Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/61—Halogen atoms or nitro radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
  • C07C59/225—Saturated compounds having only one carboxyl group and containing keto groups containing —CHO groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
  • C07C59/255—Tartaric acid

Definitions

• the present invention relates to novel salts and compositions, and their use in the treatment of hyperglycaemia and disorders characterised by hyperglycaemia, such as type 2 diabetes.
• the invention relates to novel salts, compositions and methods for the treatment of conditions such as type 2 diabetes through activation of the ⁇ 2 -adrenergic receptor.
• such salts are thought to have a beneficial side- effect profile as they do not exert their effect through significant cAMP release.
• Hyperglycaemia or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. If not treated, hyperglycaemia can be a serious problem, potentially developing into life-threatening conditions such as ketoacidosis. For example, chronic hyperglycemia may cause injury to the heart, and is strongly associated with heart attacks and death in subjects with no coronary heart disease or history of heart failure. There are various causes of hyperglycaemia, including diabetes and severe insulin resistance.
• Severe insulin resistance is a condition wherein the patent experiences very low levels of (or, in extreme cases, no significant) response to insulin.
• SIR Severe insulin resistance
• the majority of these conditions have genetic causes, such as mutations in the insulin receptor gene.
• the prevalence for Donohue’s syndrome, Rabson-Mendenhall syndrome and Type A syndrome of insulin resistance has been reported to vary from about 50 reported cases to 1 in 100,000.
• diabetes comprises two distinct diseases, type 1 (or insulin-dependent diabetes) and type 2 (insulin-independent diabetes), both of which involve the malfunction of glucose homeostasis.
• type 1 diabetes or insulin-dependent diabetes
• type 2 diabetes affects more than 400 million people in the world and the number is rising rapidly.
• Type 2 diabetes Complications of type 2 diabetes include severe cardiovascular problems, kidney failure, peripheral neuropathy, blindness and, in the later stages of the disease, even loss of limbs and, ultimately death.
• Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and there is presently no definitive cure. Most treatments used today are focused on remedying dysfunctional insulin signalling or inhibiting glucose output from the liver but many of those treatments have several drawbacks and side effects. There is thus a great interest in identifying novel insulin-independent ways to treat type 2 diabetes. In type 2 diabetes, the insulin-signalling pathway is blunted in peripheral tissues such as adipose tissue and skeletal muscle.
• Methods for treating type 2 diabetes typically include lifestyle changes, as well as 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.
• patients often require insulin injections in combination with oral medications to manage their diabetes.
• most common drugs have side effects including downregulation or desensitization of the insulin pathway and/or the promotion of lipid incorporation in adipose tissue, liver and skeletal muscle. There is thus a great interest in identifying novel ways to treat metabolic diseases including type 2 diabetes that do not include these side effects.
• Following a meal increased blood glucose levels stimulate insulin release from the pancreas.
• Insulin mediates normalization of the blood glucose levels. Important effects of insulin on glucose metabolism include facilitation of glucose uptake into skeletal muscle and adipocytes, and an increase of 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. The signalling pathway downstream from the insulin receptor has been difficult to understand in detail.
• control of glucose uptake by insulin involves activation of the insulin receptor (IR), the insulin receptor substrate (IRS), the phosphoinositide 3-kinase (PI3K) and thus stimulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), the mammalian target of rapamycin (also called the mechanistic target of rapamycin, mTOR), Akt/PKB (Akt) and TBC1D4 (AS160), leading to translocation of the glucose transporter 4 (GLUT4) to the plasma membrane.
• Akt activation is considered necessary for GLUT4 translocation.
• skeletal muscles constitute a major part of the body weight of mammals and have a vital role in the regulation of systemic glucose metabolism, being responsible for up to 85% of whole-body glucose disposal.
• Glucose uptake in skeletal muscles is regulated by several intra- and extracellular signals. Insulin is the most well studied mediator but others also exist.
• AMPK AMP activated kinase
• Blood glucose levels may be regulated by both insulin and catecholamines, but they are released in the body in response to different stimuli. Whereas insulin is released in response to the rise in blood sugar levels (e.g. after a meal), epinephrine and norepinephrine are released in response to various internal and external stimuli, such as exercise, emotions and stress, and also for maintaining tissue homeostasis.
• Insulin is an anabolic hormone that stimulates many processes involved in growth including glucose uptake, glycogen and triglyceride formation, whereas catecholamines are mainly catabolic. Although insulin and catecholamines normally have opposing effects, it has been shown that they have similar actions on glucose uptake in skeletal muscle (Nevzorova et al., Br.
