Combination of beta-2 adrenergic receptor agonists and GLP-1 receptor agonists for use in treating hyperglycemia

Abstract

This specification provides a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof for use in the treatment and / or prophylactic care of hyperglycemia or a disorder characterized by hyperglycemia, wherein the treatment and / or prophylactic care further comprises the administration of (a) insulin or a therapeutic insulin derivative, or (b) a therapeutic agent that stimulates the release of insulin.

Description

[Technical Field]

[0001] The present invention relates to methods for the treatment and / or prevention of hyperglycemia or disorders characterized by hyperglycemia. In particular, the present invention relates to methods for the treatment and / or prevention of hyperglycemia or disorders characterized by hyperglycemia, comprising treatment and / or prevention in combination with a β2-adrenergic receptor agonist and insulin or a therapeutic insulin derivative or a therapeutic agent that stimulates insulin release, as well as compositions and kit formulations for use in such methods. [Background technology]

[0002] Any listing or discussion of previously published literature in this specification should not necessarily be construed as an endorsement that such literature is part of cutting-edge technology or common general knowledge.

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

[0004] Severe insulin resistance (SIR) is a condition in which a patient experiences a very low level (or, in extreme cases, non-significant) response to insulin. Several syndromes exist that are characterized by SIR, including Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy. The majority of these conditions have a genetic cause, such as mutations in the insulin receptor gene. Reported prevalences of Donahue syndrome, Rabson-Mendenhall syndrome, and insulin-resistant type A syndrome have been reported to vary from 50 to 1 per 100,000. However, because some of these conditions are severe and extremely rare, many patients are likely to go undiagnosed before death, especially in developing regions of the world. Therefore, it is difficult to estimate the exact number of patients with these syndromes.

[0005] The current standard of treatment for hyperglycemia in patients with SIR is a controlled diet supplemented with drugs that affect insulin receptor sensitivity, such as metformin, or insulin replacement therapy. However, this treatment has proven insufficient and ultimately unsuccessful, particularly for disorders caused by mutations in the insulin receptor gene.

[0006] Diabetes encompasses two distinct diseases: type 1 (or insulin-dependent diabetes) and type 2 (insulin-independent diabetes), both of which involve dysfunction of glucose homeostasis. Type 2 diabetes affects over 400 million people worldwide, and its numbers are rapidly increasing. Complications of type 2 diabetes include severe cardiovascular problems, renal failure, peripheral neuropathy, and blindness, and in the later stages of the disease, limb loss and ultimately even death. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and there is currently no definitive cure. Most treatments used today focus on improving dysfunctional insulin signaling or suppressing glucose production from the liver, but many of these treatments have several drawbacks and side effects. Therefore, there is great interest in identifying novel insulin-independent methods for treating type 2 diabetes.

[0007] In type 2 diabetes, the insulin signaling pathway becomes blunted in peripheral tissues such as adipose tissue and skeletal muscle. Treatment methods for type 2 diabetes typically include lifestyle modifications, as well as insulin injections or oral medications to regulate glucose homeostasis. Individuals with late-stage type 2 diabetes develop "beta-cell dysfunction," a disorder in which the pancreas is unable to release insulin in response to high blood glucose levels. In the later stages of the disease, patients often require insulin injections in combination with oral medications to manage diabetes. Furthermore, the most common medications have side effects, including downregulation or desensitization of the insulin pathway, and / or increased lipid uptake in adipose tissue, the liver, and skeletal muscle. Therefore, there is considerable interest in identifying novel methods for treating metabolic diseases, including type 2 diabetes, that do not involve these side effects.

[0008] After a meal, the rise in blood glucose levels stimulates the release of insulin from the pancreas. Insulin mediates the normalization of blood glucose levels. Key effects of insulin on glucose metabolism include increased glucose uptake into skeletal muscle and adipocytes, as well as increased glycogen storage in the liver. Skeletal muscle and adipocytes are crucial sites for glucose metabolism because they are involved in insulin-mediated glucose uptake and utilization during feeding.

[0009] The downstream signaling pathways of the insulin receptor have been difficult to understand in detail. In summary, insulin regulation of glucose uptake involves the activation of the insulin receptor (IR), insulin receptor substrates (IRS), phosphoinositide 3-kinase (PI3K), and consequently the stimulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), the mammalian target of rapamycin (also known as the rapamycin mechanism target, mTOR), Akt / PKB (Akt), and TBC1D4 (AS160), leading to the transposition of glucose transporter 4 (GLUT4) to the cell membrane. Akt activation is considered necessary for GLUT4 transposition.

[0010] It should be noted that skeletal muscle constitutes the majority of mammalian body weight and plays a crucial role in regulating systemic glucose metabolism, participating in up to 85% of systemic glucose processing. Glucose uptake in skeletal muscle is regulated by several intracellular and extracellular signals. Insulin is the most well-studied intermediary, but others exist. For example, AMP-activated kinase (AMPK) functions as an intracellular energy sensor, which can increase glucose uptake and fatty acid oxidation. Given the significant impact of skeletal muscle on glucose homeostasis, further mechanisms are thought to exist. In light of the increasing prevalence of type 2 diabetes, there is considerable interest in identifying and characterizing novel insulin-independent mechanisms for increasing glucose uptake in muscle cells.

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

[0012] Insulin and catecholamines, while typically having opposing effects, have been shown to have similar effects on glucose uptake in skeletal muscle (Nevzorova et al., Br.J.Pharmacol, 137, 9, (2002)). In particular, catecholamines have been reported to stimulate glucose uptake via adrenaline receptors, supplying muscle cells with energy-rich substrates (Nevzorova et al., Br.J.Pharmacol, 147, 446, (2006), Hutchinson, Bengtsson Endocrinology 146, 901, (2005)). Therefore, in mammals, including humans, the adrenaline and insulin systems likely function independently and can regulate the energy demands of skeletal muscle under different circumstances. Insulin also stimulates many anabolic processes, including some that promote undesirable effects such as stimulated lipid uptake into tissues, which can lead to obesity; therefore, it would be beneficial if glucose uptake could be stimulated by other means, such as stimulation of adrenaline receptors (ARs).

[0013] All ARs are G protein-coupled receptors (GPCRs) located on the cell membrane, characterized by an extracellular N-terminus, followed by seven transmembrane α-helices (TM-1 to TM-7), three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3) connecting them, and finally an intracellular C-terminus. There are three distinct classes of ARs: α1-, α2-, and β-ARs, each with different expression patterns and pharmacological profiles. α1-ARs are α 1A , α 1B , and α 1D While it includes subtypes, α2-AR is α 2A , α 2B , and α 2C β-AR is classified into three subtypes: β1, β2, and β3, of which β2-AR is the major isoform in skeletal muscle cells. AR is a G protein-coupled receptor (GPCR) that signals via classical secondary messengers such as cyclic adenosine phosphate (cAMP) and phospholipase C (PLC).

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

[0015] Glucose uptake is primarily stimulated via facilitative glucose transporters (GLUTs), which mediate glucose uptake into most cells. GLUTs are transporter proteins that mediate the transport of glucose and / or fructose across the cell membrane in accordance with a concentration gradient. The GLUT family consists of 14 known members, named GLUT1-14, which are classified into three classes (Class I, Class II, and Class III) depending on their substrate specificity and tissue expression. GLUT1 and GLUT4 are the most intensively studied isoforms and, along with GLUT2 and GLUT3, belong to Class I, which primarily transports glucose (as opposed to Class II, which also transports fructose). GLUT1 is ubiquitously expressed and involved in basal glucose transport. GLUT4 is expressed only in peripheral tissues such as skeletal muscle, cardiac muscle, and adipose tissue. GLUT4 has also been reported to be expressed in the brain, kidney, and liver, for example. GLUT4 is the major isoform involved in insulin-stimulated glucose uptake. The mechanism by which insulin signaling increases glucose uptake is primarily mediated by GLUT4 transposition from intracellular storage to the cell membrane. It is known that GLUT4 transposition is induced by stimulation of β2-adrenergic receptors.

[0016] Currently, there are several therapies for diabetes and related conditions that act by increasing insulin sensitivity. These can be used alone in treatment, and thus in combination with therapeutic agents that act by increasing sensitivity to naturally occurring insulin production or by increasing insulin levels, which may allow such agents to be used at lower doses and / or less frequently.

[0017] However, such insulin sensitivity-improving therapies are known to have a range of limitations, including associations with serious adverse events.

[0018] Therefore, there remains a need for a safe and effective insulin sensitizer for use in the treatment of diabetes and related conditions. SUMMARY OF THE INVENTION

[0019] We have now surprisingly found that activation of the β2-adrenergic receptor results in increased sensitivity of the insulin receptor such that treatment and / or prophylactic treatment with a β2-adrenergic receptor agonist in combination with insulin or an insulin secretagogue enables effective treatment and / or prophylactic treatment of conditions characterized by elevated blood glucose levels (i.e., hyperglycemia), such as diabetes (e.g., type 2 diabetes).

[0020] Medical Use In a first aspect of the invention, there is provided a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof for use in the treatment and / or prophylactic treatment of hyperglycemia or a disorder characterized by hyperglycemia, wherein the treatment and / or prophylactic treatment further comprises (a) insulin or a therapeutic insulin derivative, or (b) administration of a therapeutic agent that stimulates the release of insulin There is provided a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof further comprising the above.

[0021] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0022] Any preference and option regarding a given aspect, embodiment, feature, or parameter of the invention should be considered to be disclosed in combination with any preference and option regarding all other aspects, features, and parameters of the invention, unless the context specifically indicates otherwise.

[0023] Where the term "approximately" is used herein (for example, in the context of the dose of an active ingredient), it should be understood that such a variable is an approximation and therefore may vary from the number specified herein by ±10%, for example, ±5%, preferably ±2% (for example, ±1%).

[0024] Whenever the phrase “optionally” is used in relation to a feature described herein, it shall have its usual meaning, i.e., that the feature in question may or may not exist.

[0025] In an alternative first aspect of the present invention, the use of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the treatment and / or prophylactic treatment of hyperglycemia or a disorder characterized by hyperglycemia, wherein the treatment and / or prophylactic treatment is (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release Use is provided that further includes the administration of [the substance].

[0026] In an alternative first aspect of the present invention, the use of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof in the treatment and / or prophylactic measures for hyperglycemia or a disorder characterized by hyperglycemia, wherein the treatment and / or prophylactic measures are (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release Use is provided that further includes the administration of [the substance].

