Beta2-adrenergic receptor agonists for the treatment or prevention of muscle wasting

Abstract

Provided herein is a 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder characterized by muscle wasting.

Description

[Technical Field]

[0001] The present invention relates to methods for the treatment or prevention of diseases and disorders characterized by muscle wasting, such as muscular dystrophies or muscle atrophies, in patients undergoing weight loss therapy. In particular, the present invention relates to methods for the treatment or prevention of diseases and disorders characterized by muscle wasting, including treatment with a β2-adrenergic receptor agonist, as well as compositions, combination therapies, and kits of parts for use in such methods. [Background technology]

[0002] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0003] Muscle atrophy and myasthenia are pathological manifestations of various neurological, neuromuscular, and myogenic disorders (Wei et al., Int J Mol Sci, 21, 9589 (2020)). They can also appear as secondary symptoms in conditions such as cancer and cardiopulmonary disorders, and are characteristic of progressive aging. Genetic modification has gained attention as a curative therapy for some of these diseases, but there is growing interest in developing new treatments as adjuvant therapies and for conditions that are not genetic in origin.

[0004] Currently, pharmacological approaches to the treatment of such diseases and disorders are limited to alleviating secondary and downstream pathological mechanisms. Current research is focusing on strategies based on somatic gene editing therapy, which may be an effective treatment for muscle wasting disorders caused by genetic abnormalities. However, significant progress is needed to improve the delivery and safety of these technologies, and thus, to date, there are no effective treatments on the market.

[0005] A related therapeutic area that would benefit from the development of effective treatments for muscle wasting is the prevention of muscle atrophy in patients undergoing weight loss treatment.

[0006] Obesity is a devastating global health epidemic, with the World Health Organization reporting a three-fold increase in the number of cases worldwide since 1975. It currently affects approximately 2 billion adults worldwide, leading to serious health problems.

[0007] Numerous treatments have been proposed to address obesity and induce weight loss in people classified as overweight. These include non-medical interventions, such as modifying diet and adopting exercise regimens, and medical interventions, such as drug and surgical treatments.

[0008] Despite ongoing research and a clear public health need, effective and well-tolerated treatments for obesity remain relatively scarce, and to date, those approved treatments typically suffer from limitations (e.g., undesirable side effects) due to their mechanism of action.

[0009] A key feature of weight loss treatments is to initiate body fat loss and reduce adipose tissue stores by restricting caloric intake and / or stimulating increased metabolism. However, one of the unintended consequences of weight loss treatments is the loss of muscle mass due to the catabolism of muscle tissue as an energy source.

[0010] Recently, β-agonists have been investigated as a potential treatment option for diseases characterized by muscle wasting. Such compounds have been observed to preserve muscle mass and restore muscle function, particularly in Duchenne muscular dystrophy (DMD), as well as in genetic conditions such as spinal muscular atrophy (SMA) and spinal-bulbar muscular atrophy (SBMA). Additionally, these compounds have been observed to suppress muscle wasting caused by muscle disuse due to injury and aging (Ryall and Lynch, Pharmacol Ther, 120, 219 (2008)). However, the use of β-agonists in these diseases has pitfalls, primarily due to side effects such as tremor, increased fatigue, and tachycardia, as well as eventual loss of efficacy due to β-arrestin recruitment and subsequent receptor desensitization.

[0011] The β2-adrenergic receptor is the predominant isoform of β-adrenergic receptors in skeletal muscle cells. Adrenergic receptors (ARs) are G protein-coupled receptors (GPCRs) that signal via classical second messengers, such as the canonical cyclic adenosine monophosphate (cAMP) pathway.

[0012] Generally, after β2-AR stimulation, the receptor αs It binds to the ATP subunit and activates adenylate cyclase to generate cAMP. Elevated cAMP levels drive multiple parallel signaling pathways that play important roles in regulating skeletal muscle and the CNS, among others.

[0013] cAMP enters the cell nucleus and activates cAMP-dependent protein kinase A (PKA), which phosphorylates the ubiquitous transcription factor CREB. Several studies have established that CREB plays an important role in regulating muscle mass. CREB regulates the expression of numerous genes involved in skeletal muscle cell differentiation, enhancing protein synthesis, and inhibiting protein degradation (Bartus RT et al., Neurobiology of Disease, 2016, 11-24).

[0014] Therefore, the hypertrophic and anti-atrophic effects of β2-AR agonists on skeletal muscle are thought to be mediated by activation of the cAMP / PKA / CREB pathway (Joassard QR et al., Int J Biochem Cell Bio, 2013, 2309; Bartus RT et al., Neurobiology of disease, 2016, 11-24).

[0015] There are clear drawbacks to the use of β2-AR agonists to treat muscle wasting (e.g., to maintain muscle mass in patients undergoing weight loss), as the release of cAMP is associated with side effects such as tremor, increased fatigue, and tachycardia. An additional concern associated with the use of β2-AR agonists is the eventual loss of efficacy due to the recruitment of β-arrestins and subsequent desensitization of the receptor.

[0016] Thus, there remains a need for new treatments that can reduce or ameliorate the symptoms of diseases and disorders characterized by muscle wasting, including treatments that can treat or prevent loss of muscle mass in patients undergoing weight loss. DETAILED DESCRIPTION OF THE INVENTION

[0017] Surprisingly, the inventors have discovered that activation of β2-adrenergic receptors (β2-ARs) represents a promising strategy for the treatment and prevention of diseases and disorders characterized by muscle wasting, such as muscular dystrophies or muscle atrophies, in patients undergoing weight loss, such as during treatment with therapeutic agents for the treatment or prevention of obesity, reduction in body fat composition and / or weight loss.

[0018] Furthermore, the present inventors have discovered that such effects can be achieved by activating β2-adrenergic receptors without significant cAMP production. This effect is particularly surprising, as existing literature suggests that β2-AR agonists achieve beneficial hypertrophic and / or anti-atrophic effects via cAMP (Joassard QR et al., Int J Biochem Cell Bio, 2013, 2309; Bartus RT et al., Neurobiology of Disease, 2016, 11-24).

[0019] Furthermore, it has been demonstrated that such effects are achieved without significant recruitment of β-arrestin.

[0020] medical treatment In a first aspect of the present invention, there is provided a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder characterised by muscle wasting.

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

[0022] For the avoidance of doubt, the β2-adrenergic receptor agonists as described herein may be referred to as "compounds of the invention" or the like.

[0023] Preferences and options with respect to a given aspect, embodiment, feature or parameter of the invention should be considered as disclosed in combination with all preferences and options with respect to all other aspects, features and parameters of the invention, unless the context dictates otherwise.

[0024] When the term "about" is used herein (e.g., in the context of dosage of an active ingredient), it is understood that such variable is an approximation and, as such, can vary from the numerical value specified herein by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%).

[0025] When the word "optionally" is used in connection with features described herein, it is given its ordinary meaning, i.e., that the associated feature may or may not be present.

[0026] In another first aspect, the present invention provides the use of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder characterized by muscle wasting.

[0027] In another first aspect, the present invention provides the use of a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, in the treatment or prevention of a disease or disorder characterized by muscle wasting.

[0028] In an alternative first aspect of the present invention, there is provided a method for the treatment or prevention of a disease or disorder characterized by muscle wasting, comprising administering to a patient in need thereof a therapeutically effective amount of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0029] For the avoidance of doubt, the uses, methods, compositions, combinations and kits of parts of the other aspects of the invention described herein (including all embodiments thereof) may have any of the particular features described for the first aspect of the invention, including all combinations thereof.

[0030] For the avoidance of doubt, the treatment (and associated prophylaxis) as described herein may be referred to herein as "the treatment of the invention" or the like.

[0031] Those skilled in the art will understand that references to "treatment" (and similarly, "treating") a particular condition have their ordinary meaning in the medical arts. In particular, the term can refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition. In particular, the term can refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition.

[0032] As used herein, reference to a patient refers to a living organism to be treated, including a mammalian (e.g., human) patient. In certain embodiments of related aspects of the invention (e.g., the first aspect of the invention), treatment is performed in a mammal (e.g., a human).

[0033] As used herein, the term therapeutically effective amount refers to that amount of a compound that confers a therapeutic effect on the treated patient. The effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives signs of an effect and / or feels an effect).

[0034] As used herein, the term prevention includes reference to prevention (and similarly, prophylaxis) of a disease or disorder (and vice versa). Thus, a reference to prevention can also be a reference to prophylaxis, and vice versa. In particular, the term can refer to achieving a reduction (e.g., at least a 10% reduction, at least a 20%, 30%, or 40% reduction, such as at least a 50% reduction) in the likelihood that a patient (or a healthy patient) will develop the condition.

[0035] In certain embodiments, references to use in, and methods for the treatment or prevention of, diseases and disorders defined herein refer specifically to use in, and methods for the treatment or prevention of, such diseases and disorders (i.e., treating).

[0036] For the avoidance of doubt, the term "disease or disorder characterized by muscle wasting" has its ordinary meaning in the art, e.g., referring to the primary and secondary symptoms of a disease that leads to the progressive loss of muscle mass and function.

[0037] Those skilled in the art will understand that muscle wasting referred to herein may also be referred to as muscle atrophy, and vice versa, and therefore, a disease or disorder characterized by muscle wasting may also be referred to as a disease or disorder characterized by muscle atrophy.

[0038] Those skilled in the art will understand that reference to muscle atrophy has its ordinary meaning in the art, for example, by referring to a loss of muscle mass (i.e., a loss of muscle size and / or weight) and wasting of muscle tissue (e.g., a reduction in muscle strength, i.e., muscle weakness). Accordingly, as used herein, muscle atrophy may also be referred to as a loss of muscle mass and / or muscle wasting and / or muscle atrophy.

[0039] In certain embodiments, reference to muscle atrophy refers to a loss of muscle mass.

[0040] In more specific embodiments, reference to muscle atrophy refers to a loss of lean body mass.

[0041] The term "lean muscle mass" has its ordinary meaning in the art, for example, by referring to the percentage of a patient's (or subject's) total body weight that is not fat mass (i.e., a patient's lean body mass (LBM) = the patient's total body weight - the patient's fat mass).

[0042] Those skilled in the art can use techniques well known to those skilled in the art to identify levels of muscle mass and lean body mass and therefore monitor changes therein.

[0043] Without limiting the scope of the present invention, those skilled in the art will understand that symptoms of muscle wasting may also include numbness and / or tingling in the muscles of the limbs. In some embodiments, the treatment or prevention of muscle wasting is in patients who do not have hyperglycemia or a disease characterized by hyperglycemia (e.g., have not been diagnosed with hyperglycemia, do not experience symptoms associated with hyperglycemia, and / or are not being treated for hyperglycemia), for example, patients who do not have diabetes (e.g., type 2 diabetes), which may be referred to as non-diabetic (e.g., non-type 2 diabetes) patients.

[0044] Those skilled in the art will understand that the treatment and prevention of the present invention as described herein may further comprise (i.e., be combined with) further (i.e., additional / other) treatment(s) for the same condition. Alternatively, the treatment and prevention of the present invention as described herein may be administered as a monotherapy (i.e., in the absence of other therapeutic agents for the treatment or prevention of the same disease or disorder).