• All ARs are G protein-coupled receptors (GPCRs) located in the cell membrane and characterized by an extracellular N-terminus, followed by seven transmembrane a-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus.
• GPCRs G protein-coupled receptors
• TM-1 to TM-7 seven transmembrane a-helices
• IL-1 to IL-3 three intracellular loops
• EL-1 to EL-3 extracellular C-terminus.
• the ⁇ 1 -ARs comprise the ⁇ 1A , ⁇ 1B and ⁇ 1 D subtypes while ⁇ 2 -ARs are divided into ⁇ 2A , ⁇ 2B and ⁇ 2c .
• the p-ARs are also divided into the subtypes ⁇ 1 , ⁇ 2 , and ⁇ 3 , of which ⁇ 2 -AR is the major isoform in skeletal muscle cells.
• ARs are G protein coupled receptors (GPCRs) that signal through classical secondary messengers such as cyclic adenosine monophosphate (cAMP) and phospholipase C (PLC).
• GPCRs G protein coupled receptors
• cAMP cyclic adenosine monophosphate
• PLC phospholipase C
• Glucose uptake is mainly stimulated via facilitative glucose transporters (GLUT) that mediate glucose uptake into most cells.
• GLUTS facilitative glucose transporters
• GLUT1-14 transporter proteins that mediate transport of glucose and/or fructose over the plasma membrane down the concentration gradient.
• GLUT1-14 There are fourteen known members of the GLUT family, named GLUT1-14, divided into three classes (Class I, Class II and Class III) dependent 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 mainly transports glucose (in contrast to Class II that also transports fructose).
• GLUT1 is ubiquitously expressed and is responsible for basal glucose transport.
• GLUT4 is only expressed in peripheral tissues such as skeletal muscle, cardiac muscle and adipose tissues. GLUT4 has also been reported to be expressed in, for example, the brain, kidney, and liver. GLUT4 is the major isoform involved in insulin stimulated glucose uptake. The mechanism whereby insulin signalling increases glucose uptake is mainly via GLUT4 translocation from intracellular storage to the plasma membrane. It is known that GLUT4 translocation is induced by stimulation of the ⁇ 2 -adrenergic receptor.
• a possible treatment of a condition involving dysregulation of glucose homeostasis or glucose uptake in a mammal, such as type 2 diabetes would involve the activation of the ⁇ 2 -adrenergic receptor leading to GLUT4 translocation to the plasma membrane and promotion of glucose uptake into skeletal muscle leading to normalization of whole body glucose homeostasis.
• the treatment does not involve signalling through cAMP as this would lead to a favourable side-effect profile.
• 2019/053427 has been shown to act as an agonist at the ⁇ 2 -adrenergic receptor, increasing glucose uptake in skeletal muscle but without leading to a significant release of cyclic adenosine monophosphate (cAMP).
• cAMP cyclic adenosine monophosphate
• active ingredients such as (R)- 2-(tert- butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol, so as to improve their ease of use, particularly when used in the preparation of medicaments.
• active ingredients in a form having, inter alia, improved ease of formulation, improved stability, improved bioavailability, improved taste, improved ability to be scaled up, and/or lower hygroscopicity.
• active ingredients in a form having, inter alia, improved ease of formulation, improved stability, improved bioavailability, improved taste, improved ability to be scaled up, and/or lower hygroscopicity.
• active ingredients there also remains a need to be able to obtain active ingredients as crystalline solids in a high yield and with high purity (in some circumstances including a high enantiomeric excess).
• (R )-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)- ethan-1-ol may be prepared in a scalable manner in high yield as hemi-tartrate salts having high purity and high enantiomeric excess.
• a number of other salt forms of this compound have either been not susceptible to crystallisation, obtainable in only low yields and/or low purities, found to have high hygroscopicity, unsuitable for use as pharmaceuticals (e.g. due to concerns regarding toxicity), and/or have been found to be unsuitable for scale- up production due to filtration problems.
• a hemi-tartrate salt of a compound of formula I which compound of formula I may be referred to herein as "the compound of the invention” and which hemi-tartrate salts may be referred to herein as “salts of the invention”.
• references herein to salts of particular aspects of the invention will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments.
• the compound of formula I is otherwise known by the IUPAC name (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol.
• Tartaric acid is otherwise known as 2,3-dihydroxybutanedioic acid or 2,3-dihydroxy- succinic acid, whose structure may be represented graphically as: The skilled person will understand that tartaric acid may exist as three stereoisomers due to the two asymmetric carbon centres existing in the molecule.
