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WO2025186320A1 - Combinaisons d'agonistes du récepteur bêta 2-adrénergique et d'inhibiteurs des sglt2 destinés à être utilisés dans le traitement de l'hyperglycémie ou d'un trouble caractérisé par l'hyperglycémie - Google Patents

Combinaisons d'agonistes du récepteur bêta 2-adrénergique et d'inhibiteurs des sglt2 destinés à être utilisés dans le traitement de l'hyperglycémie ou d'un trouble caractérisé par l'hyperglycémie

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Publication number
WO2025186320A1
WO2025186320A1 PCT/EP2025/056002 EP2025056002W WO2025186320A1 WO 2025186320 A1 WO2025186320 A1 WO 2025186320A1 EP 2025056002 W EP2025056002 W EP 2025056002W WO 2025186320 A1 WO2025186320 A1 WO 2025186320A1
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WIPO (PCT)
Prior art keywords
fluorophenyl
methanol
ethanol
pyridyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/056002
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English (en)
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WO2025186320A8 (fr
Inventor
Tore Bengtsson
Benjamin Pelcman
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Atrogi AB
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Atrogi AB
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Publication of WO2025186320A1 publication Critical patent/WO2025186320A1/fr
Publication of WO2025186320A8 publication Critical patent/WO2025186320A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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

Definitions

  • the present invention relates to methods for the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia.
  • the invention relates to methods for the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia, involving treatment and/or prophylaxis with a combination of a ⁇ 2-adrenergic receptor agonist and an SGLT2 inhibitor, and to compositions and kits-of-parts for use in such methods.
  • a ⁇ 2-adrenergic receptor agonist and an SGLT2 inhibitor
  • hyperglycaemia can be a serious problem, potentially developing into life-threatening conditions such as ketoacidosis.
  • chronic hyperglycaemia 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.
  • hyperglycaemia There are various causes of hyperglycaemia, including diabetes and severe insulin resistance. Severe insulin resistance (SIR) is a condition wherein the patient experiences very low levels of (or, in extreme cases, no significant) response to insulin.
  • SIR Severe insulin resistance
  • Type 2 diabetes affects more than 400 million people in the world and the number is rising rapidly. 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.
  • pancreas In the later stages of the disease patients often require insulin injections in combination with oral medications to manage their diabetes. Further, 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.
  • side effects including downregulation or desensitization of the insulin pathway and/or the promotion of lipid incorporation in adipose tissue, liver and skeletal muscle.
  • 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.
  • IR insulin receptor
  • IRS insulin receptor substrate
  • PI3K phosphoinositide 3-kinase
  • PIP3K phosphatidylinositol (3,4,5)-triphosphate
  • Akt/PKB
  • 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.
  • AMP activated kinase AMPK
  • 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.
  • ARs adrenergic receptors
  • GPCRs G protein-coupled receptors located in the cell membrane and characterized by an extracellular N-terminus, followed by seven transmembrane ⁇ -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.
  • ARs There are three different classes of ARs, with distinct expression patterns and pharmacological profiles: ⁇ 1-, ⁇ 2- and ⁇ -ARs.
  • the ⁇ 1-ARs comprise the ⁇ 1A, ⁇ 1B and ⁇ 1D subtypes while ⁇ 2-ARs are divided into ⁇ 2A, ⁇ 2B and ⁇ 2C.
  • the ⁇ -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
  • Glucose uptake is mainly stimulated via facilitative glucose transporters (GLUT) that mediate glucose uptake into most cells.
  • GLUTs are 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.
  • SGLT2 is a member of the sodium glucose cotransporter family, which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney. SGLT2 is located in the early proximal tubule, and is responsible for reabsorption of 80-90% of the glucose filtered by the kidney glomerulus. SGLT2 inhibitors (also known as gliflozins) are antihyperglycemic agents acting on the SGLT-2 proteins expressed in the proximal tubules of the kidneys.
  • SGLT2 inhibitors exert their effect by preventing the reabsorption of filtered glucose from the tubular lumen, thus leading to lower blood sugar levels.
  • Particular SGLT2 inhibitors include canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin.
  • canagliflozin dapagliflozin
  • empagliflozin empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin.
  • SGLT2 inhibitors lower blood glucose via a mechanism that is independent of insulin secretion and sensitivity. Functional pancreatic ⁇ -cells are not necessary for the activity of the medication. Therefore, therapies involving SGLT2 inhibitors are appropriate for patients with diminished ⁇ -cell function.