[0045] Compounds of the Invention As described herein, the present invention involves the use of β2-adrenergic receptor agonists, examples of which will be known to those skilled in the art.

[0046] Those of ordinary skill in the art will appreciate that the compounds described herein, for example, compounds referred to as agonists, can be provided in the form of pharmaceutically acceptable salts.

[0047] Pharmaceutically acceptable salts include acid addition salts and base addition salts, each of which may be in the form of a salt having a varying ratio of compound to counterion (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 a compound included in the compounds of the present invention with one or more equivalents of an appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., rotary evaporation under reduced pressure, lyophilization, or filtration). Salts may also be prepared by exchanging the counterion of a compound included in the salt form of the compounds of the present invention with another counterion, for example, using a suitable ion exchange resin.

[0048] Specific acid addition salts that may be mentioned include carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, hemitartrate, 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, malonate, succinate, sucrose ... salts such as benzoates, sebacates, fumarates, malates, maleates, hydroxymaleates, hippurates, phthalates, or terephthalates), halide salts (e.g., chlorides, bromides, or iodides), sulfonates (e.g., benzenesulfonates, methyl-, bromo-, or chlorobenzenesulfonates, methyl-, bromo-, or chlorobenzenesulfonates, xylenesulfonates, methanesulfonates, ethanesulfonates, propanesulfonates, hydroxyethanesulfonates, 1,2-ethanedisulfonic acid, 1- or 2-naphthalenesulfonates, or 1,5-naphthalenedisulfonates), or sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, or nitrates.

[0049] Particular base addition salts which may be mentioned include salts formed with alkali metals (e.g., Na and K salts), alkaline earth metals (e.g., Mg and Ca salts), organic bases (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine), or inorganic bases (such as ammonia and aluminum hydroxide). More particularly, base addition salts which may be mentioned include Mg salts, Ca salts, and most particularly, K salts and Na salts.

[0050] For the avoidance of doubt, the compounds described herein may exist as solids, and therefore the scope of the present invention includes all amorphous, crystalline, and partially crystalline forms thereof, and may also exist as oils. When such compounds exist in crystalline and partially crystalline form, such forms may include solvates, which are also included within the scope of the present invention. The compounds may also exist in solution.

[0051] Those skilled in the art will understand that reference to an agonist refers to a compound that is suitable to act as an agonist when administered to a subject to be treated (i.e., a patient in need of treatment, e.g., a human). Suitable compounds include compounds that achieve the required effect and compounds that are converted to a compound that achieves the required effect after administration (i.e., in vivo); these compounds may be referred to as prodrugs. The particular compound that may be mentioned may be a compound that induces the required effect.

[0052] For the avoidance of doubt, the term "agonist" may be understood to refer to an agent (i.e., a compound) that induces activation of an associated receptor (e.g., in a subject such as a human) to produce a biological response, such as by binding to the associated receptor. Accordingly, the term may also refer to a partial agonist (which is understood to refer to a compound that activates a given receptor but has partial efficacy at the receptor compared to a full agonist).

[0053] Agonists (and partial agonists) have a half maximal effective concentration (EC) of, for example, less than about 1 mM, e.g., less than about 100 μM, or less than about 10 μM, e.g., less than about 1 μM (e.g., less than about 200, about 150, about 120, about 100, about 10, or about 1 nM). 50 ) can be shown.

[0054] Unless otherwise specified or clear from the context, references herein to agonists also include pharmaceutically acceptable (e.g., "protected") derivatives of the compounds, which may not have relevant activity themselves, but which may be administered to a patient (e.g., parenterally or orally) and then metabolized in the body to form a compound having the required activity; these compounds may also be referred to as prodrugs. Suitable prodrugs of the compounds described herein, for example, suitable esters (e.g., methyl esters or ethyl esters, etc.), will be known to those skilled in the art.

[0055] For the avoidance of doubt, unless otherwise specified or clear from the context, references to compounds and pharmaceutically acceptable salts thereof that are agonists include compounds and pharmaceutically acceptable salts thereof that are prodrugs of such agonists.

[0056] Suitable β2-adrenergic receptor agonists (which may also be referred to as β2-agonists) may include those known to those skilled in the art.

[0057] In certain embodiments, suitable β2-adrenergic receptor agonists include selective agonists, a term known to those skilled in the art (i.e., compounds that are agonists of the relevant receptor(s) but do not cause significant activation of other β-adrenergic receptors).

[0058] Suitable β2-adrenergic receptor agonists can be identified using techniques known to those skilled in the art, including those described in the Examples provided herein.

[0059] Suitable β2-adrenergic receptor agonists that may be used in various aspects of the present invention include those described in WO2004 / 071388, EP0272976, FR2647310, DE2157040, DE2212600, DE2015573, ZA6705591, DE2128258, WO91 / 09596, GB1199630, DE4209989, BE611502, NL7804582, EP0043807, W2008 / 022038, DE2413102, US2,308,232, BE823841, BE660 244, WO2000 / 075114, WO2005 / 102350, WO2005 / 110990, JP56055355, AT285583, US4,223,137, US3,056,836, FR1324914, DE638650, DD45721, US3 ,801,631, DE2259282, DE2300614, EP0290122, US2004 / 0266867, US2010 / 0022658, US2010 / 0022659, DE2157040, GB2133986, WO2006 / 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.Pharmacology and Experimental Therapeutics,(2006),319(1),439-446, Engelhardt et al. al., Arzneimittel-Forschung, (1972), 22(5), 869-76, WO2019 / 241744, WO2019 / 241736, WO2020 / 198466, WO2021 / 003161, WO2021 / 081292, WO2021 / 127210, and WO2021 / 247934, the relevant disclosures of each of which (e.g., exemplary compounds described herein, and pharmaceutically acceptable salts thereof, and related methods of manufacture) are incorporated herein by reference in their entirety.

[0060] For the avoidance of doubt, references to patent publications generally refer to the first publication of the complete patent specification with its associated publication number (sometimes indicated by the suffix "A1").

[0061] Additional suitable β2-adrenergic receptor agonists (which compounds may also be identified as suitable β2-adrenergic receptor agonists) that may be used in various aspects of the present invention include those described in the following publications, the contents of which are incorporated herein by reference in their entirety (in particular, the biological examples, general compound definitions including all embodiments thereof and associated definitions, exemplary compounds described herein including pharmaceutically acceptable salts, and associated methods of preparation): WO2017 / 153737 WO2019 / 053429 WO2019 / 053426 WO2019 / 053425 WO2019 / 053427 WO2020 / 188299 WO2020 / 188301 WO2022 / 063895 WO2022 / 063889 WO2023 / 046885 WO2023 / 046882 WO2023 / 105035 WO2023 / 203223 WO2020 / 198466

[0062] Specific β2-adrenergic receptor agonists that may be mentioned are the following compounds: [ka] and pharmaceutically acceptable salts thereof.

[0063] Thus, a particular β2-adrenergic receptor agonist that may be mentioned is (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol and its pharmaceutically acceptable salts.

[0064] Particular pharmaceutically acceptable salts of (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol that may be mentioned include the HCl (hydrochloric acid) salt.

[0065] Further specific β2-adrenergic receptor agonists that may be mentioned are the following compounds: [ka] and pharmaceutically acceptable salts thereof.

[0066] Thus, a particular β2-adrenergic receptor agonist that may be mentioned is (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol and its pharmaceutically acceptable salts.

[0067] Particular pharmaceutically acceptable salts of the above compound (i.e., (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol) that may be mentioned include the hemitartrate and dihydrochloride salts (e.g., the hemitartrate).

[0068] Further specific β2-adrenergic receptor agonists that may be mentioned are the following compounds: [ka] and pharmaceutically acceptable salts thereof.

[0069] Thus, a particular β2-adrenergic receptor agonist that may be mentioned is (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)-1-ethanol and its pharmaceutically acceptable salts.

[0070] Particular pharmaceutically acceptable salts of the above compound (i.e., (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)-1-ethanol) that may be mentioned include the hydrochloride, dihydrochloride and maleate salts.

[0071] Various β2-adrenergic receptor agonists are known in the art, such as formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, benzodiazepine ... rol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetharine, zinterol, bametan, (R)-bametan, clencyclohexerol, tulobuterol, BRL-47672, tranterol, clenproperol, clenpenterol, brombuterol, ractopamine and abediterol, and pharmaceutically acceptable salts thereof.

[0072] Further specific examples of β2-adrenergic receptor agonists known in the art include those selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, corterol, hexaprenaline, carmoterol, isoxsuprine, isoetharine, zinterol, bamethan, (R)-bamethan, clencyclohexerol, tulobuterol, BRL-47672 and tranterol, and pharmaceutically acceptable salts thereof.

[0073] Specific examples of β2-adrenergic receptor agonists known in the art include those selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bametan, (R)-bametan, clencyclohexerol, tulobuterol, tranterol, and abediterol, and pharmaceutically acceptable salts thereof.

[0074] Further specific examples of β2-adrenergic receptor agonists known in the art include those selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bametan, (R)-bametan, clencyclohexerol, tulobuterol and trantinerol, and pharmaceutically acceptable salts thereof.

[0075] More specific examples of β2-adrenergic receptor agonists known in the art include those selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bametan, (R)-bametan, tulobuterol, and abediterol, and pharmaceutically acceptable salts thereof.

[0076] Even more specific examples of β2-adrenergic receptor agonists known in the art include those selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bametan, tulobuterol, and (R)-bametan, and pharmaceutically acceptable salts thereof.

[0077] For the avoidance of doubt, the structures of bamethan (CAS No. 3703-79-5) and (R)-bamethan (CAS No. 912804-58-1) are shown below. [ka]

[0078] For the avoidance of doubt, in the event of a discrepancy between a compound name and a structure depicted herein, the structure shall control.

[0079] Further examples of β2-adrenergic receptor agonists known in the art include those selected from the group consisting of formmeterol, arformerol, clenbuterol, tulobuterol, bambuterol, vilanterol, indacaterol, olodaterol, carmoterol, and abediterol, and pharmaceutically acceptable salts thereof.

[0080] Still further examples of β2-adrenergic receptor agonists known in the art include those selected from the group consisting of salbutamol, ritodrine, corterol, hexaprenaline, tulobuterol and isoxsuprine, and pharmaceutically acceptable salts thereof.

[0081] Specific examples of β2-adrenergic receptor agonists known in the art include clenbuterol and (R)-clenbuterol, or pharmaceutically acceptable salts thereof.

[0082] For the avoidance of doubt, the compound clenbuterol may be understood to have the following structure: [ka]

[0083] Specific examples of β2-adrenergic receptor agonists known in the art include tulobuterol and (R)-tulobuterol, or pharmaceutically acceptable salts thereof.

[0084] For the avoidance of doubt, the compound tulobuterol may be understood to have the following structure: [ka]

[0085] For the avoidance of doubt, the International Nonproprietary Name (INN) or investigational drug code (e.g., BRL-47672) of a compound generally refers to the stereochemical structure of the compound or to a particular mixture of stereoisomers (e.g., a racemate). Within the scope of the present invention, where relevant and unless the context dictates otherwise (e.g., where both the racemate and a single stereoisomer are explicitly named), these names may also be considered to encompass separate stereoisomers that exhibit related biological activity and that are not currently assigned an alternative INN or investigational drug code.