[0027] In an alternative first aspect of the present invention, for use in the treatment and / or prevention of hyperglycemia or disorders characterized by hyperglycemia, (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release A compound is provided, the use of which further comprises the administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0028] In an alternative first aspect of the present invention, in the manufacture of a pharmaceutical product for the treatment and / or prevention of hyperglycemia or a disorder characterized by hyperglycemia, (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release A use is provided which involves the use of a compound, further comprising the administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0029] In an alternative first aspect of the present invention, in treatment and / or preventive measures for hyperglycemia or disorders characterized by hyperglycemia, (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release A use is provided which involves the use of a compound, further comprising the administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0030] In an alternative first aspect of the present invention, a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof for use in the treatment and / or prophylactic measures of hyperglycemia or a disorder characterized by hyperglycemia, (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release A combination with the compound is provided.

[0031] In an alternative first aspect of the present invention, a method for the treatment and / or prevention of hyperglycemia or a disorder characterized by hyperglycemia, (i) therapeutically effective dose (a) A therapeutically effective dose of insulin or a therapeutic insulin derivative, (b) A therapeutically effective dose of an agent that stimulates insulin release Administration of, and (ii) Administration of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof A method is provided which includes performing this on patients who need it.

[0032] In an alternative first aspect of the present invention, a method for the treatment and / or prevention of hyperglycemia or a disorder characterized by hyperglycemia, comprising a therapeutically effective amount (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release A method is provided which includes administering to a patient in need thereof, wherein the patient is also being treated with a therapeutically effective dose of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0033] In an alternative first aspect of the present invention, a method for the treatment and / or prophylactic treatment of hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective dose of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the patient receives a therapeutically effective dose (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release But treatment is available, and methods are provided.

[0034] To avoid any doubt, the uses, methods, compositions, and kit formulations of other aspects of the present invention described herein (including all embodiments thereof) may have any of the specific features described above for the first aspect of the present invention, including all combinations thereof.

[0035] To avoid any ambiguity, the treatments (and related preventive measures) described herein may be referred to herein as "the treatments of the present invention," etc.

[0036] Those skilled in the art will understand that references to the "treatment" (and similarly, "treating") a particular condition take on their usual meanings in the field of medicine. In particular, this term may refer to achieving a reduction in the severity of one or more clinical symptoms associated with a condition.

[0037] As used herein, a reference to a patient refers to a living subject being treated, including a mammalian (e.g., human) patient. In certain embodiments of the relevant aspects of the present invention (e.g., the first aspect of the present invention), the treatment is in a mammal (e.g., human).

[0038] As used herein, the term therapeutically effective dose refers to the amount of a compound that produces a therapeutic effect in a patient being treated. Such an effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of an effect and / or feels an effect).

[0039] As used herein, the term prophylaxis includes references to the prevention of disease or disorder (and vice versa). Thus, a reference to prevention can also be a reference to prophylaxis, and vice versa. In particular, the term may refer to achieving a reduction in the likelihood that a patient (or a healthy subject) will develop a condition (e.g., a reduction of at least 10%, e.g., a reduction of at least 20%, 30%, or 40%, e.g., a reduction of at least 50%).

[0040] In certain embodiments, references to the use and methods for treating or preventing diseases and disorders specified herein will, in particular, refer to the use and methods for treating such diseases and disorders.

[0041] In certain embodiments, the treatment is the treatment of a disorder (which may also be called a condition or disease) characterized by hyperglycemia.

[0042] In a particular embodiment of the first aspect of the present invention, the disorder is type 2 diabetes, for example, a subtype of type 2 diabetes selected from the list consisting of young adult-onset diabetes (MODY), adult-onset ketotic diabetes, adult-onset latent autoimmune diabetes (LADA), and gestational diabetes.

[0043] In a further embodiment, the disorder is type 1 diabetes, and in particular, the treatment further includes treatment with insulin (or its derivatives and / or functional mimetic).

[0044] In certain embodiments, the compounds of the present invention (i.e., compounds of formula I, including all embodiments thereof) are intended for use in the treatment of type 2 diabetes (or are useful in the manufacture of a medicament for such treatment as described herein, or in a method for such treatment).

[0045] In a further specific embodiment, the treatment of type 2 diabetes is carried out in non-obese patients.

[0046] To avoid any doubt, a person skilled in the art will understand that a patient with a body mass index (BMI) greater than 30 is considered obese.

[0047] In certain embodiments, the treatment may be for the treatment of hyperglycemia (a condition that may be defined as prediabetes) in patients at risk of developing type 2 diabetes. Therefore, the compounds of the present invention may be useful in preventing type 2 diabetes (for example, in patients with prediabetes).

[0048] As used herein, the terms prevention (and similarly, the act of prevention) include references to prophylaxis of disease or disorder (and vice versa). Thus, a reference to prevention may also be a reference to prophylaxis, and vice versa. In particular, the term may refer to achieving a reduction in the likelihood that a patient (or a healthy subject) will develop a condition (e.g., a reduction of at least 10%, e.g., a reduction of at least 20%, 30%, or 40%, e.g., a reduction of at least 50%).

[0049] In a more specific embodiment, type 2 diabetes is characterized by patients exhibiting severe insulin resistance (SIR).

[0050] In further embodiments, the treatment may be for the treatment of hyperglycemia in patients with type 1 diabetes. Therefore, the compounds of the present invention may be useful for the treatment of hyperglycemia in type 1 diabetes.

[0051] In certain embodiments, the disorder characterized by hyperglycemia is type 1 diabetes or type 2 diabetes.

[0052] Those skilled in the art will understand that the compounds of the present invention may be useful in treating hyperglycemia in patients with impaired insulin production, such as patients with cystic fibrosis. In a further embodiment, the disorder characterized by hyperglycemia is cystic fibrosis-associated diabetes.

[0053] It will be understood by those skilled in the art that in certain embodiments that can be mentioned, a disorder characterized by hyperglycemia is (or is characterized by) severe insulin resistance (SIR), typically referring to a disorder in which the subject has normal insulin production, or in some cases, increased insulin production, but significantly reduced insulin sensitivity. In certain cases, such patients may be non-obese (e.g., healthy weight). Therefore, in certain embodiments, such treatment is carried out in patients who are not defined as obese (e.g., patients defined as healthy weight).

[0054] For example, SIR is based on the fact that in a patient, the patient's fasting insulin level is greater than 150 pmol / L and / or peak insulin level in a glucose tolerance test is greater than 1,500 pmol / L, in particular, 30 kg / m² 2 It can be identified in individuals with a BMI of less than a certain level (these patients may have normal glucose tolerance).

[0055] More specifically, SIR may be characterized by patients who do not have a significant response to the presence of insulin, which may be due to a defect in insulin receptor function (e.g., a gene deficiency).

[0056] Certain disorders that may be characterized by SIR include Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.

[0057] More specific disorders that may be characterized by SIR include Donahue syndrome and insulin-resistant type A syndrome, and even more specifically, Rabson-Mendenhall syndrome.

[0058] Those skilled in the art will understand that treatment with a compound according to a first aspect of the present invention may further include (i.e., be combined with) further (i.e., additional / other) treatments for the same condition. In particular, treatment with a compound according to the present invention may be combined with other means for the treatment of type 2 diabetes, for example, treatment with one or more other therapeutic agents useful for the treatment of type 2 diabetes that are known to those skilled in the art, such as therapies that involve requiring the patient to make dietary changes and / or follow an exercise program, and / or surgical procedures designed to promote weight loss (e.g., gastric band surgery).

[0059] Those skilled in the art will understand that the treatment of the first aspect of the present invention may further include (i.e., be combined with) further (i.e., additional / other) treatments for the same condition.

[0060] Compound of the invention As described herein, the present invention requires the use of a β2-adrenergic receptor agonist, examples of which will be known to those skilled in the art.

[0061] Those skilled in the art will understand that compounds referred to herein, such as compounds known as β2-adrenergic receptor agonists, may be provided in the form of pharmaceutically acceptable salts.

[0062] Pharmaceutically acceptable salts include acid addition salts and base addition salts, each of which may be in the form of a salt with varying ratios of compound counterions (e.g., including hemi salts). Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the compound contained in the formulation of the present invention with one equivalent or more of a suitable acid or base in optionally a solvent or a medium in which the salt is insoluble, and then by removing the solvent or medium using standard techniques (e.g., by rotary evaporation under reduced pressure, by freeze-drying, or by filtration). Salts may also be prepared, for example, by exchanging the counterion of the compound contained in the formulation of the present invention in the form of a salt with another counterion using a suitable ion exchange resin.

[0063] Certain acid addition salts that may be mentioned include carboxylate salts (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartarate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, 1-naphthoate, 2-naphthoate, 1-hydroxy-2-naphthoate, nicotinate, isonicotinate, cinnamate, oxalate) This includes malonates, succinates, suberates, sebacinates, fumarates, malates, maleates, hydroxymaleates, hippurates, phthalates, or terephthalates), halogenates (e.g., chlorides, bromides, or iodides), sulfons (e.g., benzenesulfons, methyl-, bromo-, or chlorobenzenesulfons, xylenesulfons, methanesulfons, ethanesulfons, propanesulfons, hydroxyethanesulfons, 1,2-ethanedisulfons, 1- or 2-naphthalenesulfons, or 1,5-naphthalenedisulfons), or sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, or nitrates.

[0064] Specific base addition salts that may be mentioned include salts formed by 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 aluminum hydroxide). More specifically, base addition salts that may be mentioned include Mg salts, Ca salts, most specifically K salts, and Na salts.

[0065] To avoid any doubt, the compounds described in this invention may exist as solids, and therefore the scope of this invention includes all amorphous, crystalline, and subcrystalline forms, and may also exist as oils. Where such compounds exist in crystalline and subcrystalline forms, such forms may include solvates, which are also included in the scope of this invention. The compounds may also exist in solution.

[0066] Those skilled in the art will understand that reference to an agonist refers to a compound suitable for acting in such a way when administered to the target being treated (i.e., a patient in need, e.g., a human). Suitable compounds may include compounds that provide the desired effect, and compounds that are converted to compounds that provide the desired effect after administration (i.e., in vivo), and these compounds may be called prodrugs. The specific compounds that may be referred to are those that produce the desired effect.

[0067] To avoid ambiguity, the term "agonist" can be understood to refer to a drug (i.e., a compound) that induces a biological response (e.g., in a subject such as a human) by binding to a relevant receptor, thereby inducing the activation of that receptor. In this sense, the term can also refer to a partial agonist (which would be understood to refer to a compound that activates a given receptor but has only partial efficacy at the receptor compared to a full agonist).