• (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 which may be represented graphically as: (S,S)-tartaric acid (also known as levotartaric acid, (2S, 3S)-tartaric acid, D-(-)-tartaric acid and D-tartaric acid) is the other of the pair of enantiomers of tartaric acid, and has the structure which may be represented graphically as: (2R,3S)-tartaric acid (also known as mesotartaric acid) is a stereoisomer of tartaric acid, and has the structure which may be represented graphically as: For the avoidance of doubt, all stereoisomers and mixtures thereof of tartaric acid (and, therefore, of tartrate) are included within the scope of the invention.
• tartrate refers to the anion of tartaric acid. It will therefore be understood that the term “tartrate salt of a compound of formula I” refers to a chemical compound consisting of an assembly of anions of tartaric acid and associated cations of the compound of formula I. Tartaric acid may exist as a monoanion (also known as the hydrogen tartrate anion or semi-tartrate anion) or as a dianion (also known as the tartrate dianion). Accordingly, as used herein, the term “tartrate” will be taken to include the tartrate monoanion, the tartrate dianion, and/or the mixtures thereof necessary to provide the appropriate charge balance within the salt.
• hemi in “hemi-tartrate salt of a compound of formula I” means that the stoichiometry between the compound of formula I and tartrate in the salt is 1:0.5 (i.e. equivalent to 2:1). Accordingly, the structure of the hemi-tartrate salt of the compound of formula I may, for example, be represented graphically as:
• salts of the first aspect of the invention are solid under ambient conditions, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof. Unless indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
• the tartrate i.e. the tartrate counterion present in the compound of the invention
• the tartrate salt comprises (2R, 3R)-tartrate.
• the tartrate salt consists essentially of (2R, 3R)-tartrate.
• the relevant stereochemical configuration i.e. of the tartaric acid
• an enantiomeric excess e.e.
• diastereomeric excess d.e.
• the tartrate component of the salts of the invention is (2R, 3R)-tartrate.
• references to the substantial absence of the corresponding opposite stereoisomer will refer to the desired stereoisomer being present at a purity of at least 80% (e.g. at least 90%, such as at least 95%) relative to the opposite stereoisomer.
• compounds may be indicated to be present in the substantial absence of the compound in the other configuration (i.e.
• references to the enantiomeric excess (e.e.) of the salts of the invention will refer to enantiomeric excess (e.e.) of the compound of formula I component the salts of the invention.
• the relevant salt form i.e.
• the salt form as claimed being a combination of the compound of formula I and the tartaric acid
• the salt has a melting point of from about 209 to about 213 °C at atmospheric pressure. In more particular embodiments, the salt has a melting point of from about 210 to about 212 °C, such as about 211 °C.
• the salt is crystalline (i.e. a crystalline solid; when observed at room temperature, e.g. 20 °C, and atmospheric pressure).
• the compound (salt) of the invention is crystalline and therefore may exist as a particular crystalline form.
• the skilled person will be familiar with techniques that may be used to characterise such crystalline forms, such as X-ray powder diffraction (XR.PD).
• the salt is characterised by X-ray powder diffraction peaks at 2 ⁇ angles comprising peaks at 11.35 17.24 and 18.19.
• the salt is characterised by X-ray powder diffraction peaks at 2 ⁇ angles comprising peaks at 11.35, 17.24, 18.19 and 18.91.
• the salt is characterised by X-ray powder diffraction peaks at 2 ⁇ angles comprising peaks at 11.35, 17.24, 18.19, 18.91 and 22.80.
• the salt is characterised by at least three X-ray powder diffraction peaks at 2 ⁇ angles selected from those indicated in Table A (below) : T
• the salt is characterised by having at least four, such as at least five, including at least six, seven, eight or nine (or, particularly, at least 10) X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table A.
• the salt is characterised by having X-ray powder diffraction peaks at 2 ⁇ angles comprising peaks corresponding (or substantially corresponding) to those in Table A.
• the salt is characterised by having an X-ray powder diffraction pattern substantially according to that shown in Figure 1.
• the salt is a solvate.
• solvent we mean that the salt contains molecules of solvent inside the crystalline structure, which solvents may be those used in the preparation thereof (e.g. i-PrOH, EtOH or a mixture of EtOH and water; see the examples provided herein).
• the salt is a hydrate.
• hydrate we mean that the salt contains molecules of water inside the crystalline structure.