  • SGLT2 inhibitors are known to have a range of limitations, including an association with serious adverse events, such as female genital mycotic infections, urinary tract infections, increased urination, nausea, and constipation.
  • Other known risks of SGLT2 inhibitors include genitourinary infections, diabetic ketoacidosis, acute kidney injury, risk for amputation, hypotension and bone fractures (see, for example, Pittampalli S. et al, Risks vs Benefits for SGLT2 Inhibitor Medications. Fed Pract. 2018 Jul;35(7):45-48).
  • Pittampalli S. et al Risks vs Benefits for SGLT2 Inhibitor Medications. Fed Pract. 2018 Jul;35(7):45-48.
  • a combination of activation of the ⁇ 2-adrenergic receptor and treatment with an SGLT2 inhibitor represents a promising strategy for the treatment and/or prophylaxis of conditions characterized by high blood sugar levels (i.e. hyperglycaemia), such as diabetes (e.g. type 2 diabetes).
  • Medical treatments In a first aspect of the invention there is provided a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia, wherein the treatment and/or prophylaxis further comprises administration of an SGLT2 inhibitor.
  • a ⁇ 2- adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia, wherein the treatment and/or prophylaxis further comprises administration of an SGLT2 inhibitor.
  • a ⁇ 2- adrenergic receptor agonist in the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia, wherein the treatment and/or prophylaxis further comprises administration of an SGLT2 inhibitor.
  • a compound that is an SGLT2 inhibitor for use in the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia wherein the use further comprises administration of a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.
  • a method for the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia comprising: (i) administration of a therapeutically effective amount of an SGLT2 inhibitor, and (ii) administration of a therapeutically effective amount of ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • a method for the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia comprising administration of a therapeutically effective amount of an SGLT2 inhibitor to a patient in need thereof, wherein the patient is also being treated with a therapeutically effective amount of a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.
  • a method for the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia comprising administration of a therapeutically effective amount of a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient is also being treated with a therapeutically effective amount of an SGLT2 inhibitor.
  • uses, methods, compositions and kits-of-parts of other aspects of the invention as described herein may have any of the particular features described above for the first aspect of the invention, including all combinations thereof.
  • 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 terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.
  • references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients.
  • mammalian e.g. human
  • the treatment is in a mammal (e.g. a human).
  • a mammal e.g. a human
  • therapeutically effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • prophylaxis includes references to the prevention of (and, similarly, preventing) the disease or disorder (and vice-versa). As such, 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).
  • references to use in and methods for the treatment or prophylaxis of diseases and disorders as specified herein will refer in particular to uses in and methods for treatment of such diseases and disorders.
  • the treatment is of a disorder (which may also be referred to as a condition or disease) characterised by hyperglycaemia.
  • 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 disorder is type 1 diabetes.
  • compounds of the invention i.e. the ⁇ 2-adrenergic receptor agonist, including all embodiments thereof are for use in the treatment of type 2 diabetes (or useful in the manufacture of a medicament for such treatment, or useful in a method for such treatment, as described herein).
  • the treatment of type 2 diabetes is in a non-obese patient.
  • 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.
  • compounds 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). As such, 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.
  • compounds of the invention may be useful in the treatment of hyperglycaemia in type 1 diabetes.
  • the disorder characterised by hyperglycaemia is Type 1 diabetes or Type 2 diabetes.
  • 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.
  • 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 ⁇ 30 kg/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’s syndrome leprechaunism
  • 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.
  • the patient has one or more of a chronic kidney disease, cardiovascular disease and heart failure.
  • the patient has cardiovascular disease.
  • treatment with compounds of the first aspect of the invention may further comprise (i.e.
  • 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).
  • treatments 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.
  • ⁇ 2-adrenergic receptor agonist examples of which will be known to those skilled in the art.
  • compounds referred to herein such as compounds referred to as a ⁇ 2-adrenergic receptor agonist, may be provided in the form of a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts, each of which may be in the form of salts in varying ratios of compound to counter ion (e.g. including hemi salts).
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound comprised in the formulations of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. by rotary evaporation under reduced pressure, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound comprised in the formulations of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Particular acid addition salts that may be mentioned include carboxylate salts (e.g.
  • sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxyethanesulphonate, 1,2-ethanedisulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalenedisulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.
  • sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphon
  • base addition salts include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.
  • compounds as described herein may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils.
  • references to an agonist will refer to compounds suitable for acting as such when administrated to a subject to be treated (i.e. a patient, e.g. a human, in need thereof).
  • Suitable compounds may include compounds which provide the required effect and compounds which are converted to compounds providing the required effect after administration (i.e. in vivo), which compounds may be referred to as pro-drugs.
  • pro-drugs Particular compounds that may be mentioned are compounds which elicit the required effect.
  • the term “agonist” may be understood to indicate an agent (i.e.
  • Agonists may display, for example, half maximal effective concentration (EC50) values of less than about 100 ⁇ M, such as less than about 10 ⁇ M, or less than about 1 ⁇ M (e.g. less than about 200, about 150 or about 120 nM).
  • EC50 half maximal effective concentration
  • references herein to agonists will also include pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds which may not possess the relevant activity per se, but may be administered (e.g. parenterally or orally) to a patient and thereafter be metabolised in the body to form compounds possessing the required activity, which compounds may be referred to as prodrugs.
  • suitable prodrugs of compounds as described herein will be known to those skilled in the art, such as suitable esters (e.g. methyl or ethyl esters, and the like).
  • references to compounds that are agonists, and pharmaceutically acceptable salts thereof will include compounds that are prodrugs of such agonists, and pharmaceutically acceptable salts thereof.
  • Suitable ⁇ 2-adrenergic receptor agonists (which may also be referred to as ⁇ 2-agonists) may include those known to those skilled in the art.
  • suitable ⁇ 2-adrenergic receptor agonists will include those that are selective, which term will be known to those skilled in the art (i.e. compounds that are agonists of the relevant receptor(s) but which do not cause significant activation of other ⁇ -adrenergic receptors).
  • Suitable ⁇ 2-adrenergic receptor agonists can be identified using techniques known to those skilled in the art, including those as described in the examples provided herein.
  • Suitable ⁇ 2-adrenergic receptor agonists that may be employed in the various aspects of the invention include, but are not limited to, those described in: WO 2004/071388, EP 0 272 976, FR 2647310, DE 2 157 040, DE 2212600, DE 2015573, ZA 6705591, DE 2128258, WO 91/09596, GB 1199 630, DE 4209989, BE 611502, NL 7804582, EP 0 043 807, WO 2008/022038, DE 2413102, US 2,308,232, BE 823841, BE 660244, WO 2000/075114, WO 2005/102350, WO 2005/110990, JP 56055355, AT 285583, US 4,223,137, US 3,056,836, FR 1324914, DE 638
  • ⁇ 2-adrenergic receptor agonists that may be employed in the various aspects of the invention (which compounds may be identified as also being suitable ⁇ 2- adrenergic receptor agonists) include those described in the following publications, the contents of which are hereby incorporated herein in their entirety (in particular, the biological examples, the generic compound definitions, including all embodiments thereof and associated definitions, and the example compounds provided therein, including pharmaceutically acceptable salts thereof, and associated methods of preparation): WO 2017/153737 WO 2019/053429 WO 2019/053426 WO 2019/053425 WO 2019/053427 WO 2020/188299 WO 2020/188301 WO 2022/063895 WO 2022/063889 WO 2023/046885 WO 2023/046882 WO 2023/105035 WO 2023/180472
  • a particular ⁇ 2-adrenergic receptor agonist that may be mentioned is the following compound: and pharmaceutically acceptable salts thereof.
  • a particular ⁇ 2-adrenergic receptor agonist that may be mentioned is (R)-2-(tert- butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol, and pharmaceutically acceptable salts thereof.
  • Particular pharmaceutically acceptable salts of the above-mentioned compound i.e. (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol
  • Particular pharmaceutically acceptable salts of the above-mentioned compound i.e. (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol
  • include the hemi-tartrate and dihydrochloride salts such as the hemi-tartrate salt.
  • a further particular ⁇ 2-adrenergic receptor agonist that may be mentioned is the following compound: and pharmaceutically acceptable salts thereof.
  • a particular ⁇ 2 -adrenergic receptor agonist that may be mentioned is (R)-2-(tert- butylamino)-1-(3-fluorophenyl)ethan-1-ol, and pharmaceutically acceptable salts thereof.