[0068] The agonist (and partial agonist) has a semi-maximal effective concentration (EC) of less than approximately 100 μM, less than approximately 10 μM, or less than approximately 1 μM (e.g., less than approximately 200, 150, or 120 nM). 50 ) may show a value.

[0069] Unless otherwise stated or evident from the context, references to agonists herein also include pharmaceutically acceptable (e.g., “protected”) derivatives of compounds that may not possess the relevant activity itself but which, when administered to a patient (e.g., parenterally or orally) and subsequently metabolized in the body to form compounds with the desired activity, and which may also be referred to as prodrugs. Suitable prodrugs of the compounds described herein, such as suitable esters (e.g., methyl esters or ethyl esters), will be known to those skilled in the art.

[0070] To avoid ambiguity, unless otherwise stated or evident from the context, references to compounds that are agonists and their pharmaceutically acceptable salts include compounds that are prodrugs of such agonists and their pharmaceutically acceptable salts.

[0071] Suitable β2-adrenergic receptor agonists (also known as β2 agonists) may include those known to those skilled in the art.

[0072] In certain embodiments, preferred β2-adrenergic receptor agonists include selective ones, the term of which will be known to those skilled in the art (i.e., compounds that are agonists of the associated receptor(s) but do not cause significant activation of other β-adrenergic receptors).

[0073] Suitable β2-adrenergic receptor agonists, including those described in the examples provided herein, can be identified using techniques known to those skilled in the art.

[0074] Suitable β2 adrenergic receptor agonists that can be used in various aspects of the present invention are described herein by reference in their respective relevant disclosures (e.g., exemplary compounds described therein, their pharmaceutically acceptable salts, and associated preparation methods), which are incorporated herein by reference in their entirety: International Publication No. 2004 / 071388, European Patent No. 0272976, French Patent No. 2647310, German Patent No. 2157040, German Patent No. 2212600, German Patent No. 2015573, South African Patent No. 6705591, German Patent No. 2128258, International Publication No. 91 / 09596, British Patent No. 1199630, German Patent No. 4209989, Belgian Patent No. 611502, Dutch Patent No. 7804582, European Patent No. 0043 Patent No. 807, International Publication No. 2008 / 022038, German Patent No. 2413102, US Patent No. 2,308,232, Belgian Patent No. 823841, Belgian Patent No. 660244, International Publication No. 2000 / 075114, International Publication No. 2005 / 102350, International Publication No. 2005 / 110990, Japanese Patent No. 56055355, Austrian Patent No. 285583, US Patent No. 4,223,137, US Patent No. 3,056,836, French Patent No. 1324914, German Patent No. 638650, East German Patent No. 45721, US Patent No. 3,801,631, German Patent No. 2259282, German Patent No. 2300614, European Patent No. 0290 No. 122, US Patent No. 2004 / 0266867, US Patent No. 2010 / 0022658, US Patent No. 2010 / 0022659, German Patent No. 2157040, UK Patent No. 2133986, International Publication No. 2006 / 122788, Woo et al.,Molecular Pharmacology,(2009),75(1)158-165, Baur et al.,J.Med.Chem.,(2010),53(9),3675-3684, Kaiser et al.,J.Med.Chem.(1974),17(1)49-57, Baker et al.,J.This includes, but is not limited to, the materials described in Pharmacology and Experimental Therapeutics, (2006), 319(1), 439-446; Engelhardt et al., Arzneimittel-Forschung, (1972), 22(5), 869-76; International Publication Nos. 2019 / 241744, 2019 / 241736, 2020 / 198466, 2021 / 003161, 2021 / 081292, 2021 / 127210, and 2021 / 247934.

[0075] To avoid any ambiguity, references to patent publications would typically refer to the first publication of the complete patent specification, which has a corresponding publication number (which may be indicated by the subscript "A1").

[0076] Further preferred β2-adrenergic receptor agonists that can be used in various embodiments of the present invention (the compounds may also be identified as preferred β2-adrenergic receptor agonists) include those described in the following publications, the contents of which (in particular, biological examples, general definitions of compounds and all embodiments thereof and related definitions, exemplary compounds provided therein and their pharmaceutically acceptable salts, and associated preparation methods) are incorporated herein in their entirety. International Publication Patent No. 2017 / 153737 International Publication Patent No. 2019 / 053429 International Publication Patent No. 2019 / 053426 International Publication Patent No. 2019 / 053425 International Publication Patent No. 2019 / 053427 International Publication Patent No. 2020 / 188299 International Publication Patent No. 2020 / 188301 International Publication Patent No. 2022 / 063895 International Publication Patent No. 2022 / 063889 International Publication Patent No. 2023 / 046885 International Publication Patent No. 2023 / 046882 International Publication Patent No. 2023 / 105035 International Publication Patent No. 2023 / 203223 International Publication Patent No. 2020 / 198466

[0077] Specific β2 adrenergic receptor agonists that may be mentioned include the following compounds: [ka] and its pharmaceutically acceptable salts.

[0078] Therefore, the specific β2-adrenergic receptor agonists that can be mentioned are (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol and its pharmaceutically acceptable salts.

[0079] Certain pharmaceutically acceptable salts of the above compounds that may be mentioned (i.e., (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol) include hemitartartrate and dihydrochloride (such as hemitartartrate).

[0080] Further specific β2 adrenergic receptor agonists that may be mentioned include the following compounds: [ka] and its pharmaceutically acceptable salts.

[0081] Therefore, the specific β2 adrenergic receptor agonists that can be mentioned are (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethane-1-ol and its pharmaceutically acceptable salts.

[0082] Certain pharmaceutically acceptable salts of (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethane-1-ol that may be mentioned include HCl (hydrochloric acid) salts.

[0083] In certain embodiments, reference to a specific stereoisomer of a compound may refer to a specific stereoisomer that exists in the substantial absence of the corresponding opposite stereoisomer (e.g., in a composition or formulation containing it).

[0084] As used herein, reference to the substantial absence of the corresponding opposite stereoisomer may refer to the desired stereoisomer that exists with a purity of at least 80% (e.g., at least 90%, e.g., at least 95%) relative to the opposite stereoisomer. Alternatively, in such cases, the compound may be shown to exist in the substantial absence of the compound in the other configuration, which may indicate that the compound in the relevant configuration exists in an enantiomer excess (ee) of at least 80% (e.g., at least 90%, at least 95%, at least 98%, or in particular, at least 99%, e.g., at least 99.9%).

[0085] In some embodiments, the compound in the relevant configuration is present in an enantiomer excess (ee) of at least 90% (at least 95%, at least 98%, or in particular, at least 99%, e.g., at least 99.9%).

[0086] In certain embodiments of the present invention, the β2 adrenergic receptor agonist is formoterol, alformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, The group consists of ritodrine, indacaterol, orodaterol, corterol, hexaprenaline, carmoterol, isoxuprine, isoetaline, sinterol, bamethan, (R)-bamethan, clencyclohexerol, tulobuterol, BRL-47672, trantinterol, clenproperol, clenpenterol, brombuterol, ractopamine, and avesiderol, as well as pharmaceutically acceptable salts thereof.

[0087] In a further specific embodiment, the β2 adrenergic receptor agonist is selected from the group consisting of formoterol, alformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, orodaterol, corterol, hexaprenaline, carmoterol, isoxuprine, isoetaline, sinterol, bamethan, (R)-bamethan, clencyclohexerol, tulobuterol, BRL-47672, and trantinterool, as well as pharmaceutically acceptable salts thereof.

[0088] In certain embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, alformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, orodaterol, carmoterol, bamethan, (R)-bamethan, clencyclohexerol, tulobuterol, trantinerol, and avesiderol, as well as pharmaceutically acceptable salts thereof.

[0089] In further specific embodiments, the β2 adrenergic receptor agonist is selected from the group consisting of formoterol, alformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, orodaterol, carmoterol, bamethan, (R)-bamethan, clencyclohexerol, tulobuterol, and tranchinarol, as well as pharmaceutically acceptable salts thereof.

[0090] In more specific embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, alformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane, and tulobuterol, as well as pharmaceutically acceptable salts thereof.

[0091] In more specific embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formoterol, alformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane, and tulobuterol, as well as pharmaceutically acceptable salts thereof.

[0092] To avoid any ambiguity, the structures of vamethane (CAS: 3703-79-5) and (R)-vamethane (CAS: 912804-58-1) are shown below. [ka]

[0093] To avoid any ambiguity, in the event of any discrepancy between the name of a compound and the structure described herein, the structure shall prevail.

[0094] In further embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of formeterol, alformeterol, salmeterol, clenbuterol, tulobuterol, bambuterolvilanterol, indacaterol, orodaterol, carmoterol, and avesiderol, as well as pharmaceutically acceptable salts thereof.

[0095] In further embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of salbutamol, ritodrine, corterol, hexaprenaline, tulobuterol, and isoxuprine, as well as pharmaceutically acceptable salts thereof.

[0096] In certain embodiments, the β2-adrenergic receptor agonist is clenbuterol or (R)-clenbuterol, or a pharmaceutically acceptable salt thereof.

[0097] To avoid any ambiguity, the compound clenbuterol can be understood to have the following structure. [ka]

[0098] In certain embodiments, the β2-adrenergic receptor agonist is tulobuterol or (R)-tulobuterol, or a pharmaceutically acceptable salt thereof.

[0099] To avoid any ambiguity, the compound tulobuterol can be understood to have the following structure. [ka]

[0100] To avoid ambiguity, the International Common Name (INN) or Development Drug Code (e.g., BRL-47672) for a compound generally indicates the stereochemical composition of the compound or a particular mixture of stereoisomers (e.g., a racemate). Within the scope of the present invention, where relevant and unless the context indicates otherwise (e.g., when both the racemate and a single stereoisomer are explicitly named), such a name may also be considered to encompass distinct stereoisomers that exhibit relevant biological activity but to which alternative INNs or Development Drug Codes have not currently been assigned.

[0101] In certain embodiments, the INN or development drug code should be understood to represent a compound to which only the relevant name or code has been assigned.

[0102] If no INN or development drug code is available for a compound, the compound may be identified by its Chemical Abstracts Service Registry Number (CAS number). As referred to herein, such compounds are identified using the notation "CAS:XXXXXX-XX-X" (the number of digits in the first set of digits may vary). Where relevant and unless the context indicates otherwise, the CAS number of a compound may also be considered to encompass other stereoisomers or mixtures thereof that exhibit the relevant biological activity but for which alternative CAS numbers (as described above for INNs and development drug codes) have not yet been assigned.