• the salt may be described as substantially non-hygroscopic or non-hygroscopic, which terms will be understood by those skilled in the art.
• substantially non-hygroscopic may be taken to mean that after exposure to conditions of 75% relative humidity at 40 °C for 2 days, the salt absorbs 0.5 wt.% or less of water (such as less than 0.3 wt.% or 0.2 wt.% water, more particularly 0.1 wt.% or less of water).
• Medical uses As indicated herein, the compounds of the invention, and therefore compositions and kits comprising the same, are useful as pharmaceuticals.
• a salt of the first aspect of the invention as hereinbefore defined (i.e. a salt as defined in the first aspect of the invention, including all embodiments and particular features thereof), for use as a pharmaceutical (or for use in medicine).
• the salts of the invention may be of particular use in treating hyperglycaemia or a disorder characterized by hyperglycaemia.
• a salt of the first aspect of the invention as hereinbefore defined, for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.
• the use of a salt of the first aspect of the invention in the manufacture of a medicament for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia 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 hyperglycaemia or a disorder characterized by hyperglycaemia.
• a method of treating hyperglycaemia or a disorder characterized by hyperglycaemia comprising administering to a patient in need thereof a therapeutically effective amount of a salt of the first aspect of the invention.
• hyperglycaemia as used herein will be understood by those skilled in the art to refer to a condition wherein an excessive amount of glucose circulates in blood plasma of the subject experiencing the same.
• it may refer to a subject (e.g a human subject) having blood glucose levels higher than about 10.0 mmol/L (such as higher than about 11.1 mmol/L, e.g.
• references to the treatment of a particular condition take their normal meanings in the field of medicine.
• the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.
• the term may refer to achieving a reduction of blood glucose levels.
• the term in the case of treating hyperglycaemia or conditions characterised by hyperglycaemia, the term may refer to achieving a reduction of blood glucose levels (for example, to or below about 10.0 mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L to about 10.0 mmol/L), such as to or below about 7.5 mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L to about 7.5 mmol/L) or to or below about 6 mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L to about 6.0 mmol/L)).
• blood glucose levels for example, to or below about 10.0 mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L to about 10.0 mmol/L), such as to or below about 7.5 mmol/mL (e.g. to levels in the range of from about 4.0 mmol/L
• references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients.
• the treatment is in a mammal (e.g. a human).
• the term therapeutically effective amount will refer to an amount of a salt 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).
• the compounds of the first aspect of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds that possess pharmacological activity.
• compounds of the first aspect of the invention are useful in the treatment of hyperglycaemia or disorders characterized by hyperglycaemia (such as type 2 diabetes), which terms will be readily understood by one of skill in the art (as described herein).
• the treatment is of a disorder (which may also be referred to as a condition or disease) characterised by hyperglycaemia.
• salts of the invention i.e. hemi-tartrate salts of the compound of formula I, including all embodiments thereof
• the disorder is type 2 diabetes, such as type 2 diabetes of a sub-type selected from the list consisting of maturity-onset diabetes in the young (MODY), ketosis-prone diabetes in adults, latent autoimmune diabetes of adults (LADA), and gestational diabetes.
• the treatment of type 2 diabetes is in a non-obese patient.
• BMI Body Mass Index
• the treatment may be of hyperglycaemia in a patient who is at risk of developing type 2 diabetes, which condition may be defined as pre-diabetes.
• salts of the invention may be useful in the prevention of type 2 diabetes (e.g. in a patient having pre-diabetes).
• prevention includes references to the prophylaxis of the disease or disorder (and vice-versa).
• references to prevention may also be references to prophylaxis, and vice versa.
• 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).
• the type 2 diabetes is characterised by the patient displaying severe insulin resistance (SIR).
• the treatment may be of hyperglycaemia in a patient having type 1 diabetes.
• salts of the invention may be useful in the treatment of hyperglycaemia in type 1 diabetes.
• the skilled person will understand that salts of the invention may be useful in treating hyperglycaemia in patients having impaired insulin production, such as in patients having cystic fibrosis.
• the disorder characterized by hyperglycaemia is cystic fibrosis-related diabetes.
• the disorder characterised by hyperglycaemia is (or is characterized by) severe insulin resistance (SIR), which may be understood by those in the art to refer to disorders wherein typically the subject has normal, or in some cases increased, insulin production but significantly reduced insulin sensitivity.
• SIR severe insulin resistance
• such patients may be non-obese (e.g. being of a healthy weight).