[0086] In certain embodiments, an INN or investigational drug code should be understood to refer only to compounds that have been assigned the associated name or code.

[0087] If an INN or investigational drug code is not available for a compound, the compound may be identified by its Chemical Abstracts Service Registry Number (CAS number). As used herein, the designation "CAS Number: XXXXXX-XX-X" (where the number of digits in the first group may vary) is used to identify such compounds. 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 related biological activity and that are not currently assigned alternative CAS numbers (as explained above for INNs and investigational drug codes).

[0088] In certain embodiments, a CAS number should be understood to represent only those compounds that have been assigned the associated name or code.

[0089] In certain embodiments, the β2-adrenergic receptor agonist is selected from the group consisting of (R)-bamethan, bamethan, clencyclohexerol, radopamine, tulobuterol, and (R)-tulobuterol.

[0090] In certain embodiments, a reference to a particular stereoisomer of a compound may refer to the presence of the particular stereoisomer (e.g., in a composition or formulation comprising it) in the substantial absence of the corresponding opposite stereoisomer.

[0091] As used herein, reference to the substantial absence of the corresponding opposite stereoisomer can refer to the desired stereoisomer being present in 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 referred to as being present in the substantial absence of compounds of other constituents, which may indicate that the compound of the relevant constituent is present in an enantiomeric excess (ee) of at least 80% (e.g., at least 90%, at least 95%, at least 98%, or particularly at least 99%, e.g., at least 99.9%).

[0092] The present invention also encompasses pharmaceutical formulations containing isotopically labeled compounds in which one or more atoms are actually replaced by atoms having an atomic mass or mass number different from that normally found in nature (or most abundant in nature), but which are identical to the compounds described herein. All isotopes of any particular atom or element identified herein are contemplated within the scope of the compounds of the present invention. Thus, the present invention also encompasses pharmaceutical formulations containing deuterated compounds, i.e., in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0093] As described herein, it will also be understood that certain compounds that act as β2-adrenergic receptor agonists can activate β2-adrenergic receptors without inducing significant cAMP production.

[0094] Thus, specific β2-adrenergic receptor agonists that may be mentioned include those that are able to activate β2-adrenergic receptors without inducing cAMP production (or with only minimal effect on cAMP production).

[0095] Furthermore, in certain embodiments, the methods and uses described herein may be performed without inducing cAMP production (or without inducing significant levels of cAMP production).

[0096] In particular, the β2-adrenergic receptor agonists described herein may be further described as β2-adrenergic receptor agonists that do not induce significant cAMP (ie, its levels and / or production).

[0097] One of skill in the art would be able to determine the level of cAMP production provided by compounds such as those described herein using techniques known to those of skill in the art, such as those described in the Examples herein.

[0098] For example, the level of cAMP production induced by a given compound can be determined using techniques known to those of skill in the art (e.g., according to the protocols described in the Biological Examples provided herein, i.e., by incubating cells such as differentiated L6 myotubes at a final concentration of 1x10 in a stimulation buffer such as HBSS supplemented with 1% BSA, 5mM HEPES, and 1mM IBMX at pH 7.4). -5 M isoprenaline or compound for 15 minutes), the amount induced by a given concentration of the compound can be determined by referencing the amount induced by the same concentration of a reference compound, such as isoprenaline.

[0099] 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 isoproterenol (e.g., according to the protocol above).

[0100] Specific compounds that act as β2-adrenergic receptor agonists and can activate β2-adrenergic receptors without inducing cAMP production (or with minimal effect on cAMP production) include those described in the following publications, the contents of which are incorporated herein by reference in their entirety (in particular, biological examples, general compound definitions including all embodiments thereof and associated definitions, exemplary compounds described herein including pharmaceutically acceptable salts, and associated methods of preparation): WO2017 / 153737 WO2019 / 053429 WO2019 / 053426 WO2019 / 053425 WO2019 / 053427 WO2020 / 188299 WO2020 / 188301 WO2022 / 063895 WO2022 / 063889 WO2023 / 046885 WO2023 / 046882 WO2023 / 105035 WO2023 / 203223

[0101] More specific compounds that act as β2-adrenergic receptor agonists and can activate β2-adrenergic receptors without inducing cAMP production (or with minimal effect on cAMP production) include compounds described in the following publications, the contents of which are incorporated herein by reference in their entirety (in particular, biological examples, general compound definitions including all embodiments thereof and associated definitions, exemplary compounds described herein including pharmaceutically acceptable salts, and associated methods of preparation): WO2020 / 198466 US10 / 947,196 US11 / 040,944 WO2021 / 247934

[0102] Compounds described in the publications referenced and incorporated herein were screened according to the procedures outlined in Biological Example 2 and Biological Example 3. The test results are given in Table 1. Activity is indicated as +++ if 10 μM of the compound exhibits greater than 75% of the activity of 10 μM isoproterenol, ++ if 75-50%, + if 50-25%, and - if less than 25%. Although compounds are shown in Table 1 as salt-free molecules, the compounds tested may contain additional salt or solvent components that do not contribute to biological activity.

[0103] In case of discrepancies between the nomenclature and the structure of a compound depicted in the figures, the latter shall prevail (unless contradicted by any experimental details that may be given and / or clear from the context). Synthetic procedures and further biological data are described in the relevant publications.

[0104] Accordingly, 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]

[0105] 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]hept-1-yl)methanol, (R)-(o-fluorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-1-yl)methanol, (R)-(5-fluoro-3-pyridyl)(4-methyl-7-azabicyclo[2.2.1]hept-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]hept-1-yl)methanol, (R)-(m-chlorophenyl)(4-methyl-7-azabicyclo[2.2.1]hept-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]hex-3-yl}(m-chlorophenyl)methanol, (S)-{(S)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(o-fluorophenyl)methanol, (S)-{(R)-1-methyl-2-azabicyclo[2.1.1]hex-3-yl}(o-fluorophenyl)methanol, (R)-{(S)-1-methyl-2-azabicyclo[2.1.1]hex-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]hex-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]hex-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}cyclohexanecarboxylate, (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}cyclohexanecarboxylate, (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]hept-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}cyclohexanecarboxylate, 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}cyclohexanecarboxylate, methyl (1R,4r)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylate, methyl (1S,4s)-4-{3-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-3-methylbutyl}cyclohexanecarboxylate, methyl (1R,4r)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarboxylate, 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-pyridinecarbonitrile, (R)-(4-benzyl-7-azabicyclo[2.2.1]hept-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]hept-1-yl)(m-fluorophenyl)methanol, (S)-2-(tert-butylamino)-1-[6-(trifluoromethyl)-2-pyridyl]-1-ethanol, ethyl [(1R,4r)-4-{1-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-1-methylethyl}cyclohexyloxy]acetate, (1S,4s)-4-{2-[(R)-2-(m-fluorophenyl)-2-hydroxyethylamino]-2-methylpropyl}cyclohexanecarbonitrile, (R)-(m-fluorophenyl){4-[(p-methoxyphenyl)methyl]-7-azabicyclo[2.2.1]hept-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]acetate, (R)-(m-fluorophenyl){4-[(p-fluorophenyl)methyl]-7-azabicyclo[2.2.1]hept-1-yl}methanol, 6-[(S)-2-{1,1-dimethyl-2-[(1r,4S)-4-aminocyclohexyl]ethylamino}-1-hydroxyethyl]-2-pyridinecarbonitrile, 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-pyridinecarbonitrile, 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]hept-1-yl)methanol, (S)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1]hept-1-yl}(m-fluorophenyl)methanol, (R)-{4-[(p-chlorophenoxy)methyl]-7-azabicyclo[2.2.1]hept-1-yl}(m-fluorophenyl)methanol, (R)-(4-{[(p-fluorophenyl)methoxy]methyl}-7-azabicyclo[2.2.1]hept-1-yl)(5-fluoro-3-pyridyl)methanol, (S)-(m-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7-azabicyclo[2.2.1]hept-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]hept-1-yl}(5-fluoro-3-pyridyl)methanol, (R)-{4-[(E)-3-phenyl-2-propenyl]-7-azabicyclo[2.2.1]hept-1-yl}(m-fluorophenyl)methanol, (R)-(m-fluorophenyl){4-(3-phenylpropyl)-7-azabicyclo[2.2.1]hept-1-yl}methanol, and (S)-(o-fluorophenyl){4-[2-(3-pyridyl)ethyl]-7-azabicyclo[2.2.1]hept-1-yl}methanol, and pharmaceutically acceptable salts thereof.

[0106] As described herein, it will also be understood that certain compounds that act as β2-adrenergic receptor agonists can activate β2-adrenergic receptors without significantly recruiting β-arrestin.

[0107] Thus, particular β2-adrenergic receptor agonists that may be mentioned include those that are able to activate β2-adrenergic receptors without significantly recruiting beta-arrestins.

[0108] Furthermore, in certain embodiments, the methods and uses described herein may be performed without significant recruitment of β-arrestin.

[0109] One of skill in the art would be able to determine the level of β-arrestin recruitment provided by compounds such as those described herein using techniques known to those of skill in the art, such as those described in the Examples herein.

[0110] Treatment method Those skilled in the art will appreciate that the compounds and pharmaceutical formulations and methods for use of the invention defined herein are useful for the treatment or prevention of diseases or disorders characterized by muscle wasting.

[0111] Those skilled in the art will understand that a disease or disorder characterized by muscle wasting refers to a disease or disorder in which muscle wasting (including muscle atrophy, increased muscle weakness / decreased muscle strength, and / or decreased muscle mass) is a significant clinical symptom.

[0112] As described herein, muscle atrophy and weakness are pathological manifestations of a variety of neurological, neuromuscular, and myogenic disorders, and can also appear as secondary symptoms in conditions such as cancer, cardiopulmonary disease, and are characteristic of progressive aging.

[0113] Thus, the compounds and pharmaceutical formulations for use, and methods of the invention defined herein may be useful for treating or preventing muscle wasting by reducing or preventing (e.g., reducing, such as to a clinically significant extent) muscle tissue degeneration.

[0114] In certain embodiments, the disease or disorder characterized by muscle wasting is a nervous system disorder, a neuromuscular disorder, or a myogenic disorder.

[0115] In an alternative embodiment, muscle wasting is a secondary symptom occurring in conditions such as cancer and cardiopulmonary disease.

[0116] In an alternative embodiment, muscle wasting is a secondary symptom of progressive aging.

[0117] In other embodiments, the muscle wasting is not primarily caused by progressive aging (ie, has a primary cause other than progressive aging).

[0118] In certain embodiments, the disease or disorder characterized by muscle wasting results from a common abnormality, which may be referred to as a genetic disease or disorder.

[0119] In alternative embodiments, the disease or disorder characterized by muscle wasting is non-genetic (ie, non-genetic).

[0120] In certain embodiments, the disease or disorder characterized by muscle wasting is a muscular dystrophy.

[0121] For the avoidance of doubt, the term "muscular dystrophy" has its ordinary meaning in the art, e.g., to refer to a group of neuromuscular diseases that cause progressive muscle weakness and loss of muscle mass, particularly those in which genetic abnormalities inhibit the production of proteins necessary for the formation of healthy muscle tissue.