[0103] In certain embodiments, the CAS number should be understood to represent a compound to which only the associated name or code has been assigned.

[0104] In certain embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of (R)-bamethan, bamethan, clencyclohexerol, radopamine, tulobuterol, and (R)-tulobuterol.

[0105] The present invention also encompasses pharmaceutical formulations comprising isotope-labeled compounds, which are identical to the compounds enumerated herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from that ordinarily found in nature (or the most abundant atomic mass or mass number found in nature). All isotopes of any particular atom or element identified herein are intended to be within the range of the compounds of the present invention. Accordingly, the present invention also encompasses pharmaceutical formulations comprising deuterated compounds, i.e., compounds in which one or more hydrogen atoms are replaced by hydrogen isotopes.

[0106] It will also be understood that certain compounds acting as β2-adrenergic receptor agonists, as described herein, can activate β2-adrenergic receptors without inducing significant cAMP production.

[0107] Thus, certain β2 - adrenergic agonists that may be mentioned include those that can activate β2 - adrenergic receptors without inducing cAMP production (or with only minimal effects thereon).

[0108] Furthermore, in certain embodiments, the methods and uses described herein may be carried out without inducing cAMP production (or without inducing a significant level thereof).

[0109] In particular, the β2 - adrenergic agonists described herein may be further described as β2 - adrenergic agonists that do not induce significant cAMP (i.e., its level and / or production).

[0110] One of ordinary skill in the art can determine the level of cAMP production provided by a compound, such as those described in the examples provided herein, using techniques known to one of ordinary skill in the art.

[0111] For example, the level of cAMP production induced by a given compound can be determined by reference to the amount induced by that compound at a defined concentration, compared to that induced by a reference compound, such as isoprenaline, at the same concentration, using techniques known to one of ordinary skill in the art (e.g., according to the protocol described in the biological examples provided in WO2019 / 053427, i.e., in a stimulation buffer supplemented with 1% BSA, 5 mM HEPES, and 1 mM IBMX in HBSS at pH 7.4, for 15 minutes, in cells such as differentiated L6 - myotubes stimulated with isoprenaline or a compound having a final concentration of 1×10 -5 M).

[0112] In such embodiments, a compound that does not induce significant cAMP may be defined as a compound that induces less than 50% (or, in some embodiments, less than 25%) of the cAMP induced by isoprenaline (for example, according to the protocol described above).

[0113] Certain compounds acting as β2-adrenergic receptor agonists that can activate β2-adrenergic receptors without inducing cAMP production (or with minimal effect thereof) include those described in the following publications, the contents of which (in particular, biological examples, definitions of general compounds and all embodiments thereof and related definitions, exemplary compounds and their pharmaceutically acceptable salts provided herein, and associated preparation methods) are incorporated herein by reference in their entirety. International Publication Patent No. 2017 / 153737 International Publication Patent No. 2019 / 053429 International Publication Patent No. 2019 / 053426 International Publication Patent No. 2019 / 053425 International Publication Patent No. 2019 / 053427 International Publication Patent No. 2020 / 188299 International Publication Patent No. 2020 / 188301 International Publication Patent No. 2022 / 063895 International Publication Patent No. 2022 / 063889 International Publication Patent No. 2023 / 046885 International Publication Patent No. 2023 / 046882 International Publication Patent No. 2023 / 105035 International Publication Patent No. 2023 / 203223

[0114] Compounds described in publications referenced and incorporated herein were screened according to the procedures outlined in Biological Examples 1 and 2 of International Publication No. 2019 / 053427. The test results are shown in Table 1. Activity is indicated as +++ if 10 μM of a compound exhibits more than 75% of the activity of 10 μM isoproterenol, as ++ if 75-50%, as + if 50-25%, and as - if less than 25%. Although the compounds are described as salt-free molecules in Table 1, the test compounds may have contained additional salts or solvent components that did not contribute to their biological activity.

[0115] Where there are discrepancies between the nomenclature and the compound structure shown in the diagram, the latter takes precedence (unless it contradicts any experimental details that may be given and / or is not clear from the context). Synthetic procedures and further biological data can be found in the relevant publications.

[0116] Therefore, the specific β2-adrenergic receptor agonists that may be mentioned are provided in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59