  • Particular pharmaceutically acceptable salts of (R)-2-(tert-butylamino)-1-(3- fluorophenyl)ethan-1-ol include the HCl (hydrochloride) salt.
  • a further particular ⁇ 2-adrenergic receptor agonist that may be mentioned is the following compound: and pharmaceutically acceptable salts thereof.
  • references to a specific steroisomer of a compound may refer to the specific stereoisomer being present (e.g. in a composition or formulation comprising the same) in the substantial absence of the corresponding opposite stereoisomer.
  • references to the substantial absence of the corresponding opposite stereoisomer may 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, which may indicate that the compound in the relevant configuration is present in an enantiomeric excess (e.e.) of at least 80% (such as at least 90%, 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%).
  • the compound in the relevant configuration is present in an enantiomeric excess (e.e.) of at least 90% (such as at least 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%).
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetarine, zinterol, bamethane, (R)- bamethane, clencyclohexerol, tulobuterol, BRL-47672, trantinterol, clenprope
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetarine, zinterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol, BRL-47672 and trantinterol, and pharmaceutically acceptable salt
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol, trantinerol and abediterol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol and trantinerol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane, trantinerol and abediterol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane and trantinerol, and pharmaceutically acceptable salts thereof.
  • formoterol arformoterol
  • salmeterol clenbuterol
  • R -clenbuterol
  • bamethane clenbuterol
  • bamethane CAS: 912804-58-1
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formeterol, arformeterol, salmeterol, clenbuterol, tulobuterol, bambuterol vilanterol, indacaterol, olodaterol, carmoterol and abediterol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of salbutamol, ritodrine, colterol, hexaprenaline and isoxsuprine, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is clenbuterol, or a pharmaceutically acceptable salt thereof.
  • the compound clenbuterol may be understood to have the following structure:
  • the international nonpropriety name (INN) or developmental drug code (e.g. BRL-47672) for a compound generally indicates the stereochemical configuration of the compound, or a particular mixture of stereoisomers (e.g. a racemate).
  • the INN or developmental drug code should be understood to represent the compound to which the relevant name or code has been assigned only.
  • the compound may be identified by its Chemical Abstracts Service Registry Number (CAS number).
  • CAS number Chemical Abstracts Service Registry Number
  • the indication “CAS: XXXXXX-XX-X” (wherein the number of figures in the first group may vary) is used to identify such compounds.
  • the CAS number for a compound may also be considered to encompass other stereoisomers, or mixtures thereof, that display the relevant biological activity, and which have not presently been assigned alternative CAS numbers (as described above for INNs and developmental drug codes).
  • the CAS number should be understood to represent the compound to which the relevant name or code has been assigned only.
  • the present invention also embraces pharmaceutical formulations comprising isotopically-labelled compounds, which are identical to the compounds recited herein but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).
  • the invention also encompasses pharmaceutical formulations comprising deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • deuterated compounds i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • certain compounds acting as ⁇ 2- adrenergic receptor agonists are able to activate the ⁇ 2-adrenergic receptor without inducing significant cAMP production.
  • particular ⁇ 2-adrenergic receptor agonists that may be mentioned include those able to activate the ⁇ 2-adrenergic receptor without (or with only a minimal effect in) inducing cAMP production.
  • the methods and uses as described herein may be performed without inducing (or without inducing significant levels of) cAMP production.
  • the ⁇ 2-adrenergic receptor agonist as described herein may be further described as being a ⁇ 2-adrenergic receptor agonist that does not induce significant cAMP (i.e. levels and/or production thereof).
  • the skilled person will be able to determine the level of cAMP production provided by compounds, such as those referred to herein, using techniques known to those skilled in the art, such as those described in the examples as provided herein.
  • the level of cAMP production induced by a given compound can be determined by reference to the amount induced by a defined concentration of that compound relative to that induced by the same concentration of a reference compound, such as isoprenaline, using techniques known to those skilled in the art (e.g. following the protocol as described in the biological examples provided in WO 2019/053427, i.e. in cells, such as differentiated L6-myotubes, having been stimulated with isoprenaline or the compound with a final concentration of 1x10 -5 M, for 15 min in stimulation buffer, such as HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, at pH 7.4).
  • stimulation buffer such as HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, at pH 7.4
  • compounds that do not induce significant cAMP may be defined as being compounds that induce less than 50% (or, in some embodiments, less than 25%) of the cAMP induced by isoprenaline (e.g. in accordance with the protocol described above).