[0122] Thus, those skilled in the art will understand that muscular dystrophies refer to a group of genetic diseases characterized by progressive muscle degeneration. In particular, such conditions are identified based on changes in a protein called dystrophin, which causes the degeneration of muscle tissue.

[0123] Thus, the compounds and pharmaceutical formulations for use, and methods of the invention defined herein may be useful for treating or preventing muscular dystrophy by reducing or preventing (e.g., reducing, such as to a clinically significant extent) degeneration of muscle tissue.

[0124] Those skilled in the art will appreciate that the class of disorders referred to as muscular dystrophies are also known to those skilled in the art as dystrophinopathies. Spinal muscular atrophy (SMA) I, SMAII, SMAIII, Spinal and bulbar muscular atrophy (SBMA), Facioscapulohumeral muscular dystrophy (FSHD), myasthenia gravis, Disuse atrophy, Muscle recovery after surgery, Muscle wasting due to cachexia, Age-related sarcopenic MS, acid maltase deficiency, ALS, Core diseases, Muscle wasting caused by drug treatments such as dexamethasone Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD, a mild form of DMD), An intermediate clinical presentation between DMD and BMD, and DMD-associated dilated cardiomyopathy (heart disease) that may be accompanied by little or no clinical skeletal or muscle disease Includes:

[0125] In certain embodiments, the muscular dystrophy is Spinal muscular atrophy (SMA) I, SMAII, SMAIII, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is selected from the group consisting of:

[0126] In more specific embodiments, the muscular dystrophy is Duchenne muscular dystrophy (DMD).

[0127] In certain embodiments, the disease or disorder characterized by muscle wasting is sarcopenia (e.g., age-related sarcopenia).

[0128] Sarcopenia is a condition characterized by loss of skeletal muscle mass and function. Sarcopenia has been recognized as a disease and has recently been assigned an ICD-10-CM (M62.84) classification. An example of a test for screening for sarcopenia is the SARC-F.

[0129] Loss of muscle mass can be associated with increased body fat, which leads to significant wasting despite normal body weight, a condition known as sarcopenic obesity.

[0130] In a more specific embodiment, the age-related sarcopenia is sarcopenic obesity.

[0131] Severe skeletal muscle wasting can occur during hospitalization, especially in intensive care units. Generalized muscle weakness of both the limbs and respiratory muscles during an ICU stay is called "intensive care unit-associated weakness" (ICUAW).

[0132] In certain embodiments, the disease or disorder characterized by muscle wasting is intensive care unit induced muscle weakness (ICUAW).

[0133] Cancer cachexia is a complex metabolic syndrome associated with an underlying disease, commonly cancer, characterized by loss of muscle mass with or without fat loss.

[0134] In certain embodiments, the disease or disorder characterized by muscle wasting is cachexia, such as cancer cachexia.

[0135] weight loss treatment In a particular embodiment, the treatment and / or prevention of muscle wasting is treatment and / or prevention of muscle atrophy in a patient undergoing weight loss.

[0136] Those skilled in the art will understand that reference to a patient undergoing weight loss treatment refers to a patient who is losing weight.

[0137] Those skilled in the art will understand that the term "subjected" has its ordinary meaning, including referring to a patient at the relevant time (i.e., continuously) undergoing and / or undergoing the process of the event. Thus, the term "subjected" may be substituted with terms such as "experience," "undergo," etc.

[0138] Depending on the nature of the weight loss, patients undergoing weight loss may be doing so as a result of the advice / action of a clinician or other healthcare professional (i.e., as a result of a therapeutic intervention) or on their own initiative (i.e., without supervision).

[0139] In certain embodiments, the weight loss is the result of one or more therapeutic interventions.

[0140] In more specific embodiments, weight loss is the result of one or more therapeutic interventions that have the effect of inducing weight loss, which particularly refers to a reduction in body fat composition.

[0141] In certain embodiments, therapeutic intervention is long-term treatment, which may refer to a treatment period of more than one month (eg, more than three months, more than six months, or more than one year).

[0142] For the avoidance of doubt, therapeutic interventions (e.g., treatment with one or more therapeutic agents, i.e., pharmaceutical agents) include those whose primary purpose is weight loss (i.e., those that are labeled and / or marketed for the purpose of achieving such an effect) and those that have weight loss as a secondary effect (i.e., those labeled as having weight loss as an effect that is not the primary purpose, e.g., labeled as a potential adverse event / side effect associated with the therapeutic agent or other therapeutic intervention).

[0143] In more particular embodiments, the intervention has weight loss as its primary goal and may be referred to as weight loss therapy.

[0144] Thus, in certain embodiments, weight loss is referred to as weight loss therapy.

[0145] Those skilled in the art will understand that weight loss treatments as described herein can be therapeutic (i.e., in patients medically in need of such treatment, such as obese patients) or non-therapeutic (e.g., cosmetic).

[0146] For example, weight loss treatment may refer to treatment in which weight loss is induced by a decrease in caloric intake and / or an increase in energy expenditure (i.e., increased metabolism, experiential, etc.), which may be voluntary (due to patient behavior) or induced (resulting from an intervention, such as a therapeutic intervention, administered by a clinician or other healthcare professional).

[0147] In certain embodiments, the weight loss treatments described herein are therapeutic.

[0148] In certain embodiments, the weight loss treatments described herein are non-therapeutic (eg, cosmetic).

[0149] As used herein, weight loss treatment includes treatments that are non-medical, for example, treatments that involve modified diets (eg, based on reduced caloric intake).

[0150] Particular weight loss treatments that may be mentioned are medical weight loss treatments, including surgical methods and treatments using therapeutic agents (ie, pharmaceutical treatments).

[0151] For example, surgical weight loss treatments that may be mentioned include treatments that involve reducing stomach volume, such as by filling a gastric band.

[0152] Specific weight loss treatments that may be mentioned include treatments that induce weight loss by reducing calorie intake and / or increasing metabolism, whereby the patient experiences an overall calorie deficit.

[0153] In certain embodiments, the weight loss treatment is treatment with a therapeutic agent (ie, a pharmaceutical agent), which may be referred to herein as a therapeutic weight loss agent.

[0154] In certain embodiments, weight loss treatment (e.g., treatment with a therapeutic weight loss agent) refers to: (i) the treatment or prevention of obesity, and / or (ii) refers to a decrease in body fat composition and / or weight loss.

[0155] In more specific embodiments, such weight loss treatment refers to the treatment or prevention of obesity.

[0156] In an even more particular embodiment, such weight loss treatment refers to the treatment or prevention of chronic obesity.

[0157] In an alternative embodiment, such weight loss treatment refers to a reduction in body fat composition and / or a loss of body weight.

[0158] For the avoidance of doubt, the term "obesity" as used herein will be understood by those skilled in the art to refer to a condition characterized by abnormal or excessive fat accumulation that may be detrimental to health, which condition is readily identifiable by those skilled in the art.

[0159] For example, in particular embodiments, obesity may be understood to be a condition characterized by abnormal or excessive fat accumulation that may be detrimental to health, in which a subject (e.g., an adult subject) has a body mass index (BMI) of 30.0 or greater (e.g., 30.0-39.9).

[0160] Those skilled in the art will understand that the term "chronic" has its ordinary meaning in the art, e.g., persisting for an extended period of time (e.g., for a period of more than one month, e.g., for a period of more than three months, for a period of more than six months, or for a period of more than one year).

[0161] For the avoidance of doubt, reference to obesity includes reference to the condition known as "morbid" obesity and / or "clinical" obesity.

[0162] For the avoidance of doubt, references to "reducing body fat composition" refer to a reduction in a patient's body fat mass, which may be indicated by a reduction in body fat percentage.

[0163] In particular, reference to reducing body fat composition refers to reducing the level of body fat in the form of adipose tissue. Similarly, reference to treating or preventing obesity may refer to treating or preventing obesity by reducing the level of body fat in the form of adipose tissue.

[0164] In particular, reference to the treatment or prevention of obesity may include reference to the treatment or prevention of obesity by reducing body fat composition (e.g., reducing the level of body fat in the form of adipose tissue) and / or reducing body weight.

[0165] For example, reference to the treatment or prevention of obesity may include reference to the treatment or prevention of obesity by reducing body fat composition (eg, reducing the level of body fat in the form of adipose tissue).

[0166] In certain embodiments, the patient is obese.

[0167] In certain embodiments, references to reducing body fat composition and / or reducing weight may refer to therapeutic methods and uses in reducing body fat composition and / or reducing weight, such as uses and methods practiced in obese patients.

[0168] In certain embodiments, references to reducing body fat composition and / or reducing weight refer to reducing body fat composition and / or reducing weight in a patient (or subject) in need thereof, for example, a patient who is of normal weight or above BMI (e.g., a BMI of 30 or greater, i.e., an obese patient), and may also be referred to as therapeutically reducing body fat composition and / or therapeutically reducing weight.

[0169] Alternatively, references to reducing body fat composition and / or reducing weight may refer to reducing body fat composition and / or reducing weight in patients (or subjects) who are normal weight or overweight (in either case, having the corresponding BMI). In certain examples, such subjects (e.g., adult subjects) are non-obese (e.g., have a BMI of less than 30.0), e.g., overweight (BMI of 25.0-29.9) or healthy weight (BMI of 18.5-24.9), which may be referred to as non-therapeutic reduction of body fat composition and / or non-therapeutic reduction of weight. Accordingly, those skilled in the art will understand that such use may be carried out in patients who are not defined as obese (e.g., healthy weight, or patients who are overweight but not obese).

[0170] In certain embodiments, the patient (or subject) is overweight.

[0171] For the avoidance of doubt, references to non-therapeutic uses and methods refer to uses and methods in patients who are not receiving treatment for a medical condition but who achieve a related effect for other purposes, such as cosmetic purposes.

[0172] As described herein, other medical uses described herein can be understood to be further characterized by reducing body fat composition and / or reducing body weight. For example, the treatment or prevention of obesity described herein can be achieved by reducing body fat composition and / or reducing body weight (e.g., reducing body fat composition).

[0173] For the avoidance of doubt, references herein to body fat may refer specifically to body fat in the form of adipose tissue.

[0174] As described herein, weight loss treatment may include (or consist of) weight loss treatment with a therapeutic agent (i.e., a pharmaceutical agent), which may be referred to as a therapeutic weight loss agent.

[0175] For the avoidance of doubt, therapeutic weight loss agents (including therapeutic agents for treating or preventing obesity and / or reducing body fat composition and / or reducing body weight) are known to those skilled in the art and include those whose primary purpose is weight loss (i.e., those that are labeled and / or marketed for the purpose of achieving such an effect).

[0176] Thus, in certain embodiments, the term "therapeutic weight loss agent" refers to a therapeutic agent whose primary purpose is weight loss.

[0177] In certain embodiments, the weight loss treatment comprises: (i) the treatment or prevention of obesity, and / or (ii) reduction in body fat composition and / or weight loss; The present invention includes (or consists of) treatment with one or more (e.g., one) therapeutic weight loss agent (i.e., weight loss treatment) for:

[0178] In a more specific embodiment, the weight loss treatment comprises (or consists of) treatment with one or more therapeutic weight loss agents for the treatment or prevention of obesity.