• such treatments are performed in patients who are not defined as being obese (e.g. in patients who are defined as being of a healthy weight).
• SIR may be identified in a patient based in said patient having fasting insulin >150 pmol/L and/or a peak insulin on glucose tolerance testing of >1,500 pmol/L, particularly in individuals with a BMI ⁇ 30kg/m 2 (which patient may otherwise have normal glucose tolerance). More particularly, SIR may be characterised by the patient having no significant response to the presence of insulin, which may result from a defect (e.g. a genetic defect) in the function of the insulin receptor.
• a defect e.g. a genetic defect
• SIR SIR-Mendenhall syndrome
• Donohue SIR
• Type A and Type B syndromes of insulin resistance the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndromes
• pseudoacromegaly and lipodystrophy.
• More particular disorders that may be characterised by SIR include Donohue’s syndrome and Type A syndrome of insulin resistance and, yet more particularly, Rabson-Mendenhall syndrome.
• treatment with salts of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
• treatment with compounds of the invention may be combined with other means for the treatment of type 2 diabetes, such as treatment with one or more other therapeutic agent that is useful in the treatment of type 2 diabetes as known to those skilled in the art, such as therapies comprising requiring the patient to undergo a change of diet and/or undertake exercise regiments, and/or surgical procedures designed to promote weight loss (such as gastric band surgery).
• treatment with salts of the invention may be performed in combination with (e.g. in a patient who is also being treated with) one or more (e.g. one) additional compounds (i.e.
• salts of the first aspect of the invention may be useful in the treatment of a non-alcoholic fatty liver disease (NAFLD).
• NAFLD non-alcoholic fatty liver disease
• steatosis steatosis
• NAFLD non-alcoholic steatohepatitis
• NASH is now considered to be one of the main causes of cirrhosis (includeing cryptogenic cirrhosis) in the developed world.
• the exact cause of NASH has yet to be elucidated, and it is almost certainly not the same in every patient. It is most closely related to insulin resistance, obesity, and the metabolic syndrome (which includes diseases related to diabetes mellitus type 2, insulin resistance, central (truncal) obesity, hyperlipidaemia, low high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and hypertension).
• diabetes mellitus type 2 insulin resistance
• central (truncal) obesity hyperlipidaemia
• HDL low high-density lipoprotein
• a salt of the invention i.e. hemi-tatrate salts of the compound of formula I, including all embodiments thereof
• a method of treating a 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. hemi-tartrate salts of the compound of formula I, including all embodiments thereof).
• steatosis i.e. hepatic steatosis
• the term “steatosis” encompasses the abnormal retention of fat (i.e. lipids) within a cell.
• the treatment or prevention is of a fatty liver disease which is characterized by steatosis.
• excess lipids accumulate in vesicles that displace the cytoplasm of the cell. Over time, the vesicles can grow large enough to distort the nucleus, and the condition is known as macrovesicular steatosis.
• microvesicular steatosis Steatosis is largely harmless in mild cases; however, large accumulations of fat in the liver can cause significant health issues. Risk factors associated with steatosis include diabetes mellitus, protein malnutrition, hypertension, obesity, anoxia, sleep apnea and the presence of toxins within the cell. As described herein, fatty liver disease is most commonly associated with alcohol or a metabolic syndrome (for example, diabetes, hypertension, obesity or dyslipidemia). Therefore, depending on the underlying cause, fatty liver disease may be diagnosed as alcohol-related fatty liver disease or non-alcoholic fatty liver disease (NAFLD).
• NAFLD non-alcoholic fatty liver disease
• Particular diseases or conditions that are associated with fatty liver disease that are not related to alcohol include metabolic conditions such as diabetes, hypertension, obesity, dyslipidemia, abetalipoproteinemia, glycogen storage diseases, Weber–Christian disease, acute fatty liver of pregnancy, and lipodystrophy.
• Other non-alcohol related factors related to fatty liver diseases include malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, polycystic ovary syndrome and diverticulosis.
• the salts of the invention have been found to be particularly useful in the treatment or prevention of NAFLD, which may be referred to as a fatty liver disease which is not alcohol related.
• a fatty liver disease which is “not alcohol related” may be diagnosed wherein alcohol consumption of the patient is not considered to be a main causative factor.
