diluted with H 2 O and brine, dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in hot EtOAc and allowed to cool. Pentane was added and the mixture was kept at -20°C overnight. The solid was collected and purified by chromatography to give the title compound (1.43g, 6.74mmol, 62%, ee=98%).

[0167] 1 H NMR (400 MHz, CDCl 3 ):δ8.43-8.27(m,2H),7.57-7.42(m,1H),4.62(dd,J=8.8,3.7Hz,1H),2.94(dd,J=12.1,3.8Hz,1H),2.53(dd,J=12.1,8.8Hz,1H),1.10(s,9H).

[0168] In the above experiments, the title compound was isolated as a free base by evaporation to dryness. However, this isolation method was typically performed on a laboratory scale. Therefore, different solvents and solvent mixtures were tested to crystallize the free base. Surprisingly, all early attempts resulted in either crystal formation or oil separation with relatively low yields (less than 50%). Therefore, it was decided to investigate the salt form.

[0169] Salt Example 1: Hemitartrate A solution of L-(+)-tartaric acid (6.21 g, 0.5 equiv.) in EtOH (175 mL) was dissolved in (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (17.57 g) in EtOH (525 mL, 30 vol.) and H 2 To a solution of 2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol was added 1H 2 O (7 mL) at room temperature. The mixture was refluxed until all precipitate was dissolved and then cooled. The resulting slurry was stirred at room temperature overnight and then at 0-5° C. for 2 h. The solid was collected to give the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (19.9 g, 83%, 100.0% purity by HPLC, 99.8% ee by HPLC).

[0170] The formation of hemitartrate is 1 This was confirmed by 1 H-NMR spectrum, which showed an amine:acid ratio of 2:1.

[0171] Characterization of the solid-state properties of the title salt using XRPD, DSC, and DVS techniques showed that the material was crystalline with a high melting point at 211° C. The salt was not hygroscopic and was physically stable under the conditions tested (40° C. and 75% RH for 2 days).

[0172] During the experiment, it was observed that the filtration of hemitartrate was very good, so further experiments were carried out to optimize the conditions for the formation of hemitartrate on a large scale, the results of which are shown in the table below.

[0173] [Table 3]

[0174] Overall, the hemitartrate salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol was obtained in high yield, high purity, and with an enantiomeric excess of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol of more than 99%. In particular, the use of the free base of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol with a purity of only 95.6% (by HPLC) was used to prepare the hemitartrate salt with a purity of more than 99.8% (by HPLC), which indicated a significant purification effect during crystallization.

[0175] Furthermore, the synthesis could be easily upscaled and, unlike many of the other salt forms of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol, it had low hygroscopicity and did not suffer from slow filtration issues that were believed to be due to the formation of small crystals.

[0176] A sample of the hemitartrate salt was analyzed by X-ray powder diffraction and found to have a diffraction pattern producing peaks as shown in Figure 1. The relevant peak data is summarized in the table below.

[0177] [Table 4]

[0178] Comparative Salt Example 2: Dihydrochloride Aqueous hydrochloric acid (37%, 1.1 equiv.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (300 mg, 1.0 equiv.) in iPrOH (10 vol.) at 40° C. The resulting slurry was stirred at room temperature overnight. The solid was collected to give the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (47%).

[0179] The synthesis was repeated using different solvents and acids and the results are shown in the table below.

[0180] [Table 5]

[0181] DSC analysis of the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol showed a broad endothermic event at about 150° C., mass loss due to possible dehydration or desolvation, and a second endothermic event at about 220° C. Based on the observations and information gathered during the synthesis of the dihydrochloride salt, it is believed that the product has a high tendency to form hydrates or solvates during salt preparation. Since good yields and purity of the dihydrochloride salt were not achieved, it was decided to discontinue work on this salt form.

[0182] Comparative Salt Example 3: Edisylate 1,2-Ethanedisulfonic acid (1.05 equiv.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (500 mg, 1.0 equiv.) in iPrOH (20 vol.) at room temperature. The resulting slurry was stirred at room temperature overnight. The solid was collected to give the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol.

[0183] The salt was found to be hygroscopic under the test conditions (40°C and 75% RH for 2 days).

[0184] During the experiment, it was observed that the filtration of the edisylate salt was very slow due to the formation of very fine solids.

[0185] The synthesis was repeated using different solvents and acids and the results are shown in the table below.

[0186] [Table 6]

[0187] Due to the low purification achieved from the salt formation and due to the limited commercial availability of pharmaceutical grade 1,2-ethanedisulfonic acid in bulk quantities, further development of the edisylate salt for production was not undertaken.