[0179] In a more specific embodiment, the weight loss treatment comprises (or consists of) treatment with one or more therapeutic weight loss agents for the treatment or prevention of chronic obesity.

[0180] In an alternative embodiment, the weight loss treatment comprises treatment with one or more therapeutic weight loss agents to reduce body fat composition and / or reduce body weight.

[0181] For the avoidance of doubt, the therapeutic agent may be referred to as a therapeutic weight loss agent.

[0182] In particular, therapeutic weight loss agents for the treatment or prevention of obesity and / or reduction in body fat composition and / or weight loss include those that act by inducing a decrease in caloric intake and / or an increase in metabolism.

[0183] Particular therapeutic weight loss agents (eg, therapeutic agents for the treatment or prevention of obesity) that may be mentioned include GLP-1 receptor agonists.

[0184] Thus, in certain embodiments, the therapeutic weight loss agent (ie, weight loss therapy) is a GLP-1 receptor agonist.

[0185] In certain embodiments, the therapeutic weight loss agent (ie, weight loss therapy) is a GLP-1 receptor agonist.

[0186] Thus, in certain embodiments, the patient undergoing weight loss is undergoing weight loss due to (ie, as a result / effect of) treatment with a GLP-1 receptor agonist.

[0187] Accordingly, for the avoidance of doubt, the scope of the present invention also includes a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of muscle wasting in a patient who is being treated (or is being treated) with a therapeutic weight loss agent (e.g., a GLP-1 receptor agonist).

[0188] Also within the scope of the present invention is a method for the treatment or prevention of muscle wasting in a patient who is being treated (or is being treated) with a therapeutic weight loss agent (e.g., a GLP-1 receptor agonist), the method comprising administering to a patient in need thereof a therapeutically effective amount of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

[0189] A variety of GLP-1 receptor agonists are known to those skilled in the art, including those currently approved for sale in the United States (i.e., by the Food and Drug Administration) and Europe (e.g., by the European Medicines Agency).

[0190] Particular GLP-1 receptor agonists that may be mentioned include exenatide, exenatide extended release, tirzepatide, liraglutide, lixisenatide, semaglutide, albiglutide and dulaglutide.

[0191] In certain embodiments, the GLP-1 receptor agonist is liraglutide or semaglutide.

[0192] In a more particular embodiment, the GLP-1 receptor agonist is liraglutide.

[0193] Those skilled in the art will appreciate that GLP-1 receptor agonists, ie, agonists of the glucagon-like peptide-1 receptor, as well as derivatives thereof, mimic the action of glucagon-like peptide-1.

[0194] The GLP-1 receptor agonist may have affinity for the GIP receptor, i.e., gastric inhibitory polypeptide receptor, in addition to the GLP-1 receptor. Alternatively, the GLP-1 receptor agonist may have no, or substantially no, affinity for the GIP receptor.

[0195] Those skilled in the art will understand that GLP-1 receptor agonist can also be peptide.Furthermore, it can be provided as a liquid or suspension, in the form of an injection, such as a pre-filled injection pen, and / or as a sustained-release preparation.In one example, GLP-1 receptor agonist can be administered subcutaneously.GLP-1 receptor agonist can be administered once or multiple times a day, or once a week.

[0196] The following are examples of GLP-1 receptor agonists:

[0197] Exenatide, CAS number 141758-74-9, is a peptide sold under the trade names Byetta and Bydureon. It can be administered subcutaneously and / or in doses ranging from 5 micrograms to 2 mg.

[0198] Tirzepatide, CAS number 2023788-19-2, is a linear polypeptide of 39 amino acids chemically modified by lipidation. It is sold under the trade name Mounjaro. It may be administered subcutaneously as an injection. Dosages range from 2.5 mg / 0.5 mL to 15 mg / 0.5 mL.

[0199] Liraglutide, CAS number 204656-20-2, is a peptide sold under the trade names Saxenda, Victoza, and Xultophy. It may be administered subcutaneously as an injection. The dosage may be, for example, 0.6 mg to 1.8 mg once daily for one week or more. For example, the dosage may be 0.6 mg, 1.2 mg, or 1.8 mg once daily for one week or more.

[0200] Lixisenatide, CAS number 320367-13-3, is sold under the trade names Lyxumia and Adlyxin. It may be administered in the form of an injection, such as a subcutaneous injection. For example, it may be administered once daily. The dosage may be 10 micrograms to 20 micrograms, for example, once weekly.

[0201] Semaglutide, CAS number 910463-68-2, is a peptide sold under the trade names Ozempic, Rybelsus, and Wegovy. It may be administered in an injectable form, such as a subcutaneous injection (Ozempic and Wegovy), or orally (Rybelsus). Dosages range from 0.25 mg to 2 mg, administered weekly.

[0202] Albiglutide, CAS number 782500-75-8, is a peptide sold under the trade names Eperzan and Tanzeum. It may also be referred to as GSK-716155. It may be administered in an injectable form, such as a subcutaneous injection. The dosage may be, for example, 30 mg to 50 mg once a week.

[0203] Dulaglutide, CAS number 923950-08-7, is a peptide sold under trade names such as Trulicity. It may be administered via an injection pen. For example, it may be administered subcutaneously. The dosage of dulaglutide may 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.

[0204] Pharmaceutical preparations Those skilled in the art will understand that both the β2-adrenergic receptor agonists or pharmaceutically acceptable salts thereof described herein, and optionally, the therapeutic weight loss agents, may be administered in the form of pharmaceutical formulations that may optionally further include one or more pharmaceutically acceptable excipients.

[0205] Suitable pharmaceutical formulations may be commercially available or may be found in Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995) and Martindale - The Complete Drug Reference (35 th Edition), as well as references therein, the relevant disclosures of all of which are incorporated herein by reference in their entirety. Otherwise, the preparation of suitable formulations, particularly combination formulations comprising both a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and optionally a therapeutic weight loss agent, can be accomplished by one of ordinary skill in the art using routine techniques.

[0206] Reference to pharmaceutically acceptable excipient(s) may be understood to include pharmaceutically acceptable diluents, carriers and / or adjuvants, as would be known to a person skilled in the art.

[0207] In a second aspect of the present invention, there is provided a pharmaceutical formulation comprising a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, for use in the treatment or prevention of a disease or disorder characterised by muscle wasting.

[0208] In a second alternative aspect of the present invention, there is provided a method for the treatment or prevention of a disease or disorder characterized by muscle wasting, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0209] For the avoidance of doubt, formulations for use according to the second aspect of the invention may have any of the particular features set out above according to the first aspect of the invention (including all combinations thereof).

[0210] In a third aspect of the present invention, (a) a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof; (b) therapeutic weight loss agents; and optionally one or more pharmaceutically acceptable excipients; The present invention provides a pharmaceutical formulation comprising:

[0211] In certain embodiments, the pharmaceutical preparation is used for the treatment or prevention of a disease or disorder.

[0212] In a more particular embodiment, the pharmaceutical preparation is used for the treatment or prevention of muscle wasting, as defined herein, in a patient undergoing weight loss therapy.

[0213] In a fourth aspect of the present invention, (a) a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof; (b) therapeutic weight loss agents; and optionally one or more pharmaceutically acceptable excipients; The present invention provides a pharmaceutical formulation for use in the treatment or prevention of muscle atrophy in a patient undergoing weight loss treatment, comprising:

[0214] In an alternative fourth aspect of the present invention, there is provided a method for treating or preventing muscle wasting in a patient undergoing weight loss therapy, comprising administering to a patient in need thereof: (a) a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof; (b) therapeutic weight loss agents; and optionally one or more pharmaceutically acceptable excipients; The present invention provides a method for treating a rheumatoid arthritis, comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising:

[0215] For the avoidance of doubt, the formulations of the second, third and fourth aspects of the invention may have any of the particular features set out above of the first aspect of the invention (including all combinations thereof).

[0216] Thus, in particular embodiments of the third and fourth aspects of the invention, the therapeutic weight loss agent is as described in the first aspect of the invention (including all embodiments and features thereof).

[0217] Combinations and Parts-Kits (Lightweight) Those skilled in the art will appreciate that the present invention includes combinations of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof with a therapeutic weight loss agent (i.e., combination products), and that the combinations may also be provided in the form of a kit of parts containing the same.

[0218] In a fifth aspect of the present invention, a composition comprising the following ingredients: (A) a pharmaceutical formulation comprising a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, optionally in admixture with one or more pharmaceutically acceptable excipients; and (B) a pharmaceutical formulation comprising a therapeutic weight loss agent, optionally in admixture with one or more pharmaceutically acceptable excipients; Including, Components (A) and (B) are each provided in a form suitable for administration in combination with the other, Offer combinations or kits of parts.

[0219] In a particular embodiment, the combination or kit-of-parts is for use in the treatment or prevention of muscle wasting in patients undergoing weight loss.

[0220] In certain embodiments, there is provided a method for the treatment or prevention of muscle wasting in a patient undergoing weight loss, comprising administering a therapeutically effective amount of the combination or kit of parts to a patient in need thereof.

[0221] In certain embodiments, the kit-of-parts of the fifth aspect of the invention further comprises instructions for using each component in combination with the other components in the treatment or prevention of muscle wasting in patients undergoing weight loss therapy.

[0222] For the avoidance of doubt, the combinations and kits of parts of the fifth aspect of the invention may have any of the above-mentioned specific features of the first, second, third and fourth aspects of the invention (including all combinations thereof).

[0223] In certain embodiments, the combinations and kits of parts described herein may include multiple formulations containing appropriate amounts / doses of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt and / or prodrug thereof, and / or multiple formulations containing appropriate amounts / doses of a therapeutic weight loss agent, for repeated administration. When more than one formulation (containing any active compound) is present, such formulations may be the same or different with respect to the dosage, chemical composition(s) and / or physical form(s) of any compound.

[0224] Those skilled in the art will understand that with respect to the treatments, formulations, combinations and kits of parts described herein, reference to treatment with or administration of each component refers to the administration of said component in combination with other components.

[0225] Other medical uses Those skilled in the art will appreciate that the formulations, combinations and kits of parts comprising the therapeutic weight loss agents described herein may also be used in the treatment of conditions such as obesity and weight loss, and are particularly suitable for use in patients suffering from or at risk of developing muscle wasting disorders as defined herein.

[0226] Thus, in alternative embodiments of the second, third, fourth and fifth aspects of the invention, the pharmaceutical formulation, combination or kit-of-parts comprises: (i) the treatment and / or prevention of obesity, and / or (ii) a decrease in body fat composition and / or weight loss; Used for:

[0227] In further alternative embodiments of the second, third, fourth and fifth aspects of the invention, (i) the treatment and / or prevention of obesity, and / or (ii) reduction in body fat composition and / or weight loss; The present invention provides a method for It involves administering a therapeutically effective amount of the pharmaceutical formulation, combination or kit of parts to a patient in need thereof.

[0228] As described herein, certain therapeutic weight loss agents induce weight loss as a secondary effect and have a primary effect in the treatment of other diseases or disorders, such as diabetes.