• a typical threshold for diagnosing a fatty liver disease as “not alcohol related” is a daily consumption of less than 20 g for female subjects and less than 30 g for male subjects. If left untreated, subjects suffering from fatty liver disease may begin to experience inflammation of the the liver (hepatitis). It has been postulated that one of the possible causes of this inflammation may be lipid peroxidative damage to the membranes of the liver cells. Inflammation of a fatty liver can lead to a number of serious conditions and it is therefore desirable to treat or prevent fatty liver disease before inflammation occurs.
• the treatment or prevention is of a NAFLD which is associated with inflammation.
• NAFLD Non-alcoholic steatohepatitis
• steatosis is the most aggressive form of NAFLD, and is a condition in which excessive fat accumulation (steatosis) is accompanied by inflammation of the liver. If advanced, NASH can lead to the development of scar tissue in the liver (fibrosis) and, eventiually, cirrhosis.
• the compounds of the invention have been found to be useful in the treatment or prevention of NAFLD, particularly when accompanied by inflamation of the liver. It follows that the salts of the invention are also useful in the treatment or prevention of NASH.
• the treatment or prevention is of non-alcoholic steatohepatitis (NASH).
• NASH non-alcoholic steatohepatitis
• treatment with salts of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
• treatment with salts of the invention may be combined with other means for the treatment of a fatty liver disease, as described herein, such as treatment with one or more other therapeutic agent that is useful in the treatment of a fatty liver disease as known to those skilled in the art; for example, therapies comprising requiring the patient to undergo a change of diet and/or undertake exercise regiments, and/or surgical procedures designed to promote weight loss (such as gastric band surgery).
• treatment with salts of the invention may be performed in combination with (e.g. in a patient who is also being treated with) one or more (e.g. one) additional compounds (i.e. therapeutic agents) that are capable of reducing the level of fat (e.g. triglycerides) in the liver.
• additional compounds i.e. therapeutic agents
• References to treatment of a fatty liver disease may refer to achieving a therapeutically significant reduction of fat (e.g. triglycerides levels) in liver cells (such as a reduction of at least 5% by weight, e.g. a reduction of at least 10%, or at least 20% or even 25%).
• Pharmaceutical compositions As described herein, salts of the first aspect of the invention are useful as pharmaceuticals.
• Such salts may be administered alone or may be administered by way of known pharmaceutical compositions/formulations.
• 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 pharmaceutically acceptable adjuvant, diluent and/or carrier.
• references herein to salts of the first aspect of the invention being for particular uses (and, similarly, to 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.
• a pharmaceutical composition for use in the treatment of hyperglycaemia or a disoder characterized by hyperglycaemia comprising a salt as defined in the first aspect of the invention, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.
• a pharmaceutical composition for use in the treatment or prevention of a non-alcoholic fatty liver disease as defined herein.
• salts of the first (and, therefore, second and third) aspect of the invention may act systemically and/or locally (i.e. at a particular site).
• salts and compositions as described in the first to fifth aspects of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
• Pharmaceutical compositions as described herein will 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.
• pharmaceutical compositions may be formulated for topical administration.
• the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants, intranasal dosage forms, or forms suitable for topical administration.
• a pharmaceutically acceptable dosage form including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants, intranasal dosage forms, or forms suitable for topical administration.
• salts of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.
• the salt in the preparation of pharmaceutical formulations for oral administration, may 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 disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
• disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
• the mixture may then be processed into granules or compressed into tablets.
• Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g.
• hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
• Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready- made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
• Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g.
• solutions or suspensions containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol.
• liquid preparations may contain colouring agents, flavouring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agent.
• Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
• Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials.
• Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
• suitable solvent extemporaneously before use.
• salts of the invention may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art.
• Oral, pulmonary and topical dosages may range from between about 0.01 ⁇ g/kg/day of body weight per day ( ⁇ g/kg/day) to about 20 mg/kg/day of body weight per day (mg/kg/day), preferably about 0.1 ⁇ g/kg/day to about 5 mg/kg/day, and more preferably about 1 ⁇ g/kg/day to about 2 mg/kg/day (e.g. about 10 ⁇ g/kg/day to about 1 mg/kg/day).
• treatment with such salts may comprise administration of a formulations typically containing between about 1 ⁇ g to about 2000 mg, for example between about 10 ⁇ g to about 500 mg, or between 100 ⁇ g to about 200 mg (e.g. about 1 mg to about 100 mg), of the active ingredient(s).
• the most preferred doses will range from about 0.001 to about 10 ⁇ g/kg/hour during constant rate infusion.
• treatment may comprise administration of such salts and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g.