[0117] In certain embodiments, the β2-adrenergic receptor agonist is, 2-(butylamino)-1-(p-hydroxyphenyl)-1-ethanol, 2-(tert-butylamino)-1-(p-hydroxyphenyl)-1-ethanol, 2-[(cyclohexylmethyl)amino]-1-(p-hydroxyphenyl)-1-ethanol, (R)-2-(butylamino)-1-(p-hydroxyphenyl)-1-ethanol, 1-(m-hydroxyphenyl)-2-(1-methylbutylamino)-1-ethanol, 2-(3-cyclohexylpropylamino)-1-(p-hydroxyphenyl)-1-ethanol, (R)-2-[(R)-1-methylbutylamino]-1-(p-hydroxyphenyl)-1-ethanol, 1-(4-amino-3,5-dichlorophenyl)-2-(butylamino)-1-ethanol, 2-(3-cyclopropylpropylamino)-1-(p-hydroxyphenyl)-1-ethanol, 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-2-(butylamino)-1-ethanol, 2-(butylamino)-1-(4-chloro-3-hydroxyphenyl)-1-ethanol, 1-(4-chloro-3-hydroxyphenyl)-2-(1-methylbutylamino)-1-ethanol, m-{(R)-[(2R,5R)-5-methyl-2-pyrrolidinyl]hydroxymethyl}phenol and m-{(S)-[(2S,5S)-5-methyl-2-pyrrolidinyl]hydroxymethyl}phenol, 1-(3-amino-2,4-difluorophenyl)-2-(butylamino)-1-ethanol, (R)-[(2R,6R)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol, (R)-2-[(R)-1-methylbutylamino]-1-(m-fluorophenyl)-1-ethanol, (R)-2-[(S)-1-methylbutylamino]-1-(m-fluorophenyl)-1-ethanol, (R)-2-(tert-butylamino)-1-(m-fluorophenyl)-1-ethanol, (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](m-fluorophenyl)methanol, (R)-2-(1,1-dimethylbutylamino)-1-(m-fluorophenyl)-1-ethanol, (R)-[(2R,6S)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol, (R)-2-(tert-butylamino)-1-(2,3-difluorophenyl)-1-ethanol, (R)-2-(butylamino)-1-(2,3-difluorophenyl)-1-ethanol, (R)-2-(tert-butylamino)-1-(o-fluorophenyl)-1-ethanol, (R)-2-(butylamino)-1-(o-fluorophenyl)-1-ethanol, (R)-1-(m-fluorophenyl)-2-(1-methylcyclopropylamino)-1-ethanol, (R)-1-(m-fluorophenyl)-2-(1-methylcyclobutylamino)-1-ethanol, (R)-2-(butylamino)-1-(4-fluoro-3-hydroxyphenyl)-1-ethanol, (R)-2-(butylamino)-1-(2-fluoro-3-hydroxyphenyl)-1-ethanol, (R)-1-(3-amino-2-fluorophenyl)-2-(tert-butylamino)-1-ethanol, 4-[(R)-2-(tert-butylamino)-1-hydroxyethyl]-1-methyl-2(1H)-pyridinone, (R)-2-(tert-butylamino)-1-(5-fluoro-3-pyridyl)-1-ethanol, 5-[(R)-2-(tert-butylamino)-1-hydroxyethyl]-3-pyridinol, (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](m-fluorophenyl)methanol, m-{(R)-[(R)-5,5-dimethyl-2-pyrrolidinyl]hydroxymethyl}phenol, (R)-[(2S,6R)-6-propyl-2-piperidyl](m-chlorophenyl)methanol, (S)-[(2S,6S)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol, 4-[2-(tert-butylamino)-1-hydroxyethyl]-3-pyridinol, (R)-[(2S,6R)-6-propyl-2-piperidyl](m-hydroxyphenyl)methanol, (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](o-chlorophenyl)methanol, (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)-1-ethanol, (R)-2-(tert-butylamino)-1-(3-fluoro-2-tolyl)-1-ethanol, (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](o-chlorophenyl)methanol, (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](m-chlorophenyl)methanol, (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](5-fluoro-3-pyridyl)methanol, (R)-[(2R,5R)-5-propyl-2-pyrrolidinyl](5-fluoro-3-pyridyl)methanol, (S)-[(R)-6,6-dimethyl-2-piperidyl](o-chlorophenyl)methanol, (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](o-fluorophenyl)methanol, (S)-[(R)-6,6-dimethyl-2-piperidyl](o-fluorophenyl)methanol, (S)-(o-fluorophenyl)(4-methyl-7-azabicyclo[2.2.1]hepta-1-yl)methanol, (R)-(o-fluorophenyl)(4-methyl-7-azabicyclo[2.2.1]hepta-1-yl)methanol, (R)-(5-fluoro-3-pyridyl)(4-methyl-7-azabicyclo[2.2.1]hepta-1-yl)methanol, (R)-[(S)-6,6-dimethyl-2-piperidyl](m-fluorophenyl)methanol, (R)-[(S)-6,6-dimethyl-2-piperidyl](o-fluorophenyl)methanol, (R)-(o-chlorophenyl)(4-methyl-7-azabicyclo[2.2.1]hepta-1-yl)methanol, (R)-(m-chlorophenyl)(4-methyl-7-azabicyclo[2.2.1]hepta-1-yl)methanol, (R)-[(R)-4,4-dimethyl-2-azetidinyl](m-fluorophenyl)methanol, (R)-[(R)-4,4-dimethyl-2-azetidinyl](o-fluorophenyl)methanol, (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hexa-3-yl}(m-chlorophenyl)methanol, (S)-{(S)-1-methyl-2-azabicyclo[2.1.1]hexa-3-yl}(o-fluorophenyl)methanol, (S)-{(R)-1-methyl-2-azabicyclo[2.1.1]hexa-3-yl}(o-fluorophenyl)methanol, (R)-{(S)-1-methyl-2-azabicyclo[2.1.1]hexa-3-yl}(o-fluorophenyl)methanol, (R)-[(R)-4,4-dimethyl-2-azetidinyl](5-fluoro-3-pyridyl)methanol, (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hexa-3-yl}(5-fluoro-3-pyridyl)methanol, (R)-[(R)-5,5-dimethyl-2-pyrrolidinyl](3-amino-2-fluorophenyl)methanol, (R)-[(R)-4,4-dimethyl-2-azetidinyl](m-chlorophenyl)methanol, (R)-[(2S,7S)-7-propyl-2-azepanyl](5-fluoro-3-pyridyl)methanol, (S)-[(R)-5,5-dimethyl-2-pyrrolidinyl](4-amino-3,5-difluorophenyl)methanol, (R)-1-(5-fluoro-3-pyridyl)-2-{2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-ethanol, (R)-1-(m-fluorophenyl)-2-{1-methyl-1-[(1r,4R)-4-methoxycyclohexyl]ethylamino}-1-ethanol, (R)-1-(5-fluoro-3-pyridyl)-2-{1-methyl-1-[(1r,4R)-4-methoxycyclohexyl]ethylamino}-1-ethanol, (R)-{(R)-1-methyl-2-azabicyclo[2.1.1]hexa-3-yl}(3-amino-2-fluorophenyl)methanol, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-methoxycyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-methoxycyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1-[(1S,3R)-3-methoxycyclohexyl]-1-methylethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1-[(1R,3S)-3-methoxycyclohexyl]-1-methylethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-1-(5-fluoro-3-pyridyl)-2-{3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-ethanol, (R)-1-(5-fluoro-3-pyridyl)-2-({[(1s,4S)-4-(benzyloxy)cyclohexyl]methyl}amino)-1-ethanol, (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-methoxycyclohexyl]propylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, (R)-1-(m-fluorophenyl)-2-{1-methyl-1-[(1s,4S)-4-(benzyloxy)cyclohexyl]ethylamino}-1-ethanol, (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-hydroxycyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-hydroxycyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, N-[(1R,4r)-4-{[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]methyl}cyclohexyl]benzamide, (R)-2-{1,1-dimethyl-3-[(1r,4S)-4-hydroxycyclohexyl]propylamino}-1-(o-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-3-[(1s,4R)-4-hydroxycyclohexyl]propylamino}-1-(o-fluorophenyl)-1-ethanol, Methyl(1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarboxylic acid, (S)-[(2R,5S)-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol, (R)-[(2R,5S)-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol, Methyl(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarboxylic acid, (1S,4s)-8-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-7-methoxy-p-menthan-7-one, (R)-(m-fluorophenyl){4-(methoxymethyl)-7-azabicyclo[2.2.1]hepta-1-yl}methanol, (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol, (R)-[(2R,5S)-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}2-pyrrolidinyl](o-fluorophenyl)methanol, (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}2-pyrrolidinyl](o-fluorophenyl)methanol, (R)-[(2R,5R)-5-{[(1r,4R)-4-methoxycyclohexyl]methyl}2-pyrrolidinyl](5-fluoro-3-pyridyl)methanol, Methyl(1R,4r)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylic acid, N-[(1R,4r)-4-{1-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-1-methylethyl}cyclohexyl]acetamide, (1S,4s)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylic acid, Methyl(1S,4s)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylic acid, Methyl(1R,4r)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylic acid, Methyl(1S,4s)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylic acid, Methyl(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarboxylic acid, N-[(1R,4r)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-aminocyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(mesylamino)cyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, N-[(1R,4r)-4-{3-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexyl]acetamide, (S)-[(2R,5S)-5-methyl-5-{[(1r,4S)-4-methoxycyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol, (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-5-methyl-2-pyrrolidinyl}(m-fluorophenyl)methanol, (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-5-methyl-2-pyrrolidinyl}(m-fluorophenyl)methanol, (1R,4r)-8-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-7-methoxy-p-menthan-7-one, (1R,4r)-8-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-7-methoxy-p-menthan-7-one, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-aminocyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (S)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol, (R)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol, (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol, (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol, (R)-2-(tert-butylamino)-1-(2-methyl-3-pyridyl)-1-ethanol, (S)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol, (R)-{(2R,5S)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol, (R)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol, (S)-{(2R,5R)-5-[(p-methoxyphenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(mesylamino)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide, N-[(1R,4r)-4-{1-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-1-methylethyl}cyclohexyl]acetamide, 6-[(S)-2-(tert-butylamino)-1-hydroxyethyl]-2-pyridinecarbonitride, (R)-(4-benzyl-7-azabicyclo[2.2.1]hepta-1-yl)(m-fluorophenyl)methanol, (R)-{(2R,5S)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol, (R)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(m-fluorophenyl)methanol, (R)-(4-{[(p-chlorophenyl)methoxy]methyl}-7-azabicyclo[2.2.1]hepta-1-yl)(m-fluorophenyl)methanol, (S)-2-(tert-butylamino)-1-[6-(trifluoromethyl)-2-pyridyl]-1-ethanol, [(1R,4r)-4-{1-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-1-methylethyl}cyclohexyloxyacetic acid, (1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarbonitride, (R)-(m-fluorophenyl){4-[(p-methoxyphenyl)methyl]-7-azabicyclo[2.2.1]hepta-1-yl}methanol, (R)-{(2R,5S)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol, (S)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol, (R)-{(2R,5R)-5-[(p-chlorophenyl)methyl]-2-pyrrolidinyl}(5-fluoro-3-pyridyl)methanol, Ethyl[(1R,4r)-4-{1-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-1-methylethyl}cyclohexyloxy]acetic acid, (R)-(m-fluorophenyl){4-[(p-fluorophenyl)methyl]-7-azabicyclo[2.2.1]hepta-1-yl}methanol, 6-[(S)-2-{1,1-dimethyl-2-[(1r,4S)-4-aminocyclohexyl]ethylamino}-1-hydroxyethyl]-2-pyridinecarbonitride, N-[(1R,4s)-4-{2-[(S)-2-(6-cyano-2-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide, N-[(1S,4r)-4-{2-[(S)-2-(6-cyano-2-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide, 6-[(S)-2-{1,1-dimethyl-2-[(1r,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-hydroxyethyl]-2-pyridinecarbonitride, N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]2,2-dimethylpropionamide, N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]trifluoroacetamide, N-[(1R,4r)-4-{2-[(R)-2-hydroxy-2-(2-methyl-3-pyridyl)ethylamino]-2-methylpropyl}cyclohexyl]acetamide, (R)-(m-fluorophenyl)(4-{[(p-fluorophenyl)methoxy]methyl}-7-azabicyclo[2.2.1]hepta-1-yl)methanol, (S)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1]hepta-1-yl}(m-fluorophenyl)methanol, (R)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1]hepta-1-yl}(m-fluorophenyl)methanol, (R)-(4-{[(p-fluorophenyl)methoxy]methyl}-7-azabicyclo[2.2.1]hepta-1-yl)(5-fluoro-3-pyridyl)methanol, (S)-(m-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7-azabicyclo[2.2.1]hepta-1-yl}methanol, N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]cyclopropanecarboxamide, N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, N-[(1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]trifluoroacetamide, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-aminocyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(3,3-dimethylureido)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(trifluoromesylamino)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (1S,4r)-4-(2-{(S)-2-hydroxy-2-[6-(trifluoromethyl)-2-pyridyl]ethylamino}-2-methylpropyl)cyclohexyl 2-methyl-2-propanecarbamate, N-[(1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]acetamide, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(mesylamino)cyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl 2-methyl-2-propanecarbamate, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(dimethylaminosulfonyl)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, (R)-2-{1,1-dimethyl-2-[(1r,4R)-4-(methylaminosulfonyl)cyclohexyl]ethylamino}-1-(m-fluorophenyl)-1-ethanol, N-[(1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]-N-methylacetamide, N-[(1R,4r)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexyl]-N-methylacetamide, (R)-[(2R,5S)-5-{[(1s,4R)-4-(mesylamino)cyclohexyl]methyl}-2-pyrrolidinyl](m-fluorophenyl)methanol, (1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanesulfonamide, (1S,4s)-4-{2-[(R)-2-(5-fluoro-3-pyridyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanesulfonamide, (R)-2-{1,1-dimethyl-2-[(1s,4S)-4-(trifluoromesylamino)cyclohexyl]ethylamino}-1-(5-fluoro-3-pyridyl)-1-ethanol, (R)-{4-[(E)-3-phenyl-2-propenyl]-7-azabicyclo[2.2.1]hepta-1-yl}(5-fluoro-3-pyridyl)methanol, (R)-{4-[(E)-3-phenyl-2-propenyl]-7-azabicyclo[2.2.1]hepta-1-yl}(m-fluorophenyl)methanol, (R)-(m-fluorophenyl){4-(3-phenylpropyl)-7-azabicyclo[2.2.1]hepta-1-yl}methanol, and (S)-(o-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7-azabicyclo[2.2.1]hepta-1-yl}methanol, The group is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0118] Therapeutic drugs As described in this specification, the present invention is (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release Relates to uses and methods including treatment and / or prophylactic measures in

[0119] One of ordinary skill in the art will recognize the various forms in which insulin can be used in treatment, administered to patients who need it, or administered by patients who need it.

[0120] In certain embodiments, the invention relates to uses and methods including treatment with insulin or therapeutic insulin derivatives.

[0121] As used herein, the term "therapeutic insulin derivative" will refer to derivatives of insulin that deliver an equivalent or enhanced biological response (i.e., the biological response when administered to a patient is of the same type as that achieved by administration of insulin, and its effect is at a therapeutically equivalent or enhanced level, such as by providing beneficially modified pharmacokinetics when compared to insulin). Such derivatives may also include combinations of insulin derivatives.

[0122] Certain forms of insulin and therapeutic insulin derivatives that may be mentioned are as follows: Short-acting insulin, for example, Humulin R U-100, Novolin R FlexPen, Novolin R ReliOn, and Novolin R FlexPen ReliOn, Rapid-acting insulin, for example, Inhaled insulin (e.g., Afrezza), Insulin aspart (e.g., Fiasp, Fiasp FlexTouch, Fiasp PenFill, NovoLog, NovoLog FlexPen, NovoLog FlexTouch, NovoLog PenFill, ReliOn NovoLog, ReliOn NovoLog FlexPen), Insulin glulisine (e.g., Apidra, Apidra SoloStar), Insulin lispro (e.g., Admelog, Admelog SoloStar, Humalog, Humalog KwikPen, Humalog Junior KwikPen), and Insulin lispro-aabc (e.g., Lyumjev, Lyumjev KwikPen), Intermediate-acting insulin, e.g., Insulin isophane (e.g., Humulin N U-100, Humulin N KwikPen, Novolin N, Novolin N FlexPen, Novolin N ReliOn, Novolin N FlexPen ReliOn), Long-acting insulin, e.g., Insulin degludec (e.g., Tresiba, Tresiba FlexTouch), Insulin detemir (e.g., Levemir), Insulin glargine (e.g., Basaglar KwikPen, Lantus, Lantus SoloStar, Toujeo SoloStar, Toujeo Max SoloStar), Insulin glargine-yfgn (e.g., Semglee-yfgn), and Concentrated regular insulin (e.g., Humulin R U-500, Humulin R U-500 KwikPen), Combination (pre-mixed) insulin, e.g., Insulin aspart protamine / insulin aspart 70 / 30 (e.g., NovoLog Mix 70 / 30, NovoLog Mix 70 / 30 FlexPen), Insulin isophane / regular insulin 70 / 30 (e.g., Humulin 70 / 30, Humulin 70 / 30 KwikPen, Novolin 70 / 30, Novolin 70 / 30 FlexPen, Novolin 70 / 30 FlexPen ReliOn), Insulin lispro protamine / insulin lispro 50 / 50 (e.g., Humalog Mix 50 / 50, Humalog Mix 50 / 50 KwikPen), and Includes insulin lisproprotamine / insulin lispro 75 / 25 (e.g., Humalog Mix 75 / 25, Humalog Mix 75 / 25 KwikPen).