[0229] Thus, in further alternative embodiments of the second, third, fourth and fifth aspects of the present invention, when the therapeutic weight loss agent is a therapeutic agent for the treatment of type 1 diabetes or type 2 diabetes (e.g. type 2 diabetes), the pharmaceutical formulation, combination or kit-of-parts is for the treatment of type 1 diabetes or type 2 diabetes (e.g. type 2 diabetes).

[0230] In further alternative embodiments of the second, third, fourth and fifth aspects of the present invention, where the therapeutic weight loss agent is a therapeutic agent for the treatment of type 1 diabetes or type 2 diabetes (e.g., type 2 diabetes), there is provided a method of treating type 1 diabetes or type 2 diabetes (e.g., type 2 diabetes), comprising administering a therapeutically effective amount of the pharmaceutical formulation, combination or kit-of-parts to a patient in need thereof.

[0231] For the avoidance of doubt, all embodiments and features of the second, third, fourth and fifth aspects of the present invention apply to the corresponding alternatives.

[0232] Thus, in certain embodiments, the therapeutic weight loss agent is a GLP-1 receptor agonist (which may also be understood to be a therapeutic agent for the treatment of type 1 diabetes or type 2 diabetes (e.g., type 2 diabetes)).

[0233] In a more particular embodiment, the therapeutic weight loss agent is liraglutide.

[0234] Furthermore, specific β2-adrenergic receptor agonists that may be mentioned are the following compounds: [ka] and pharmaceutically acceptable salts thereof.

[0235] Further beta2-adrenergic receptor agonists that may be mentioned are the following compounds: [ka] and pharmaceutically acceptable salts thereof.

[0236] Further beta2-adrenergic receptor agonists that may be mentioned are the following compounds: [ka] and pharmaceutically acceptable salts thereof.

[0237] In certain embodiments, - Treatment and / or prevention of obesity and / or reduction of body fat composition and / or weight loss, or - Treatment of type 1 diabetes or type 2 diabetes (e.g., type 2 diabetes) It is performed in patients who have (ie, have experienced, for example, been diagnosed with, muscle atrophy) or are at risk of developing muscle atrophy.

[0238] In certain embodiments, the treatment and / or prevention of obesity and / or reduction in body fat composition and / or weight loss is the treatment of obesity.

[0239] Administration method Those skilled in the art will appreciate that the compounds and pharmaceutical formulations defined herein are typically administered in pharmaceutically acceptable dosage forms by oral, intravenous, subcutaneous, buccal, rectal, cutaneous, transdermal, nasal, tracheal, bronchial, sublingual, intranasal, topical, other parenteral routes, or by inhalation. Pharmaceutical formulations described herein include compositions in the form of tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

[0240] In certain embodiments, the compounds and pharmaceutical formulations described herein are administered orally. Thus, in certain embodiments, the pharmaceutical formulations described herein can be described as oral pharmaceutical formulations.

[0241] Thus, in certain embodiments, the pharmaceutical formulation(s) are provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquids taken orally or by injection, suppositories, creams, gels, foams, transdermal patches, plasters, inhalants (e.g., intranasal applications). For the avoidance of doubt, in such embodiments, the compounds of the invention may exist in solid (e.g., solid dispersion), liquid (e.g., in solution), or other forms such as micellar form.

[0242] In more particular embodiments, the pharmaceutical formulation(s) are provided in a pharmaceutically acceptable oral dosage form, including a tablet or capsule, which dosage form may be prepared using techniques known to those skilled in the art.

[0243] For example, in preparing pharmaceutical formulations for oral administration, the compound may be mixed with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredients, as well as disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol waxes, and the mixture may then be processed into granules or compressed into tablets.

[0244] Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g., a compound of the first aspect of the invention, and therefore the second through fifth aspects, and optionally an additional therapeutic agent) together with, for example, vegetable oil, fat, or other suitable excipients for soft gelatin capsules. Similarly, hard gelatin capsules may contain such compound(s) in combination with a solid powdered ingredient such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.

[0245] Dosage units for rectal administration may be prepared in the form of (i) suppositories containing the compound(s) mixed with a neutral fat base, (ii) gelatin rectal capsules containing the active substance mixed with vegetable oil, paraffin oil or other suitable excipients for gelatin rectal capsules, (iii) ready-made microenemas, or (iv) dry microenema preparations to be reconstituted with a suitable solvent immediately prior to administration.

[0246] Liquid preparations for oral administration may be prepared in the form of a syrup or suspension, such as a solution or suspension, containing the compound(s) and the remainder of the formulation consisting of a mixture of sugar or sugar alcohol, ethanol, water, glycerol, propylene glycol, and polyethylene glycol. If necessary, such liquid preparations may contain coloring agents, flavoring agents, saccharin, carboxymethylcellulose, or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent before use.

[0247] Solutions for parenteral administration may be prepared as solutions of compound(s) in a pharmaceutically acceptable solvent. These solutions may contain stabilizing and / or buffering components and are dispensed as unit doses in the form of ampoules or vials. Solutions for parenteral administration may be prepared as dry preparations that are reconstituted with a suitable solvent immediately before use.

[0248] Those skilled in the art will appreciate that the compounds described herein, and formulations and kits of parts comprising same, may be administered in a variety of doses (e.g., as formulations described herein above), and that appropriate doses will be readily determined by those skilled in the art.

[0249] In any event, one skilled in the art (e.g., a physician) will be able to determine the actual dosage that will be most suitable for an individual patient, which may vary depending on the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated. The dosages set forth above are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are required; such instances are within the scope of this invention.

[0250] For example, appropriate dosages of a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof may therefore include those discussed in the above publications incorporated herein by reference.

[0251] Similarly, appropriate dosages of therapeutic weight loss agents may be determined in accordance with those described herein and known to those skilled in the art (see British National Formulary 85, the contents of which are incorporated herein by reference). th and the like).

[0252] As noted herein above, those skilled in the art will understand that the treatments (and methods for prevention) described herein may further comprise (i.e., be combined with) additional (i.e., other) treatment(s) for the same condition. In particular, the treatments (and methods for prevention) described herein may be combined with other measures for the treatment of excess weight or a disorder characterized by excess weight (e.g., obesity, as defined herein), such as treatment with one or more other therapeutic agents useful in the treatment of excess weight or a disorder characterized by excess weight (e.g., obesity, as defined herein). Similarly, the treatments (and methods for prevention) described herein may be combined with other measures for the treatment or prevention of muscle wasting disorders.

[0253] Such agents are readily identified by those skilled in the art and include, in particular, marketed therapeutic agents (e.g., agents that are the subject of marketing authorization in one or more regions, such as European or US marketing authorization).

[0254] Those skilled in the art will appreciate that in certain embodiments, the present invention (i.e., the pharmaceutical formulations, combinations, kits of parts, compounds for use, uses and methods of treatment described herein, including all embodiments and specific features thereof) relates to two components administered in combination with each other: a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof and a therapeutic weight loss agent.

[0255] References to administration of each component in combination with other components include administration of the components sequentially, separately, or simultaneously as part of a medical intervention directed to treating the relevant condition. In particular, such references can include administration of the components sufficiently closely in time to provide a greater beneficial effect to the patient in the course of treatment for the relevant condition than if the other component were administered in the absence of that component in the course of treatment.

[0256] The determination of whether a combination provides a greater beneficial effect with respect to the treatment of a particular condition, and over the course of treatment, will depend on the condition being treated or prevented, but can be routinely accomplished by one of ordinary skill in the art.

[0257] Those skilled in the art will understand that references to the components (i.e., the β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and the therapeutic weight loss agent) being administered sequentially (and therefore separately) include individual doses of each component being administered (i.e., ingested by the patient, e.g., orally) within 48 hours (e.g., within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes) of each other.

[0258] Similarly, references to components being administered simultaneously (whether in a combined form or administered separately) will be understood to include components being administered substantially simultaneously (i.e., ingested by the patient, for example orally).

[0259] In certain embodiments, the components are administered (ie, taken by the patient, eg, orally) sequentially (and thus as separate doses).

[0260] For example, in certain embodiments, the components are administered consecutively at least 2 hours apart (i.e., at least 4 hours between administrations of each component to a patient, e.g., oral administrations), e.g., at 2 to 48 hours apart, or at 2 to 24 hours apart, or at 2 to 12 hours apart.

[0261] For the avoidance of doubt, references to the β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, and the components as a therapeutic weight loss agent include references to components (A) and (B) respectively of the fifth aspect of the invention (i.e., components (A) and (B) respectively of the combination or kit-of-parts of the fifth aspect of the invention).

[0262] Methods for preparing formulations and kits of parts Pharmaceutical formulations may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0263] Thus, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition / formulation as defined herein above, which process comprises combining a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents and / or carriers).

[0264] In some embodiments, the process comprises combining a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof and a therapeutic weight loss agent with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents and / or carriers).

[0265] There is further provided a method of preparing the kit-of-parts defined herein above, the method comprising combining component (A) with component (B) thereby rendering the two components suitable for administration in conjunction with one another. Reference to combining will therefore mean making the two components suitable for administration in conjunction with one another.

[0266] Thus, with respect to the process for the preparation of a kit-of-parts as defined herein above by "combining" two components with one another, the two components of the kit-of-parts are (i) may be provided as separate formulations (i.e., independently of each other) and then combined for use in conjunction with each other in combination therapy; or (ii) It is contemplated that they may be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

[0267] Those skilled in the art will appreciate that the use of the compounds and pharmaceutical formulations described herein, and the methods associated therewith, in treating the conditions described herein above, whether used for the above indications or not, may have the advantage of being more convenient for the physician and / or patient, more effective, less toxic, having a broader spectrum of activity, more potent, having fewer side effects, or having other useful pharmacological properties, as compared to similar methods (treatments) known in the prior art. In particular, such pharmaceutical formulations, kits of parts, methods and uses may have the advantage of being more effective and / or exhibiting advantageous properties in vivo.

[0268] Without being bound by theory, it is believed that the β2-adrenergic receptor agonist described herein can achieve a strong in vivo effect, which allows the effective treatment of muscular dystrophy.In particular, this effect can be more effectively exerted by the compound that activates β2-adrenergic receptor without significantly increasing cAMP, such as compound A, B and C, thus enabling treatment without significant level of adverse events caused by the increase of cAMP.In addition, this effect can be exerted by the compound that does not induce significant recruitment of beta-arrestin, thus inhibiting the internalization of β2-AR and the resulting desensitization.

[0269] Without wishing to be bound by theory, it is believed that the use of β2-adrenergic receptor agonists allows for the prevention and / or treatment of muscle atrophy, particularly loss of lean muscle mass, that may occur in patients undergoing weight loss treatment, such as weight loss treatment using therapeutic weight loss agents.

[0270] It is noteworthy that, previously, the beneficial effect of muscle mass observed by β agonists is thought to be mediated through cAMP-dependent pathway.However, surprisingly, it has now been discovered that certain β2-AR agonists, which do not cause significant release of cAMP, also exert beneficial effects on muscle mass (for example, treat muscle atrophy or prevent muscle mass loss).Importantly, this type of β2-AR agonist allows treatment without the significant adverse events caused by increasing cAMP.