[0188] Comparative Salt Example 4: Maleate Maleic acid (1.1 equiv.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (50 mg, 1.0 equiv.) in iPrOH (10 vol.) at 40° C. The resulting slurry was stirred at room temperature overnight. The solid was collected to give the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol.

[0189] The salt was slightly hygroscopic under the test conditions (40°C and 75% RH for 2 days), where a mass loss of 0.9 wt% to 1.4 wt% was attributed to water observed between 25 and 155°C during subsequent TGMS analysis.

[0190] During the experiment, it was observed that the filtration of the maleate salt was very slow due to the formation of very fine solids.

[0191] The title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol was used in recrystallization trials to find conditions that promote the formation of larger particles and improved filtration. The conditions identified in the screening experiments were further applied to salt formation experiments on a 50 mg scale, the results of which are shown in the table below.

[0192] [Table 7]

[0193] Comparative Salt Example 5: Citrate An aqueous solution of citric acid (1M, 1.1 eq.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (40 mg, 1.0 eq.) in THF / water (50:50 v:v) at room temperature. The resulting mixture was lyophilized overnight. No crystallization occurred.

[0194] Half of the mixture was dissolved in EtOAc; the other half of the mixture was dissolved in MeCN. The solution was subjected to three temperature cycles from 5° C. to 50° C. for 12 hours each, then left at room temperature for 3 days. No crystallization occurred.

[0195] Comparative Salt Example 6: Succinate Succinic acid (1.0 equiv.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (100 mg, 1.0 equiv.) in iPrOH (20 vol.) at 40° C. The resulting mixture was stirred at room temperature overnight. No crystallization occurred.

[0196] Comparative Salt Example 7: p-Toluenesulfonate p-Toluenesulfonic acid (1.2 equiv.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (100 mg, 1.0 equiv.) in i-PrOH (20 volumes) at 40° C. The resulting slurry was stirred at room temperature overnight. The solid was collected to give the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (106%, 86.9% pure by HPLC).

[0197] During the experiment, it was observed that the filtration of the p-toluenesulfonate salt was very slow due to the formation of very fine solids.

[0198] The salt was slightly hygroscopic under the test conditions (40 °C and 75% RH for 2 days), where a mass loss of 1.6 wt% to 2.1 wt% was attributed to water observed between 25 and 160 °C during subsequent TGMS analysis.

[0199] Comparative Salt Example 8: Fumarate Fumaric acid (1.2 equiv.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (100 mg, 1.0 equiv.) in EtOH (10 vol.) at 40° C. The resulting mixture was stirred at room temperature overnight. No crystallization occurred.

[0200] The mixture was evaporated to dryness and then crystallized from iPrOH. The solid was collected to give the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol.

[0201] Comparative Salt Example 9: Oxalate An aqueous solution of oxalic acid (1M, 1.1 equiv.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (40 mg, 1.0 equiv.) in THF / water (50:50 v:v) at room temperature. The resulting mixture was lyophilized overnight.

[0202] Half of the mixture was dissolved in EtOAc; the other half of the mixture was dissolved in MeCN. The solution was subjected to three temperature cycles from 5° C. to 50° C. for 12 hours each, then left at room temperature for 3 days. In each case, the solid was collected to give the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (98.1% purity by HPLC).

[0203] The formation of oxalate is 1 This was confirmed by 1 H-NMR spectrum, which showed an amine:acid ratio of 1:1.

[0204] Characterization of the solid-state properties of the title salt using XRPD, DSC, and DVS techniques showed that the material was crystalline with a high melting point at 171 °C. The salt was physically stable and not hygroscopic under the conditions tested (40 °C and 75% RH for 2 days) and showed no significant mass loss from 60 to 160 °C upon subsequent TGMS analysis.

[0205] Due to concerns regarding potential nephrotoxicity in diabetic patients, further scale-up of the title salt was not performed.

[0206] Comparative Salt Example 10: Tartrate An aqueous solution of L-(+)-tartaric acid (1M, 1.1 eq.) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (40 mg, 1.0 eq.) in THF / water (50:50 v:v) at room temperature. The resulting mixture was lyophilized overnight. No crystallization occurred.

[0207] Half of the mixture was dissolved in EtOAc; the other half of the mixture was dissolved in MeCN. The solution was subjected to three temperature cycles from 5° C. to 50° C. for 12 hours each, then left at room temperature for 3 days. No crystallization occurred.