[0123] In certain embodiments, the present invention relates to uses and methods including treatment with a therapeutic agent that stimulates insulin release.

[0124] As used herein, the term “insulin-releasing therapeutic agent” will refer to a therapeutically active ingredient (i.e., a pharmaceutical product) that stimulates the pancreas’ association with insulin after administration to a patient (i.e., during use) (this effect may be provided in conjunction with other biological effects). Such therapeutic agents may also be referred to as insulin secretagogues.

[0125] Certain therapeutic agents that stimulate insulin release may be mentioned. Sulfonylureas such as tolbutamide, glimelpiride, glipizide, and glybrid (including micronized glybrid), Glinides such as repaglinide and nateglinide, DPP-4 inhibitors such as alogliptin, sitagliptin, saxagliptin, and linagliptin, This includes GLP-1 receptor agonists (including GLP-1 derivatives) such as exenatide, sustained-release exenatide, tylzepatide, liraglutide, lixisenatide, semaglutide, albiglutide, and dulaglutide.

[0126] Those skilled in the art will understand that GLP-1 receptor agonists, i.e., agonists of the glucagon-like peptide 1 receptor, and their derivatives mimic the action of glucagon-like peptide 1.

[0127] GLP-1 receptor agonists may have affinity for GIP receptors, i.e., gastric inhibitory polypeptide receptors, in addition to GLP-1 receptors. Alternatively, GLP-1 receptor agonists may not have affinity for GIP receptors, or may have substantially no affinity for them.

[0128] Those skilled in the art will understand that GLP-1 receptor agonists may be peptides. Furthermore, they may be provided as liquids or suspensions, in injectable forms such as pre-filled pens for injection, and / or as sustained-release formulations. In one example, a GLP-1 receptor agonist may be administered subcutaneously. GLP-1 receptor agonists may be administered once or several times a day or week.

[0129] The following are examples of GLP-1 receptor agonists.

[0130] Exenatide, with CAS number 141758-74-9, is a peptide marketed under the trade names Byetta and Bydureon. It can be administered subcutaneously and / or in doses of 5 micrograms to 2 mg.

[0131] Chilzepatide, with CAS number 2023788-19-2, is a linear polypeptide of 39 amino acids chemically modified by lipidization. It is marketed under the trade name Mounjaro. It can be administered subcutaneously as an injectable solution. Dosages can range from 2.5 mg / 0.5 mL to 15 mg / 0.5 mL.

[0132] Liraglutide, with CAS number 204656-20-2, is a peptide marketed under the brand names Saxenda, Victoza, and Xultophy. It can be administered subcutaneously as an injectable solution. The dosage may range from 0.6 mg to 1.8 mg, for example, once daily for more than one week. For example, the dosage may be 0.6 mg, 1.2 mg, or 1.8 mg once daily for more than one week.

[0133] Liraglutide, which has the CAS number 320367-13-3, is sold under the brand names Lyxumia and Adlyxin. It can be administered in an injectable form such as subcutaneously. For example, it can be administered once daily. The dosage can be, for example, 10 micrograms to 20 micrograms once a week.

[0134] Semaglutide, which has the CAS number 910463-68-2, is a peptide sold under the brand names Ozempic, Rybelsus, and Wegovy. It can be administered in an injectable form such as subcutaneously (Ozempic and Wegovy) or orally (Rybelsus). The dosage can be 0.25 mg to 2 mg and is administered weekly.

[0135] Albiglutide, which has the CAS number 782500-75-8, is a peptide sold under the trade names Eperzan and Tanzeum. It can also be referred to as GSK-716155. It can be administered in an injectable form such as subcutaneously. The dosage can be, for example, 30 mg to 50 mg once a week.

[0136] Dulaglutide, which has the CAS number 923950-08-7, is a peptide sold especially under the brand name Trulicity. It can be administered with an injection pen. For example, it can be administered subcutaneously. The dosage of dulaglutide can be 0.75 mg / 0.5 mL, 1.5 mg / 0.5 mL, 3 mg / 0.5 mL, or 4.5 mg / 0.5 mL.

[0137] Pharmaceutical preparation Those skilled in the art will understand that both a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic insulin derivative or a therapeutic agent that stimulates the release of insulin, can be administered in the form of a pharmaceutical preparation that may further contain one or more pharmaceutically acceptable excipients.

[0138] Suitable pharmaceutical formulations are either commercially available or otherwise as described in Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995), and Martindale - The Complete Drug Reference (35 th The relevant disclosures in the literature, including the edition of the β2-adrenergic receptor agonist and the documents referenced therein, are incorporated herein by reference in their entirety. Otherwise, the preparation of suitable formulations, in particular combination preparations comprising both a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic insulin derivative or an insulin release stimulating agent, can be achieved by those skilled in the art using ordinary techniques.

[0139] References to pharmaceutically acceptable excipients(s) may be understood to include pharmaceutically acceptable diluents, carriers, and / or adjuvants, as is known to those skilled in the art.

[0140] Therefore, in a second aspect of the present invention, (I) (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release The compound, and (II) β2-adrenergic receptor agonists or pharmaceutically acceptable salts thereof in addition, one or more pharmaceutically acceptable excipients of any choice. Pharmaceutical formulations including the following are provided: These formulations may be referred to as "the formulations of the present invention," etc.

[0141] In certain embodiments, the pharmaceutical formulation is intended for use in the treatment and / or preventive measures for a disease or disorder.

[0142] In a third aspect of the present invention, for use in the treatment and / or prevention of hyperglycemia or disorders characterized by hyperglycemia, (I) (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release The compound, and (II) β2-adrenergic receptor agonists or pharmaceutically acceptable salts thereof in addition, one or more pharmaceutically acceptable excipients of any choice. A pharmaceutical formulation including the above is provided.

[0143] In an alternative third aspect of the present invention, a method for the treatment and / or prevention of hyperglycemia or a disorder characterized by hyperglycemia, (I) (a) insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release The compound, and (II) β2-adrenergic receptor agonists or pharmaceutically acceptable salts thereof in addition, one or more pharmaceutically acceptable excipients of any choice. A method is provided which includes administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need thereof.

[0144] To avoid any doubt, formulations of the second and third embodiments of the present invention may have any of the specific features described above for the first embodiment of the present invention, including all combinations thereof.

[0145] Combination and kit formulations Those skilled in the art will understand that the present invention may also relate to a combination product comprising a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic insulin derivative or a therapeutic agent that stimulates insulin release, as well as the use thereof.

[0146] Those skilled in the art will understand that combinations of β2-adrenergic receptor agonists or pharmaceutically acceptable salts thereof with insulin or therapeutic insulin derivatives or therapeutic agents that stimulate insulin release may also be provided in the form of kit formulations containing them.

[0147] In a fourth aspect of the present invention, the components are: (A) Pharmaceutical preparations comprising a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, mixed with one or more pharmaceutically acceptable excipients of any choice, and (B) Pharmaceutical formulations comprising insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, mixed with one or more pharmaceutically acceptable excipients of any choice. Includes, A combination or kit formulation is provided in which components (A) and (B) are each provided in a form suitable for administration in combination with the other.

[0148] In certain embodiments, the kit formulation is intended for use in the treatment and / or prophylactic care of hyperglycemia or disorders characterized by hyperglycemia.

[0149] In certain embodiments, a kit formulation according to a fourth aspect of the present invention further includes instructions for using each component in conjunction with other treatments for hyperglycemia or disorders characterized by hyperglycemia.

[0150] In an alternative fourth aspect of the present invention, (I) one of the components (A) or (B) as defined above, and (II) Instructions for the use of this component in combination with the other of two components in the treatment of hyperglycemia or a disorder characterized by hyperglycemia. A kit formulation containing the following is provided.

[0151] To avoid any ambiguity, a kit formulation of the fourth aspect of the present invention may have any of the specific features described above for the first, second, or third aspects of the present invention, including all combinations thereof.

[0152] In certain embodiments, the kit formulations described herein may comprise two or more formulations comprising an appropriate amount / dose of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof and / or a prodrug thereof, and / or two or more formulations comprising an appropriate amount / dose of insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release. If two or more formulations (containing any of the active compounds) exist, such formulations may be identical or different in terms of the dosage, chemical composition, and / or physical form(s) of any of the compounds.

[0153] With respect to the treatments, formulations, and kit formulations of the present invention as described herein, any reference to treatment or administration of each component will refer to that component administered in combination with the other.

[0154] Method of administration Those skilled in the art will understand that the present invention (i.e., the pharmaceutical formulations, kit formulations, compounds for use, uses, and methods of treatment described herein, including all embodiments thereof and their preferred features) relates to two components administered together: a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release.

[0155] References to components administered in conjunction with the other may include components administered sequentially, separately, or simultaneously as part of a medical intervention aimed at treating the related condition. In particular, such references may include components administered over the course of treatment for the related condition, for a period of time close enough to enable a more beneficial effect to the patient than if administered over the same course of treatment in the absence of the other components.

[0156] Whether a combination provides a greater beneficial effect with respect to the treatment of a particular condition, and over the course of that treatment, depends on the condition being treated or prevented, but can be achieved by ordinary means by those skilled in the art.

[0157] Those skilled in the art will understand that references to components administered consecutively (and therefore separately) (i.e., β2-adrenergic receptor agonists or their pharmaceutically acceptable salts, and insulin or therapeutic insulin derivatives, or therapeutic agents that stimulate insulin release) include the fact that individual doses of each component are administered (i.e., ingested by the patient, such as by oral ingestion) within 48 hours of each other (e.g., within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes).