  • Test results are given in Table 1 and Table 2. If a compound at 10 ⁇ M shows activity of more than 75 % of that of isoproterenol at 10 ⁇ M, the activity is denoted with +++; if it is between 75 and 50 % it is denoted with ++; if it is between 50 and 25 % it is denoted with +; if it less than 25 % it is denoted with -. Compounds are drawn as salt-free molecules in Table 1, but the tested compounds might have been containing additional salt or solvent components that do not contribute to the biological activity.
  • Particular ⁇ 2-adrenergic receptor agonists that may be mentioned are provided in Table 2 below.
  • Table 2 Particular compounds of the invention Biological Biological example 2 example 1 of WO Structure Name* of WO 2019/053 2019/053 427 427 (GU) (cAMP) (R)-(m- fluorophenyl)[(2R,5R)-5- 548 (p-methoxyphenyl)-2- + - pyrrolidinyl]methanol (S)-(m- fluorophenyl)[(2R,5R)-5- 549 (p-methoxyphenyl)-2- + - pyrrolidinyl]methanol (R)-(5-fluoro-3- pyridyl)[(2R,5R)-5-(p- methoxyphenyl)-2- 550 pyrrolidinyl]methanol + - (S)-(5-fluoro-3- pyridyl)[(2R,5R)
  • the present invention relates to uses and methods comprising treatment and/or prophylaxis with an SGLT2 inhibitor.
  • SGLT2 inhibitors also known as gliflozins
  • SGLT2 inhibitors are antihyperglycemic agents acting on the SGLT2 proteins expressed in the proximal tubules of the kidneys.
  • SGLT2 inhibitors exert their effect by preventing the reabsorption of filtered glucose from the tubular lumen, thus leading to lower blood sugar levels.
  • the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin.
  • the SGLT2 inhibitor is empagliflozin.
  • Pharmaceutical formulations The skilled person will understand that both the ⁇ 2-adrenergic receptor agonist, or pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor, may be administered in the form of a pharmaceutical formulation, which may further comprise one or more pharmaceutically acceptable excipient.
  • Suitable pharmaceutical formulations may be commercially available or otherwise are described in the literature, such as, Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995), and Martindale – The Complete Drug Reference (35 th Edition), and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference in their entirety. Otherwise, the preparation of suitable formulations, and in particular combined preparations including both a ⁇ 2-adrenergic receptor agonist, or pharmaceutically acceptable salts thereof, and an SGLT2 inhibitor, may be achieved by the skilled person using routine techniques.
  • references to pharmaceutically acceptable excipient(s) may be understood to include pharmaceutically acceptable, diluents, carriers and/or adjuvants, as known to those skilled in the art. Accordingly, in a second aspect of the invention, there is provided a pharmaceutical formulation comprising: (I) a compound that is an SGLT2 inhibitor, and (II) a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, which formulations may be referred to as the “formulations of the invention”, or the like. In a particular embodiment, the pharmaceutical formulation is for use in the treatment and/or prophylaxis of a disease or disorder.
  • a pharmaceutical formulation comprising: (I) a compound that is an SGLT2 inhibitor, and (II) a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, for use in for use in the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia.
  • a method for the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising: (I) a compound that is an SGLT2 inhibitor, and (II) a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient.
  • a pharmaceutical formulation comprising: (I) a compound that is an SGLT2 inhibitor, and (II) a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient.
  • Combinations and kits-of-parts may also relate to combination products comprising a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor, and uses thereof.
  • combination of a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor may also be provided in the form of a kit-of-parts comprising the same.
  • kits-of-parts comprising components: (A) a pharmaceutical formulation comprising a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, optionally in admixture with one or more pharmaceutically acceptable excipient, and (B) a pharmaceutical formulation comprising an SGLT2 inhibitor, optionally in admixture with one or more pharmaceutically acceptable excipient, wherein components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.
  • the kit-of-parts is for use in the treatment and/or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia.
  • kit-of-parts of the fourth aspect of the invention further comprises instructions to use each component in conjunction with the other the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.
  • a kit-of-parts comprising: (I) one of components (A) or (B) as defined hereinabove, and (II) instructions to use that component in conjunction with the other of the two components in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.
  • kits-of-parts of the fourth aspect of the invention may have any of the particular features described above for the first, second or third aspects of the invention, including all combinations thereof.