[0271] Advantageously, compounds of the present invention may achieve a "redistribution effect" by inducing an increase in lean tissue and a decrease in body fat. Additionally, compounds of the present invention may result in improved muscle tissue quality (e.g., improved muscle fiber organization and / or a decrease in adipose tissue embedded in muscle tissue). [Brief explanation of the drawings]

[0272] [Figure 1a] 1 shows that the glucose uptake promoted by Compound A is inhibited in a dose-dependent manner by the selective β2-adrenergic receptor antagonist ICI-118551. [Figure 1b] 1 shows that the glucose uptake promoted by Compound B is inhibited in a dose-dependent manner by the selective β2-adrenergic receptor antagonist ICI-118551. [Figure 1c] 1 shows that the glucose uptake promoted by Compound C is inhibited in a dose-dependent manner by the selective β2-adrenergic receptor antagonist ICI-118551. [Figure 2a] It is shown that isoprenaline results in significantly less cAMP formation while resulting in complete glucose uptake (GU). [Figure 2b] Figure 1 shows that compared to isoprenaline, Compound A results in significantly less cAMP formation while providing complete glucose uptake (GU). [Figure 2c]Figure 1 shows that compared to isoprenaline, Compound B results in significantly less cAMP formation while providing complete glucose uptake (GU). [Figure 2d] Figure 1 shows that compared to isoprenaline, Compound C results in significantly less cAMP formation while providing complete glucose uptake (GU). [Figure 3a] 1 shows that Compound A recruits significantly less β-arrestin 2 compared to isoprenaline. [Figure 3b] 1 shows that Compound B recruits significantly less β-arrestin 2 compared to isoprenaline. [Figure 3c] 1 shows that Compound C recruits significantly less β-arrestin 2 compared to isoprenaline. [Figure 4] Figure 1 shows that Compound A reverses dexamethasone-induced weight loss in mice. [Figure 5] Figure 1 shows that Compound A reverses dexamethasone-induced loss of lean body mass in mice. [Figure 6] Myofiber organization in wild-type sibling control zebrafish embryos (containing dystrophin protein, top panel) and dystrophin (- / -) knockout zebrafish embryos (bottom panel). [Figure 7a] The effect of increasing concentrations of salbutamol versus the control is shown. [Figure 7b] The effect of increasing concentrations of salbutamol versus the control is shown. [Figure 8a] The effect of increasing concentrations of Compound A relative to the control is shown. [Figure 8b] The effect of increasing concentrations of Compound A relative to the control is shown. [Figure 9a] 1 shows cumulative food intake for Compound B over the course of the experiment described in Biological Example 7. [Figure 9b] 1 shows cumulative food intake for Compound C over the course of the experiment described in Biological Example 8. [Figure 10a] 1 shows the change in body weight for Compound B over the course of the experiment described in Biological Example 7. [Figure 10b] 1 shows the change in body weight for Compound C over the course of the experiment described in Biological Example 8. [Figure 11a] 1 shows the change in fat mass for Compound B over the course of the experiment described in Biological Example 7. [Figure 11b] 1 shows the change in fat mass for Compound C over the course of the experiment described in Biological Example 8. [Figure 12a] 1 shows the change in lean body mass for Compound B over the course of the experiment described in Biological Example 7. [Figure 12b] 1 shows the change in lean body mass for Compound C over the course of the experiment described in Biological Example 8. [Example]

[0273] The present invention is illustrated by the following examples, which are not intended to limit the overall scope of the invention.

[0274] For the avoidance of doubt, in the event of a discrepancy between a compound name and a structure depicted herein, the structure shall control.

[0275] The synthesis of (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol and its biological testing are described in WO2019 / 053426 (see, e.g., Example 5 therein), the contents of which are incorporated herein by reference.

[0276] The synthesis of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol dihydrochloride and its biological testing are described in WO2019 / 053427 (see, for example, Example 17 therein), the contents of which are incorporated herein by reference. The preparation of the corresponding hemitartrate salt (Compound B) is described in WO2023 / 105035, the contents of which are incorporated herein by reference.

[0277] The synthesis of (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol and its biological testing are described in WO2019 / 053426 (see, e.g., Example 31 therein), the contents of which are incorporated herein by reference.

[0278] Exemplary Compounds Compound Example 1 Compound A: (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol hydrochloride [ka] (a) (R)-2-Bromo-1-(3-fluorophenyl)ethan-1-ol [ka] Borane (1 M in THF, 0.68 mL, 0.68 mmol) was added dropwise to a mixture of (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 0.85 mL, 0.85 mmol) and tetrahydrofuran (THF, 0.8 mL) at room temperature (rt). The mixture was stirred at rt for 15 min, and a solution of 3-fluorophenacyl bromide (185 mg, 0.85 mmol) in THF (1.9 mL) was added dropwise (0.09 mL / min). After 6 h at rt, MeOH (10 mL) was added. The mixture was stirred for 30 min and concentrated. Purification by chromatography afforded the subtitle compound (150 mg, 0.68 mmol, 80%).

[0279] (b) (R)-2-(3-fluorophenyl)oxirane [ka] K2CO3 (137 mg, 0.99 mol) was added to a mixture of (R)-2-bromo-1-(3-fluorophenyl)ethan-1-ol (145 mg, 0.66 mmol) in MeOH (6.8 mL) at rt. The mixture was stirred for 30 min, filtered, and concentrated. The residue was extracted with CHCl2. The combined extracts were concentrated to give the subtitle compound (70 mg, 0.51 mmol, 77%), which was used in the next step without further purification.

[0280] (c) (R)-2-(tert-butylamino)-1-(3-fluorophenyl)ethan-1-ol [ka] A mixture of (R)-2-(3-fluorophenyl)oxirane (30 mg, 0.22 mmol), tert-butylamine (66 mg, 0.90 mmol), and MeOH (0.2 mL) was stirred at reflux for 16 h, cooled, concentrated, and dissolved in EtO. EtO / pentane (1:3) was added, and the solution was kept at −20° C. overnight. The solid that formed was collected to give the title compound (25 mg, 0.12 mmol, 54%).

[0281] 1 H NMR (400MHz, CDCl3): δ7.33-7.26(m,1H),7.14-7.09(m,2H),6.98-6.93(m,1H),4.57(dd,J =8.4,3.6Hz,1H),2.92(dd,J=12.0,4.0Hz,1H),2.55(dd,J=12.0,8.4Hz,1H),1.10(s,9H).

[0282] This compound is used in the biological examples described herein in the form of its HCl salt (obtained using standard techniques known to those skilled in the art) and is referred to herein as Compound A.

[0283] Compound Example 2 Compound B: (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol hemitartrate [ka] (a) 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-one [ka] Isopropylmagnesium chloride (2 M 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 rt. After 15 min at rt, 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 rt for 2 h and cooled in an ice bath. A solution of 2-chloro-N-methoxy-N-methylacetamide (2.62 g, 19.04 mmol) in THF (30 mL) was added dropwise, and the mixture was stirred at rt for 2 h. NH4Cl (aqueous, 10%) was added, and the mixture was extracted with Et2O. The combined extracts were washed with saturated brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography to give the subtitle compound (1.52 g, 20.94 mmol, 46%).

[0284] (b) (R)-2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-ol [ka] RhClCp* [(1S,2S)-p-TsNCH(CH)CH(CH)NH] / HCl.EtN (68.0 mg, 87.6 μmol), prepared from dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, (1S,2S)-(+)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine, and EtN as described in WO 2008 / 054155, was added to a solution of 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-one (1.52 g, 8.76 mmol) in DMF (75 mL). Formic acid / EtN (5:2, 25 mL) was added, and the mixture was stirred at rt for 15 min. HO (60 mL) and EtOAc (60 mL) were added, and the layers were separated. The aqueous layer was washed with EtOAc (2 x 60 mL) and the combined organic phases were washed with H2O, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography to give the subtitle compound (1.35 g, 7.69 mmol, 88%, ee = 92.5%).

[0285] (c) (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol [ka] tert-Butylamine (11.37 mL, 108.21 mmol) was added, followed by NaOH (476.08 mg, 11.90 mmol) to a mixture of 2-chloro-1-(5-fluoropyridin-3-yl)ethan-1-one (1.90 g, 10.82 mmol) and iPrOH (1.66 mL, 21.64 mmol) at rt. The mixture was heated at 75 °C for 4 h, allowed to cool, diluted with EtOAc, washed with HO and saturated brine, dried (NaSO), and concentrated. The residue was dissolved in hot EtOAc and allowed to cool. Pentane was added, and the mixture was kept at -20 °C overnight. The solid was collected and purified by chromatography to give the title compound (1.43 g, 6.74 mmol, 62%, ee=98%).

[0286] 1H NMR (400MHz, CDCl3): δ8.43-8.27(m,2H),7.57-7.42(m,1H),4.62(dd,J=8.8,3.7 Hz, 1H), 2.94 (dd, J=12.1, 3.8Hz, 1H), 2.53 (dd, J=12.1, 8.8Hz, 1H), 1.10 (s, 9H).

[0287] (d) (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol hemitartrate [ka] A solution of L-(+)-tartaric acid (6.21 g, 0.5 equiv.) in EtOH (175 mL) was added to a solution of (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol (17.57 g) and HO (7 mL) in EtOH (525 mL, 30 vol) at rt. The mixture was refluxed until all precipitate dissolved and then cooled. The resulting slurry was stirred at rt overnight and then at 0–5°C for 2 h. The solid was collected to give the title (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol salt (19.9 g, 83%, 100.0% purity by HPLC, 99.8% ee by HPLC).

[0288] The formation of hemitartrate is 1 This was confirmed by 1 H-NMR spectroscopy, which showed an amine:acid ratio of 2:1.

[0289] This compound was used in the biological examples described herein and is referred to herein as Compound B.

[0290] Compound Example 3 Compound C: (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-ol maleate [ka] (a) N-(2,6-difluoro-3-methylphenyl)acetamide [ka] The subtitle compound was prepared from 2,6-difluoro-3-methylaniline according to the procedure of Example 6, step (a) of WO2019 / 053426.

[0291] (b) 3-acetamido-2,4-difluorobenzoic acid [ka] The subtitle compound was prepared from N-(2,6-difluoro-3-methylphenyl)acetamide according to the procedure of Example 7, step (b) of WO2019 / 053426.

[0292] (c) N-(3-(2-chloroacetyl)-2,6-difluorophenyl)acetamide [ka] A mixture of 3-acetamido-2,4-difluorobenzoic acid (250 mg, 1.16 mmol) and SOCl2 (2.6 mL) was heated at 60 °C for 4 h and allowed to cool. Toluene was added and the mixture was concentrated. The procedure of adding toluene and then concentrating was repeated three times. The residue was dissolved in CHCl2 and trimethylsilyldiazomethane (1.16 mL, 2.32 mmol) was added dropwise at 0 °C. The mixture was allowed to warm to rt over 18 h and cooled to 0 °C. HCl (4 M in dioxane, 1.45 mL, 5.81 mmol) was added dropwise. The mixture was allowed to warm to rt over 1 h, diluted with EtOAc, washed with Na2CO3 (aq, sat), dried over MgSO4, and concentrated. The residue was purified by chromatography to give the subtitle compound (198 mg, 0.80 mmol, 69%).