[0208] Biological Examples L6-myoblasts were grown in Dulbecco's modified Eagle's medium (DMEM) containing 1 g / L glucose supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 50 U / mL penicillin, 50 μg / mL streptomycin, and 10 mM HEPES. Cells were plated at 1 × 10 5 After reaching 90% confluence, the cells were grown in medium containing 2% FBS for 7 days, where they were allowed to differentiate into myotubes.

[0209] Biological Example 1: Glucose Uptake Differentiated L6-myotubes were serum-starved overnight in medium containing 0.5% fatty acid-free BSA and incubated with 1 × 10 -5 After 1 hour and 40 minutes, cells were washed twice with warm glucose-free medium or PBS, and another portion of agonist was added in glucose-free medium. After 20 minutes, cells were stimulated with 50 nM 3 After exposure to H-2-deoxyglucose for 10 min, cells were washed three times with ice-cold glucose-free medium or PBS and lysed in 0.2 M NaOH (400 μL / well) for 1 h at 60° C. Cell lysates were mixed with 4 mL of scintillation buffer (Emulsifier Safe, Perkin Elmer) and radioactivity was detected in a β-counter (Tri-Carb 4810TR, Perkin Elmer).

[0210] Compound Example 1 exhibited activity greater than 75% of that of isoproterenol.

[0211] Biological Example 2: Measurement of Intracellular cAMP Levels Differentiated cells were serum-starved overnight and then resuspended in stimulation buffer (HBSS, pH 7.4 supplemented with 1% BSA, 5 mM HEPES, and 1 mM IBMX) at a final concentration of 1 × 10 -5The cells were stimulated with M agonists for 15 min. The medium was then aspirated, 100 μL of 95% EtOH was added to each well of the 24-well plate, and the cells were kept overnight at −20° C. The EtOH was evaporated, and 500 μL of lysis buffer (1% BSA, 5 mM HEPES, and 0.3% Tween 20, pH 7.4) was added to each well. The plates were kept at −80° C. for 30 min, and then at −20° C. until the day of detection when the samples were thawed. The intracellular cAMP level was detected using an AlphaScreen cAMP kit (Perkin Elmer 6760635D).

[0212] Compound Example 1 exhibited activity that was less than 50% of that of isoproterenol.

Claims

1. Compounds of Formula I: 【Chemistry 1】 Hemitartrate salt of.

2. 2. The salt of claim 1, wherein the hemitartrate salt comprises a (2R,3R)-tartrate salt.

3. 3. The salt of claim 2, wherein the hemitartrate tartrate consists essentially of (2R,3R)-tartrate.

4. The salt of any one of claims 1 to 3, wherein the salt has a purity of greater than about 90%.

5. 4. The salt according to any one of claims 1 to 3, wherein the salt has a melting point of about 209 to about 213°C at atmospheric pressure.

6. A pharmaceutical composition comprising a salt according to any one of claims 1 to 3, and optionally one or more pharmaceutically acceptable adjuvants, diluents and / or carriers.

7. 7. The pharmaceutical composition of claim 6, wherein the compound of formula I has an enantiomeric excess of at least 90%.

8. Use of a salt according to one of claims 1 to 3 for the manufacture of a medicament for the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

9. 7. The pharmaceutical composition of claim 6 for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.

10. 10. The composition for use of claim 9, wherein the hyperglycemia or disorder characterized by hyperglycemia is or is characterized by a patient exhibiting severe insulin resistance.

11. 10. The composition for use according to claim 9, wherein the disorder characterized by hyperglycemia is selected from the group consisting of type 2 diabetes, Rabson-Mendenhall syndrome, Donahue syndrome (leprechaunism), insulin resistance types A and B syndrome, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.

12. A combination product comprising: (a) a salt according to any one of claims 1 to 3; (b) one or more other therapeutic agents useful in said treatment of hyperglycemia or a disorder characterized by hyperglycemia; and Including, wherein each of components (a) and (b) is optionally formulated in admixture with one or more pharmaceutically acceptable adjuvants, diluents, or carriers; Combination products.

13. A kit of parts comprising: (a) the pharmaceutical composition of claim 6; (b) one or more other therapeutic agents useful in said treatment of hyperglycemia or a disorder characterized by hyperglycemia, optionally mixed with one or more pharmaceutically acceptable adjuvants, diluents, or carriers; and Including, A kit-of-parts, wherein components (a) and (b) are each provided in a form suitable for administration in conjunction with the other.

14. A process for the preparation of the salt according to any one of claims 1 to 3, comprising reacting a compound of formula (I): 【Chemistry 2】 with tartaric acid or a solution of tartaric acid.

15. The process of claim 14, wherein the solvent for the solution of tartaric acid is ethanol or an ethanol-water mixture.

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