  • kits-of-parts described herein may comprise more than one formulation including an appropriate quantity/dose of a ⁇ 2-adrenergic receptor agonist, or pharmaceutically acceptable salt and/or pro drug thereof, and/or more than one formulation including an appropriate quantity/dose of an SGLT2 inhibitor, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s). With respect to the treatments, formulations and kits-of-parts of the invention as described herein, references to treatment with or administration of each component will refer to said component being administered in conjunction with the other.
  • references to the components being administered simultaneously will include the components being administered (i.e. taken by the patient, such as being taken orally) at substantially the same time.
  • the components are administered (i.e. taken by the patient, such as being taken orally) sequentially (and, therefore, as separate doses).
  • the components are administered sequentially at least 2 hours apart (i.e. the interval between the administration of each component to the patient, e.g.
  • references to the components as the ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor will include references to the respective components (II) and (I) of the third aspect of the invention, and the respective components (A) and (B) of the fourth aspect of the invention.
  • compounds and pharmaceutical formulations as described herein are administered orally.
  • pharmaceutical formulations as described herein may be described as oral pharmaceutical formulations.
  • the pharmaceutical formulation(s) is/are provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, transdermal patches, plasters, inhalants (e.g. to be applied intranasally).
  • a pharmaceutically acceptable dosage form including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, transdermal patches, plasters, inhalants (e.g. to be applied intranasally).
  • compounds 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 pharmaceutical formulation(s) is/are provided in a pharmaceutically acceptable oral dosage form, including tablets or capsules, which forms may be prepared using techniques known to those skilled in the art.
  • the compound in the preparation of pharmaceutical formulations for oral administration, the compound 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. 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. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
  • active compounds e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents
  • 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 gelatine 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, 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 doses may include those discussed in the above-mentioned publications, as incorporated herein by reference.
  • suitable doses of an SGLT2 inhibitor may include those described herein and those known to those skilled in the art (including those indicated in relevant drug formularies, such as the British National Formulary 85 th Edition, the contents of which are incorporated herein by reference).
  • the skilled person e.g. the physician
  • treatments (and methods of prophylaxis) as described here may further comprise (i.e. be combined with) additional (i.e. other) treatment(s) for the same condition.
  • treatments (and methods of prophylaxis) described herein may be combined with other means for the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia.
  • agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g.
  • compositions and kits-of-parts 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 ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and an SGLT2 inhibitor with one or more pharmaceutically-acceptable excipients (e.g. an adjuvant, diluent and/or carrier).
  • kits-of-parts as defined hereinbefore, which method comprises bringing component (A) into association with component (B), thus rendering the two components suitable for administration in conjunction with each other.
  • references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
  • the two components of the kit of parts may be: (i) provided as separate formulations (i.e.
  • kits-of-parts, methods and uses described herein may have the advantage that, in the treatment of the conditions mentioned hereinbefore, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar methods (treatments) known in the prior art whether for use in the above-stated indications or otherwise.
  • such pharmaceutical formulations, kits of parts, methods and uses may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.
  • a ⁇ 2- adrenergic receptor agonist and an SGLT2 inhibitor provides an improved therapeutic effect compared to ⁇ 2-adrenergic receptor agonist or SGLT2 inhibitor monotherapies in the treatment or prophylaxis of hyperglycaemia or a disorder characterized by hyperglycaemia, such as type 1 and type 2 diabetes.
  • a ⁇ 2-adrenergic receptor agonist and an SGLT2 inhibitor provides an unexpected, combined effect in the reduction of blood sugar levels, allowing for a more effective means for treatment or prophylaxis.
  • the combined effect of the ⁇ 2-adrenergic receptor agonist and the SGLT2 inhibitor allows for administration of one or both compounds (i.e. the ⁇ 2-adrenergic receptor agonist and/or the SGLT2 inhibitor) at lower doses compared to monotherapy. This is particularly advantageous in view of the undesired side effects associated with the use of SGLT2 inhibitors.
  • a combination of a ⁇ 2-adrenergic receptor agonist and an SGLT2 inhibitor as defined herein may allow for obtaining a suitable therapeutic effect with fewer (or lower level of) undesired side effects compared to SGLT2 inhibitor monotherapy (i.e. where a higher dose of the SGLT2 inhibitor would be needed for achieving the same therapeutic effect).