• the skilled person e.g. the physician
• treatment with salts of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
• treatment with salts of the invention may be combined with other means for the treatment of hyperglycaemia or a disoder characterized by hyperglycaemia (as defined herein, such as type 2 diabetes), such as treatment with one or more other therapeutic agent that is useful in the treatment of hyperglycaemia or a disoder characterized by hyperglycaemia(as defined herein, such as type 2 diabetes).
• the pharmaceutical composition may further comprise one or more additional (i.e. other) therapeutic agent.
• the one or more additional therapeutic agent is an agent for the treatment of type 2 diabetes as known to those skilled in the art, such as metformin, sulfonylureas (e.g.
• glipizide glucotrol
• gliclazide glibenclamide
• glyburide Micronase
• glibornuride gliquidone
• glisoxepide glyclopyramide
• glimepiride Amaryl
• glimiprime JB253 or JB558
• thiazolidinediones e.g. pioglitazone, rosiglitazone (Avandia), lobeglitazone (Duvie) and troglitazone (Rezulin)
• dipeptidyl peptidase-4 inhibitors e.g.
• sitagliptin vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, dutogliptin and omarigliptin
• SGLT2 inhibitors e.g.
• glucagon-like peptide-1 GLP- 1 analogues.
• GLP-1 glucagon-like peptide-1
• a combination product comprising: (A) a salt as defined in the first aspect of the invention; and (B) one or more additional therapeutic agent, wherein each of components (A) and (B) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.
• kits-of-parts comprising: (a) a salt as defined in the first (or second and/or third) aspect of the invention, (or a pharmaceutical composition comprising the same) or a pharmaceutical composition as defined in the fourth or fifth aspect of the invention; and (b) one or more other therapeutic agent, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
• a salt as defined in the first (or second and/or third) aspect of the invention, (or a pharmaceutical composition comprising the same) or a pharmaceutical composition as defined in the fourth or fifth aspect of the invention
• one or more other therapeutic agent optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
• the additional therapeutic agent is a therapeutic agent that is useful for the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (e.g. type 2 diabetes), as known to those skilled in the art (such as those described herein).
• the additional therapeutic agent is an agent that: (i) is capable of reducing blood sugar levels; and/or (ii) is an insulin sensitizer; and/or (iii) is able to enhance insulin release, which agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).
• references to therapeutic agents capable of reducing blood glucose levels may refer to compounds capable of reducing levels of blood by at least 10% (such as at least 20%, at least 30% or at least 40%, for example at least 50%, at least 60%, at least 70% or at least 80%, e.g. at least 90%) when compared to the blood glucose levels prior to treatment with the relevant compound.
• the additional therapeutic agent is an agent for the treatment or prevention of a non-alcoholic fatty liver disease (such as NASH), which agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).
• compositions/formulations, combination products and kits as described herein may be prepared in accordance with standard and/or accepted pharmaceutical practice.
• a process for the preparation of a pharmaceutical composition/formulation, as hereinbefore defined which process comprises bringing into association a salt of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable adjuvant, diluent or carrier.
• a process for the preparation of a combination product or kit-of-parts as hereinbefore defined comprises bringing into association a salt of the invention, as hereinbefore defined, with the other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (e.g. type 2 diabetes), and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
• a salt of the invention as hereinbefore defined
• the other therapeutic agent that is useful in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia (e.g. type 2 diabetes)
• at least one pharmaceutically-acceptable adjuvant, diluent or carrier e.g. type 2 diabetes
• kits of parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.
• Preparation of compounds and salts The compounds as defined in the first (and, therefore, second and third) aspect of the invention (i.e. the compound of formula I) may be prepared in accordance with techniques that are well known to those skilled in the art, such as those described in the examples provided hereinafter.
• the compound of formula I may be made in accordance with the techniques described in international patent application WO 2019/053427, the content of which (in particular, the examples) is hereby incorporated by reference.
• the salts of the first (and, therefore, second and third) aspect of the invention i.e. the salts of the invention
• the compound of formula I may be reacted with tartaric acid or a solution of tartaric acid (or vice versa). Salt switching techniques may also be used to convert one salt into another salt.
• the salt of the invention is prepared by reacting a compound of formula I with a solution of tartaric acid (or vice versa).
• 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 scaling up of the manufacture of the hemi-tartrate salt of the compound of formula I with a high yield, high purity and high enantiomeric purity.
• Salts as described herein may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
• such salts may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.
• compounds of the invention are thought to be potent agonists of the ⁇ 2 -adrenergic receptor, which allows for increased glucose uptake in skeletal muscle cells.