[0158] Similarly, references to components administered simultaneously (which may be in combined or separate forms) would include components administered substantially simultaneously (i.e., ingested by the patient, such as orally).

[0159] In certain embodiments, the components are administered sequentially (and therefore as separate doses) (i.e., ingested by the patient, such as orally).

[0160] For example, in certain embodiments, the components are administered consecutively with at least two hours between doses (i.e., the interval between administration of each component to the patient is at least four hours, for example, if administered orally), for example, between two and forty-eight hours, or between two and twenty-four hours, or between two and twelve hours.

[0161] To avoid any ambiguity, references to β2-adrenergic receptor agonists or pharmaceutically acceptable salts thereof, and to insulin or therapeutic insulin derivatives, or components as therapeutic agents that stimulate insulin release, will include references to components (II) and (I) of the third aspect of the present invention, and to components (A) and (B) of the fourth aspect of the present invention.

[0162] Those skilled in the art will understand that the compounds and pharmaceutical formulations defined herein are typically administered in pharmaceutically acceptable dosage forms by oral, intravenous, subcutaneous, buccal, rectal, skin, transdermal, nasal, tracheal, bronchial, sublingual, intranasal, topical, any other parenteral route, or by inhalation. Pharmaceutical formulations described herein may 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.

[0163] In certain embodiments, the compounds and pharmaceutical formulations described herein are administered orally. As such, in certain embodiments, the pharmaceutical formulations described herein may be described as oral pharmaceutical formulations.

[0164] Therefore, in certain embodiments, the pharmaceutical formulation(s) are provided in pharmaceutically acceptable dosage forms, including tablets or capsules, liquid forms taken orally or by injection, suppositories, creams, gels, foams, transdermal patches, ointments, and inhalants (e.g., applied intranasally). To avoid doubt, in such embodiments, the compounds of the present invention may exist in other forms, such as solids (e.g., solid dispersions), liquids (e.g., in the form of solutions), or micelles.

[0165] In more specific embodiments, the pharmaceutical formulation(s) may be provided in a pharmaceutically acceptable oral dosage form, including tablets or capsules, which may be prepared using techniques known to those skilled in the art.

[0166] For example, in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with a solid powder component such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable component, and with disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol wax. The mixture may then be processed into granules or compressed into tablets.

[0167] Soft gelatin capsules can be prepared using capsules containing one or more active compounds (e.g., compounds of the first, and by extension, second and third embodiments of the present invention, and optionally additional therapeutic agents) together with, for example, vegetable oil, fat, or other vehicles suitable for soft gelatin capsules. Similarly, hard gelatin capsules can contain such compounds(s) in combination with solid powder components such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.

[0168] Dosage units for rectal administration may be prepared in the form of (i) suppositories containing the compound(s) mixed with a neutral lipid base, (ii) gelatin rectal capsules containing the active substance in a mixture with vegetable oil, paraffin oil, or other vehicle suitable for gelatin rectal capsules, (iii) ready-made microenemas, or (iv) dried microenemas that are reconstituted in a suitable solvent immediately before administration.

[0169] Liquid preparations for oral administration may be prepared in the form of a solution or suspension containing, for example, a syrup or suspension, the compound(s), a sugar or sugar alcohol, and the remainder of a formulation consisting of a mixture of ethanol, water, glycerol, propylene glycol, and polyethylene glycol. If desired, such liquid preparations may contain colorants, flavorings, saccharin, and carboxymethylcellulose or other thickeners. Liquid preparations for oral administration may also be prepared in the form of a dry powder reconstituted with a suitable solvent before use.

[0170] 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 and / or buffering components 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 that is reconstituted improvisationally with a suitable solvent before use.

[0171] Those skilled in the art will understand that the compounds described herein, formulations and kit formulations containing them may be administered in variable doses (for example, as formulations as described above), and that preferred doses can be easily determined by those skilled in the art.

[0172] For example, preferred doses of β2-adrenergic receptor agonists or pharmaceutically acceptable salts thereof may include those discussed in the aforementioned publications, which are incorporated herein by reference.

[0173] Similarly, preferred doses of insulin, therapeutic insulin derivatives, and therapeutic agents that stimulate insulin release are as described herein and as known to those skilled in the art (the contents of which are incorporated herein by reference, British National Formulary 85). th This may include those listed in related drug compendiums, such as Edition.

[0174] In any case, a person skilled in the art (e.g., a physician) can determine the most appropriate actual dosage for an individual patient, which is likely to vary depending on the route of administration, the type and severity of the condition being treated, and the race, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated. The above dosages are examples for the average case, but naturally, there may be individual cases where a higher or lower dosage range is appropriate, and such cases are within the scope of the present invention.

[0175] As described herein above, those skilled in the art will understand that the treatments (and preventive measures) described herein may further include (i.e., be combined with) additional (i.e., other) treatments for the same condition. In particular, the treatments (and preventive measures) described herein may be combined with other means for the treatment of hyperglycemia or disorders characterized by hyperglycemia.

[0176] Such drugs are readily identifiable by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g., drugs that are subject to a marketing authorization in one or more regions, such as a marketing authorization in Europe or the United States).

[0177] Preparation of formulations and kit formulations The pharmaceutical formulations and kit formulations described herein may be prepared in accordance with standard and / or acceptable pharmaceutical practices.

[0178] Therefore, in a further aspect of the present invention, a process is provided for the preparation of a pharmaceutical composition / formulation as defined above, the process comprising associating a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents, and / or carriers).

[0179] A method for preparing a kit formulation as defined above is further provided, which includes associating component (A) with component (B) to make the two components suitable for combined administration. In this sense, reference to associating would mean making the two components suitable for combined administration.

[0180] Therefore, with respect to the process for preparing a kit formulation as defined above by "associating" two components with each other, the two components of the kit formulation are: (i) They may be provided as separate formulations (i.e., independently of each other) and then combined for use in combination therapy, or (ii) They may be packaged and presented together as separate components of a “combination pack” for use in combination therapy.

[0181] Those skilled in the art will understand that the pharmaceutical formulations, kit formulations, methods, and uses described herein may have advantages over similar methods (treatments) known in the prior art, in the treatment of the conditions mentioned above, whether or not they are more convenient for physicians and / or patients, more effective, less toxic, have a broader range of activity, are more potent, produce fewer side effects, or have other useful pharmacological properties compared to similar methods (treatments) known in the prior art. In particular, such pharmaceutical formulations, kit formulations, methods, and uses may have the advantage of being more effective and / or exhibiting advantageous properties in vivo.

[0182] While we do not wish to be bound by theory, β2-adrenergic receptor agonists may act as insulin sensitivity enhancers and thus are thought to increase the effectiveness of insulin therapy in the treatment of hyperglycemia or disorders characterized by hyperglycemia, such as type 1 and type 2 diabetes, whether through insulin administration or stimulation of insulin production.

[0183] Furthermore, certain compounds acting as β2-adrenergic receptor agonists, such as those described herein, can activate β2-adrenergic receptors without inducing cAMP production (or with minimal effect in that regard). This is thought to allow the therapeutic effects described herein to be obtained with a lower level of side effects than those resulting from other treatments.

[0184] Therefore, combinations of these therapeutic agents are useful in treating hyperglycemia or disorders characterized by hyperglycemia and may have advantages over compounds used in the manner described in the prior art, such as the ability to administer one or more of the administered compounds at lower doses, the ability to achieve greater efficacy, and / or the ability to induce lower levels of adverse events. [Brief explanation of the drawing]

[0185] [Figure 1]This study demonstrates that glucose uptake facilitated by compound A is dose-dependently inhibited by the selective β2-adrenergic receptor antagonist ICI-118551. [Figure 2] Fasting blood glucose concentrations are shown for the control, liraglutide, compound A, and the combination of liraglutide and compound A, as described in Biological Example 2. [Figure 3] Fasting insulin levels are shown for the control, liraglutide, compound A, and the combination of liraglutide and compound A, as described in Biological Example 2. [Figure 4] The HOMA-IR levels for the control, liraglutide, compound A, and the combination of liraglutide and compound A, as described in Biological Example 2, are shown. [Figure 5] The glucose tolerance of the control, liraglutide, compound A, and the combination of liraglutide and compound A, as described in Biological Example 2, is shown. [Examples]

[0186] The present invention is illustrated by the following embodiments, which are not intended to limit the overall scope of the invention.

[0187] To avoid any ambiguity, in the event of any discrepancy between the name of a compound and the structure described herein, the structure shall prevail.

[0188] I bought a mouse from Scanbur (Charles River).

[0189] Examples of compounds The following compound, referred to herein as Compound A, was used in the specified salt form in the biological examples provided herein (in that context, references to Compound A will refer to its salt form).

[0190] [ka] The synthesis of compound A is described in International Patent Publication No. 2019 / 053427 (see Example 17 therein), which is incorporated herein by reference.

[0191] Compound Example 1 Compound A: (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol [ka] (a) 2-Chloro-1-(5-fluoropyridine-3-yl)ethane-1-one [ka] Isopropylmagnesium chloride (2M in THF, 10.47 mL, 20.94 mmol) was added to a solution of LiCl (887.69 mg, 20.94 mmol) in THF (8 mL) at room temperature. After 15 minutes at room temperature, 3-bromo-5-fluoropyridine (3.35 g, 19.04 mmol) in THF (30 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours and cooled in an ice bath. A solution of 2-chloro-N-methoxy-N-methylacetamide (2.62 g, 19.04 mmol) in THF (30 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. NH4Cl (aqueous solution, 10%) was added, and the mixture was extracted with Et2O. The combined extract was washed with brine, dried, and concentrated in (Na2SO4). The residue was purified by chromatography to obtain the subtitle compound (1.52 g, 20.94 mmol, 46%).

[0192] (b)(R)-2-chloro-1-(5-fluoropyridine-3-yl)ethane-1-one [ka] RhClCp * [(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2] / HCl.Et3N (68.0 mg, 87.6 μmol) was added to a mixture of 2-chloro-1-(5-fluoropyridine-3-yl)ethane-1-one (1.52 g, 8.76 mmol) in DMF (75 mL). Formic acid / Et3N (5:2, 25 mL) was added, and the mixture was stirred at room temperature for 15 minutes. H2O (60 mL) and RINKAN (60 mL) were added, and the layers were separated. The aqueous layer was washed with RINKAN (2 × 60 mL), the combined organic phase was washed with H2O, dried with (Na2SO4), filtered, and concentrated. The residue was purified by chromatography to obtain the subtitle compound (1.35 g, 7.69 mmol, 88%, ee=92.5%).