  • certain of the compounds acting as ⁇ 2-adrenergic receptor agonists, such as those described herein are able to activate the ⁇ 2-adrenergic receptor without (or with only a minimal effect in) inducing cAMP production. It is thought that this allows for therapeutic effects as described herein to be obtained with lower levels of side effects than would result from other treatments.
  • Figure 1 shows that the glucose uptake promoted by Compound A is inhibited in a dose-dependent manner by the selective ⁇ 2-adrenergic receptor antagonist ICI- 118551, as described in Biological Example 1.
  • Figure 2 shows urinary glucose during the experiment described in Biological Example 2.
  • Figure 3 shows the change fasting blood glucose levels over the period of the experiment described in Biological Example 2.
  • Figure 4 shows the change in glucose tolerance over the period of the experiment described in Biological Example 2.
  • the present invention is illustrated by way of the following examples, which are not intended to be limiting on the overall scope of the invention. For the avoidance of doubt, in the case of a discrepancy between the name of the compound and the structure drawn in this specification, the structure should prevail. Mice were purchased from Scanbur (Charles River).
  • Example compounds The following compound, which be referred to herein as Compound A, was used in the biological examples provided herein in the salt form as specified (and, in the context of which, references to Compound A will refer to that salt form).
  • Compound A The synthesis of Compound A is described in WO 2019/053427 (see Example 17 therein), the contents of which are incorporated herein by reference.
  • Biological Example 1 Glucose uptake in the presence of a selective ⁇ 2-adrenergic receptor inhibitor L6-myoblasts were grown in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 1 g/L glucose supplemented with 10 % fetal bovine serum (FBS), 2 mM L-glutamine, 50 U/mL penicillin, 50 ⁇ g/mL streptomycin and 10 mM HEPES.
  • DMEM Dulbecco’s Modified Eagle’s Medium
  • FBS % fetal bovine serum
  • FBS fetal bovine serum
  • Cells were plated at 1x 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. The differentiated L6-myotubes were serum-starved overnight in medium containing 0.5 % fatty-acid free BSA and stimulated with Compound A at a final concentration of 1x10 -5 M in the presence of the selective ⁇ 2-adrenergic receptor antagonist ICI-118551. After 1 h 40 min the cells were washed with warm, glucose free medium twice and another portion of agonist was added to the glucose free medium.
  • the cells were exposed to 50 nM 3 H-2-deoxyglucose for 10 min before washed in ice cold glucose free medium three times and lysed in 400 ⁇ l/well 0.2 M NaOH for 1 h at 60 °C.
  • the cell lysate was mixed with 4 ml scintillation buffer (Emulsifier Safe, Perkin Elmer) and the radioactivity was detected in a ⁇ -counter (Tri- Carb 4810TR, Perkin Elmer).
  • mice were treated daily for 7 weeks by oral gavage with either vehicle, empagliflozin (10 mg/kg), Compound A (1 mg/kg), or a mixture of empagliflozin (10 mg/kg) and Compound A (1 mg/kg).
  • Urinary glucose levels were measured at 7 weeks.
  • a glucose tolerance test (GTT) was performed after 3-4 weeks: mice were fasted for 5 hours and then injected intraperitoneally with glucose (2.5 g/kg lean mass). Blood glucose concentrations were determined with a glucometer using blood taken from cut tail tips. Values are means ⁇ SEM of 10-13 mice in each group. Fasting blood glucose values were determined from blood samples collected just before the glucose injection.
  • empagliflozin and Compound A will allow for the administration of a lower dose of empagliflozin, thus leading to fewer (or lower levels of) undesired side effects, while achieving the same or greater therapeutic effect compared to empagliflozin monotherapy.

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Abstract

L'invention concerne un agoniste du récepteur bêta2-adrénergique, ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé dans le traitement et/ou la prophylaxie de l'hyperglycémie ou d'un trouble caractérisé par l'hyperglycémie, le traitement et/ou la prophylaxie comprenant en outre l'administration d'un inhibiteur des SGLT2.
PCT/EP2025/056002 2024-03-05 2025-03-05 Combinaisons d'agonistes du récepteur bêta 2-adrénergique et d'inhibiteurs des sglt2 destinés à être utilisés dans le traitement de l'hyperglycémie ou d'un trouble caractérisé par l'hyperglycémie Pending WO2025186320A1 (fr)

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WO2021003161A1 (fr) 2019-07-01 2021-01-07 Curasen Therapeutics, Inc. Agoniste bêta-adrénergique et procédés d'utilisation associés
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