• Compounds of the invention are also believed to provide suitable levels of metabolic stability.
• salts as described herein are thought to be agonists of the ⁇ 2 -adrenergic receptor without (or with only a relatively minimal effect in, such as a relatively lesser effect in (when compared to the effect in inducing increased glucose uptake)) inducing cAMP production. It is thought that this allows for the increased glucose uptake in skeletal muscle cells with lower levels of side effects than would result from other treatments.
• salts and compositions of the invention may have a number of advantages compared to the corresponding free base (i.e. the free base of the compound of formula I).
• the salts and compositions of the 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 lower hygroscopicity compared to the corresponding free base.
• Such salts will also ideally have low toxicity and thus be suitable for use in medicine (i.e. pharmaceutically acceptable).
• the free base of the compound of formula I is difficult to prepare as a solid, either being obtained as an oil or as a solid in low yield.
• Other salts of the compound of formula I either could not be crystallised, could only be crystallised in low yield and/or low purity, or formed such small crystals that filtration, isolation and subsequent scale- up of the synthesis was difficult.
• the hemi- tartrate salt of the compound of formula I may be readily obtained as a crystalline solid in high yield, with high purity (and in high enantiomeric excess) and in a form that demonstrates low hygroscopicity.
• Figure 1 shows an XRPD analysis of the hemitartrate salt of (R)-2-(tert--butylamino)-1- (5-fluoropyridin-3-yl)ethan-1-ol Examples
• the present invention is illustrated by way of the following examples. Chemicals and reagents were obtained from commercial suppliers and were used as received unless otherwise stated. All reactions involving moisture sensitive reagents were performed in oven or flame dried glassware under a positive pressure of nitrogen or argon. Abbreviations Abbreviations as used herein will be known to those skilled in the art. In particular, the following abbreviations may be used herein.
• Salt Example 1 Hemi-tartrate A solution of L-(+)-tartaric acid (6.21g, 0.5 eq) in EtOH (175 mL) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (17.57 g) in EtOH (525 mL, 30 vol) and H 2 O (7 mL) at rt. The mixture was refluxed until all precipitate was dissolved, then cooled. The resultant slurry was stirred at rt overnight and then at 0 to 5 °C for 2 h.
• Comparative Salt Example 10 Tartrate An aqueous solution of L-(+)-tartaric acid (1 M, 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 rt. The resultant mixture was freeze-dried overnight. No crystallisation occurred. Half of the mixture was dissolved in EtOAc; the other half of the mixture was dissolved in MeCN. The solutions were subjected to three temperature cycles between 5 and 50 °C of 12 h each, then left at rt for 3 days. No crystallisation occurred.
• 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 ⁇ g/mL streptomycin and 10 mM HEPES. Cells were plated at 1 ⁇ 10 5 cells per mL in 24- well plates. After reaching 90 % confluence the cells were grown in medium containing 2 % FBS for 7 days where upon cells differentiated into myotubes.
• DMEM Dulbecco’s Modified Eagle’s Medium
• Biological example 1 Glucose uptake Differentiated L6-myotubes were serum-starved overnight in medium containing 0.5 % fatty-acid free BSA and stimulated with an agonist, with a final concentration of 1 ⁇ 10 -5 M. After 1 h 40 min the cells were washed with warm glucose free medium or PBS twice and another portion of agonist was added to the glucose free medium. After 20 min the cells were exposed to 50 nM 3 H-2-deoxyglucose for 10 min before washed with ice cold glucose free medium or PBS three times and lysed with 0.2 M NaOH, 400 ⁇ L/well, for 1 h at 60 °C.
• Biological example 2 Measurement of intracellular cAMP levels Differentiated cells were serum-starved overnight and stimulated with an agonist, final concentration 1 ⁇ 10 -5 M, for 15 min in stimulation buffer (HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, pH 7.4).
• the medium was aspirated and 100 ⁇ L of 95 % EtOH was added to each well of the 24-well plate and cells were kept at -20 °C overnight.
• the EtOH was allowed to evaporate and 500 ⁇ L of lysis buffer (1 % BSA, 5 mM HEPES and 0.3 % Tween- 20, pH 7.4) was added to each well.
• the plate was kept at -80 °C for 30 min and then at -20 °C until the day of detection when the samples were thawed.
• Intracellular cAMP levels were detected using an alpha screen cAMP kit (6760635D from Perkin Elmer).
• the compound of Compound Example 1 showed an activity of less than 50% of that of isoproterenol.

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