[0193] (c)(R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol [ka] tert-butylamine (11.37 mL, 108.21 mmol), followed by NaOH (476.08 mg, 11.90 mmol), was added at room temperature to a mixture of 2-chloro-1-(5-fluoropyridine-3-yl)ethane-1-one (1.90 g, 10.82 mmol) and iPrOH (1.66 mL, 21.64 mmol). The mixture was heated at 75°C for 4 hours, cooled, diluted with phenylethylamine, washed with H2O and brine, dried, and concentrated in (Na2SO4). The residue was dissolved in hot phenylethylamine and cooled. Pentane was added, and the mixture was kept overnight at -20°C. The solid was collected and purified by chromatography to obtain the title compound (1.43 g, 6.74 mmol, 62%, ee=98%). 1H NMR(400MHz,CDCl3):δ 8.43-8.27(m,2H),7.57-7.42(m,1H),4.62(dd,J=8.8,3.7Hz,1H),2.94(dd,J=12.1,3.8Hz,1H),2.53(dd,J=12.1,8.8Hz,1H),1.10(s,9H).

[0194] Compound Example 2 Compound A semi-tartrate: (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol semi-tartrate A solution of L-(+)-tartaric acid (6.21 g, 0.5 equivalents) in EtOH (175 mL) was added at room temperature to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol (17.57 g) in EtOH (525 mL, 30 vol) and H2O (7 mL). The mixture was refluxed until all precipitates dissolved, and then cooled. The resulting slurry was stirred overnight at room temperature, then at 0-5°C for 2 hours. The solid was collected to obtain the title salt of (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol (19.9 g, 83%, 100.0% purity by HPLC, 99.8% e,e, by HPLC).

[0195] The formation of semi-tartrates is 1 This was confirmed by 1H-NMR spectroscopy, which showed an amine:acid ratio of 2:1.

[0196] Compound Example 3 Compound A dihydrochloride: (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol dihydrochloride HCl (48 mmol, 2 M in Et2O, 24 mL) was added dropwise to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridine-3-yl)ethane-1-ol (5.10 g, 24 mmol) in Et2O (90 mL) at room temperature. After 15 minutes, the precipitate was collected, vacuum-dried, and recrystallized from MeCN (250 mL). After reaching room temperature, the mixture was stored in a refrigerator for 5 hours, the solid was collected, and vacuum-dried over P2O5 for 5 days to obtain the title compound (6.41 g, 94%). Elemental analysis confirmed the following composition: C 46.45%, H 6.75%, N 9.80%. C 11 H 19 Cl2FN2 requires: C, 46.32%, H, 6.71%, and N, 9.82%.

[0197] Biological examples International Patent Publication No. 2019 / 053427, whose contents are incorporated herein by reference, describes a biological assay demonstrating that compound A provides significant glucose uptake without inducing significant levels of cAMP (see Biological Examples 1 and 2 therein).

[0198] In this example: In Biological Example 1, compound A was used in the form of a dihydrochloride (2HCl) salt, and in Biological Example 2, compound A was used in the form of a hemitartartrate salt.

[0199] Biological Example 1: Glucose uptake in the presence of a selective β2-adrenergic receptor inhibitor L6 myoblasts were grown in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS), 2 mM L-glutamine, 50 U / ml penicillin, 50 μg / ml streptomycin, and 1 g / L glucose supplemented with 10 mM HEPES. The cells were placed in 24-well plates at a rate of 1 × 10⁶ cells. 5Cells were seeded at a concentration of cells / mL. After reaching 90% confluence, the cells were grown in a medium containing 2% FBS for 7 days to differentiate them into myotubes. The differentiated L6-myotubes were serum-starved overnight in a medium containing 0.5% fatty acid-free BSA, and selective β2-adrenergic receptor antagonist ICI was used. In the presence of -118551, 1 × 10 -5 The cells were stimulated with compound A at a final concentration of M. After 1 hour and 40 minutes, the cells were washed twice with warm glucose-free medium, and the agonist from the other part was added to the glucose-free medium. After incubation for another 20 minutes, the cells were stimulated with 50 nM of compound A. 3 After exposure to H-2-deoxyglucose for 10 minutes, the cells were washed three times in ice-cold glucose-free medium and lysed in 400 μl / well of 0.2 M NaOH at 60°C for 1 hour. The cell lysates were mixed with 4 ml of scintillation buffer (Emulsifier Safe, Perkin Elmer), and radioactivity was detected using a β-counter (Tri-Carb 4810TR, Perkin Elmer).

[0200] Figure 1 shows that glucose uptake facilitated by compound A is dose-dependently inhibited by the selective β2-adrenergic receptor antagonist ICI-118551, demonstrating that glucose uptake facilitated by compound A is mediated through the β2-adrenergic receptor. In this document, the antagonist ICI-118551 is understood to have CAS number 72795-01-8.

[0201] Biological Example 2: Combination of Compound A and Liraglutide Male C57Bl / 6N mice aged 2.5 months were caged in groups (4-5 mice per cage), kept at 30°C, and fed a high-fat, high-sucrose diet (45% fat) for 5.5 months. The mice were divided into four groups (2-3 mice per cage) according to their fasting blood glucose concentration, glucose tolerance, body weight, body fat, and lean body mass, and were treated subcutaneously daily for 2 weeks with either vehicle, liraglutide (0.1 mg / kg), compound A (1 mg / kg), or a mixture of liraglutide (0.1 mg / kg) and compound A (1 mg / kg). Mice were fasted for 5 hours, and fasting blood glucose concentration and fasting serum insulin levels were recorded. Glucose (2.5 g / kg lean body mass) was injected intraperitoneally, and glucose concentrations were recorded at 15, 30, 60, 90, and 120 minutes. Using these results, HOMA-IR (fasting blood glucose (mM) x fasting insulin (μIU / mL) / 22.5) and glucose tolerance (area under the curve from 0 to 120 minutes over a blood glucose concentration of 5.5 mM) were calculated.

[0202] The results obtained over the duration of the experiment are presented below. Figure 2 shows fasting blood glucose concentration, Figure 3 shows fasting insulin level, Figure 4 shows HOMA-IR, and Figure 5 shows the results of the glucose tolerance test (measured as the area under the curve over a glucose concentration of 5.5 mM).

[0203] When compound A is added in combination with liraglutide, it has an additional positive effect on glucose homeostasis (blood sugar levels, glucose tolerance, and insulin sensitivity), illustrating that combination therapy with compound A in combination with GLP1-RA or insulin may be beneficial for diabetic patients.

Claims

1. For use in the treatment and / or prophylactic measures of hyperglycemia or disorders characterized by hyperglycemia, β ２ Adrenergic receptor agonists or pharmaceutically acceptable salts thereof, wherein the therapeutic and / or prophylactic measures are (a) Insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release The administration of, further including, β ２ Adrenergic receptor agonists or their pharmaceutically acceptable salts.

2. For use in the treatment and / or prophylactic measures of hyperglycemia or disorders characterized by hyperglycemia, (a) Insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release A compound which is β ２ A compound further comprising the administration of an adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

3. For use in the treatment and / or prophylactic measures of hyperglycemia or disorders characterized by hyperglycemia, β ２ Adrenergic receptor agonists or their pharmaceutically acceptable salts, (a) Insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release A combination with the compound.

4. A method for the treatment and / or prevention of hyperglycemia or a disorder characterized by hyperglycemia, (i) therapeutic effective dose (a) Insulin or therapeutic insulin derivatives, (b) Therapeutic agents that stimulate insulin release Administration of, and (ii) Therapeutic dose of β ２ Administration of an adrenergic receptor agonist or a pharmaceutically acceptable salt thereof. A method that includes performing it on patients who need it.

5. (I) (a) Insulin or therapeutic insulin derivatives, (b) A therapeutic agent that stimulates insulin release, Compounds, and (II) β ２ Adrenergic receptor agonists or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients of optional choice. Pharmaceutical preparations, including those mentioned above.

6. component: (A) β mixed with one or more pharmaceutically acceptable excipients of any choice ２ Pharmaceutical preparations containing adrenergic receptor agonists or pharmaceutically acceptable salts thereof, and (B) A pharmaceutical preparation comprising insulin or a therapeutic insulin derivative, or a therapeutic agent that stimulates insulin release, mixed with one or more pharmaceutically acceptable excipients of any choice, A combination or kit formulation wherein components (A) and (B) are provided in a form suitable for administration in combination with the other.

7. A formulation, combination, or kit formulation according to any one of claims 5 and 6, for use in the treatment and / or prophylactic measures for hyperglycemia or disorders characterized by hyperglycemia.

8. The β for use according to any one of claims 1 to 4 and 7, wherein the disorder characterized by hyperglycemia is selected from the group consisting of type 1 diabetes, type 2 diabetes, Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy. ２ Adrenergic receptor agonists, compounds for use, methods, formulations for use, combinations for use, or kit formulations for use.

9. The disorder characterized by hyperglycemia is a patient showing severe insulin resistance or is characterized by that, and the β for use according to any one of claims 1 to 4 and 7 and 8 ２ adrenergic receptor agonist, compound for use, method, formulation, combination for use, or kit formulation for use.

10. The use of β according to any one of claims 8 and 9, wherein the disorder characterized by hyperglycemia is type 1 diabetes or type 2 diabetes. ２ Adrenergic receptor agonists, compounds for use, methods, formulations, combinations for use, or kit formulations for use.

11. Said β ２ The adrenergic receptor agonist is selected from the compounds in Table 1, according to any one of claims 1 to 10, for use in the β ２ Adrenergic receptor agonists, compounds for use, methods, formulations, combinations, kit formulations, formulations for use, combinations for use, or kit formulations for use.

12. Said β ２ Adrenergic receptor agonists, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 11, β ２ Adrenergic receptor agonists, compounds for use, methods, formulations, combinations, kit formulations, formulations for use, combinations for use, or kit formulations for use.

13. The therapeutic agent that stimulates insulin release is a GLP-1 receptor agonist, for use according to any one of claims 1 to 12, β ２ Adrenergic receptor agonists, compounds for use, methods, formulations, combinations, kit formulations, formulations for use, combinations for use, or kit formulations for use.

14. The use of the β for the purpose of claim 13, wherein the GLP-1 receptor agonist is liraglutide. ２ Adrenergic receptor agonists, compounds for use, methods, formulations, combinations, kit formulations, formulations for use, combinations for use, or kit formulations for use.

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