[0293] (d) (R)-N-(3-(2-chloro-1-hydroxyethyl)-2,6-difluorophenyl)acetamide [ka] RhClCp*(1S,2S)-p-TsNCH(CH)CH(CH)NH] / HCl.EtN (5.02 mg, 0.0065 mmol), prepared from dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, (1S,2S)-(+)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine, and EtN as described in WO 2008 / 054155, was added to a mixture of N-(3-(2-chloroacetyl)-2,6-difluorophenyl)acetamide (160 mg, 0.65 mmol) in DMF (2.7 mL). Formic acid / EtN (5:2, 0.90 mL) was added, and the mixture was stirred at rt for 20 min. The mixture was diluted with EtOAc, washed with HO and brine, dried (NaSO), filtered, and concentrated. The residue was crystallized from CH2Cl2 / hexane to give the subtitle compound (101 mg, 0.41 mmol, 63%, ee=97%).

[0294] (e) (R)-N-(3-(2-(tert-butylamino)-1-hydroxyethyl)-2,6-difluorophenyl)acetamide [ka] The subtitle compound was prepared from (R)—N-(3-(2-chloro-1-hydroxyethyl)-2,6-difluorophenyl)acetamide according to Example 25, step (d) of WO2019 / 053426.

[0295] (f) (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-ol hydrochloride [ka] NaOH (aq, 10%, 0.52 mL) was added to a solution of (R)-N-(3-(2-(tert-butylamino)-1-hydroxyethyl)-2,6-difluorophenyl)acetamide (52 mg, 0.18 mmol) in EtOH (0.52 mL), and the mixture was heated at 75° C. for 20 h. EtOH was removed in vacuo, and the residue was extracted with CHCl. ​​The combined extracts were washed with water, dried over NaSO, filtered, and concentrated. The residue was dissolved in EtO. HCl (2 M in EtO, 0.13 mL, 0.27 mmol) was added. The solid was collected and dried to give the subtitle compound (32 mg, 0.11 mmol, 63%).

[0296] 1 H NMR (400MHz, D2O): δ7.11-7.01(m,2H),5.29-5.15(dd,J=9.6,3.2Hz,1H),3.36-3.23(m,2H),1.40(s,9H).

[0297] (g) (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-ol maleate [ka] A solution of maleic acid (43 mg, 0.37 mmol) in iPrOH (0.4 mL) was added to a solution of (R)-1-(3-amino-2,4-difluorophenyl)-2-(tert-butylamino)ethan-1-ol (98 mg, 0.40 mmol, free base, prepared as in step (f)) in iPrOH (1.5 mL) at rt. The mixture was stirred at rt for 1 h and centrifuged. The supernatant was removed, and the residue was dried and crystallized from EtOAc and dried to give the title compound (71 mg, 0.20 mmol, 50%).

[0298] The formation of maleate salts is 1 This was confirmed by 1 H-NMR spectroscopy, which showed a 1:1 amine:acid ratio.

[0299] This compound was used in the biological examples described herein and is referred to herein as Compound C.

[0300] Biological Examples Biological Example 1: Glucose uptake in the presence of selective β2 adrenergic receptor inhibitors L6 myoblasts were grown in Dulbecco's modified Eagle's medium (DMEM) containing 1 g / L glucose supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 50 U / mL penicillin, 50 μg / mL streptomycin, and 10 mM HEPES. Cells were grown at 1 × 10 per mL in 24-well plates. 5 After reaching 90% confluence, cells were grown for 7 days in medium containing 2% FBS to differentiate into myotubes. Differentiated L6 myotubes were serum-starved overnight in medium containing 0.5% fatty acid-free BSA and plated at a final concentration of 1 × 10 cells. -5 Cells were stimulated with M test compound in the presence of various concentrations of the selective β2-adrenergic receptor antagonist ICI-118551. After 1 hour and 40 minutes, cells were washed twice with warm glucose-free medium, and another portion of agonist was added to glucose-free medium. After another 20 minutes of incubation, cells were washed three times with ice-cold glucose-free medium and treated with 50 nM agonist before being lysed with 400 μL / well of 0.2 M NaOH at 60°C for 1 hour. 3 After exposure to H-2-deoxyglucose for 10 minutes, the cell lysate was mixed with 4 mL of scintillation buffer (Emulsifier Safe, Perkin Elmer), and radioactivity was detected using a β-counter (Tri-Carb 4810TR, Perkin Elmer).

[0301] The results are shown in Figures 1a, 1b and 1c, which show that glucose uptake stimulated by compounds A, B and C, respectively, is dose-dependently inhibited by the selective β2-adrenergic receptor antagonist ICI-118551.

[0302] Biological Example 2: Glucose Uptake Differentiated L6 myotubes were serum-starved overnight in medium containing 0.5% fatty acid-free BSA, at a final concentration of 1 × 10 -5 After 1 hour and 40 minutes, cells were washed twice with warm glucose-free medium or PBS, and agonists were added again in glucose-free medium. After 20 minutes, cells were washed three times with ice-cold glucose-free medium or PBS and lysed with 50 nM isoprenaline or test compound at 60°C for 1 hour before being lysed with 0.2 M NaOH, 400 μL / well. 3 After exposure to H-2-deoxyglucose for 10 minutes, the cell lysate was mixed with 4 mL of scintillation buffer (Emulsifier Safe, Perkin Elmer), and radioactivity was detected using a β-counter (Tri-Carb 4810TR, Perkin Elmer).

[0303] The results for the various compounds tested are shown in Table 1.

[0304] Biological Example 3: Measurement of Intracellular cAMP Levels Differentiated L6 myotubes were serum-starved overnight and incubated at a final concentration of 1 × 10 in stimulation buffer (HBSS, pH 7.4, supplemented with 1% BSA, 5 mM HEPES, and 1 mM IBMX). -5 The cells were stimulated with 100 μL of isopropanol or test compound for 15 minutes. The medium was aspirated, and 100 μL of 95% EtOH was added to each well of a 24-well plate, and the cells were stored at -20°C overnight. The EtOH was evaporated, and 500 μL of lysis buffer (1% BSA, 5 mM HEPES, and 0.3% Tween-20, pH 7.4) was added to each well. The plates were stored at -80°C for 30 minutes and then at -20°C until the day of detection, when the samples were thawed. Intracellular cAMP levels were detected using the AlphaScreen cAMP Kit (Perkin Elmer, 6760635D).

[0305] The results are shown in Figure 2a, which shows the glucose uptake and intracellular cAMP levels when cells were treated with isoproterenol; Figure 2b, which shows the glucose uptake and intracellular cAMP levels when cells were treated with compound A; Figure 2c, which shows the glucose uptake and intracellular cAMP levels when cells were treated with compound B; and Figure 2d, which shows the glucose uptake and intracellular cAMP levels when cells were treated with compound C. Isoprenaline and compounds A, B, and C all showed complete glucose uptake responses, whereas compounds A, B, and C, in contrast to isoprenaline, showed only low intracellular cAMP levels.

[0306] Additional results for other compounds tested are shown in Table 1.

[0307] Biological Example 4: Measurement of β-arrestin recruitment HEK293 cells were transfected with both the β2-adrenergic receptor fused with the Large BiT SNAP-tag protein and the β-arrestin2 fused with the Small BiT SNAP-tag protein. When the cells were stimulated and the receptor recruited β-arrestin2, the Small BiT and Large BiT proteins fused to form a functional luciferase enzyme that emitted light in the presence of furimazine. After 31 minutes, light was measured using a luminescence plate reader.

[0308] The results are shown in Figure 3a, which shows the difference in β-arrestin 2 recruitment between isoprenaline and Compound A; Figure 3b, which shows the difference in β-arrestin 2 recruitment between isoprenaline and Compound B; and Figure 3c, which shows the difference in β-arrestin 2 recruitment between isoprenaline and Compound C, demonstrating that in contrast to isoprenaline, Compounds A, B, and C only minimally induced β-arrestin 2 recruitment.

[0309] Biological Example 5: Effects of Compound A on Body Weight and Lean Mass in Dexamethasone-Treated Mice Forty 8-week-old male C57Bl / 6 mice were maintained on a standard diet and group-assigned (2-3 mice per cage) at 21°C. Mice were matched for body weight and composition and divided into four groups (n = 10) and treated daily with subcutaneous injections of dexamethasone sodium phosphate (10 mg / kg), Compound A (47.1 μmol / kg, equivalent to a 10 mg / kg free base dose), or a combination of dexamethasone and Compound A for 3 weeks. Control mice received saline. Body weight and lean mass were measured after 6, 12, and 20 days of treatment.

[0310] The results are: Figure 4 shows that mice treated with dexamethasone lost weight compared to the control group, and that the effect was reversed when treated with Compound A at the same time; and This is shown in Figure 5, which shows that when mice were treated with dexamethasone, lean body mass was reduced compared to the control group, and that the effect was reversed when treated simultaneously with Compound A.

[0311] Biological Example 6: Zebrafish Model The Sepje zebrafish lacks the dystrophin gene, and like humans, dystrophin loss leads to the progressive breakdown of muscle fibers and subsequent loss of muscle mass. The Sepje model is comparable to the MDX mouse, which also lacks the dystrophin gene.

[0312] FIG. 6 shows the organization of muscle fibers in wild-type sibling control zebrafish embryos (containing dystrophin protein, top panel) and dystrophin (− / −) knockout zebrafish embryos (bottom panel) as measured using birefringence microscopy.

[0313] Dystrophin deficiency causes poor fiber organization, and germ layers often begin to die at 4-5 days post-fertilization (dpf). Wild-type or dystrophin(- / -) embryos were treated with vehicle control or increasing concentrations of salbutamol or Compound A (10, 30, and 100 μM) from 1-5 dpf.

[0314] Figure 7a shows the effect of increasing salbutamol concentrations on birefringence compared to the control group, and Figure 7b shows the effect of increasing salbutamol concentrations on muscle fiber organization as measured using birefringence microscopy.

[0315] Figure 8a shows the effect of increasing concentrations of Compound A on birefringence compared to the control group, and Figure 8b shows the effect of increasing concentrations of Compound A on muscle fiber organization as measured using birefringence microscopy.

[0316] Biological Example 7: Combination of Compound B with Liraglutide Male C57Bl / 6N mice, 2.5 months old, were housed in cages (4-5 mice per cage) at 30°C and fed a high-fat, high-sucrose diet (45% fat) for 5.5 months. Mice were divided into four groups (2-3 mice per cage) based on fasting blood glucose level, glucose tolerance, body weight, body fat, and lean mass. Each group was treated daily for 2 weeks with subcutaneous administration of either vehicle, liraglutide (0.1 mg / kg), Compound B (1.4 mg / kg), or a mixture of liraglutide (0.1 mg / kg) and Compound A (1.4 mg / kg). Food intake was measured twice weekly, and body weight, body fat, and lean mass were measured weekly.

[0317] The results obtained during the experimental period are shown as follows: Figure 9a shows cumulative food intake, Figure 10a shows the change in body weight, Figure 11a shows the change in fat mass, and Figure 12a shows the change in lean body mass.

[0318] These data confirm that administration of liraglutide and the combination of liraglutide and Compound B, respectively, reduced food intake compared to the control group. Furthermore, both liraglutide and the combination of liraglutide and Compound B significantly reduced body weight and fat mass. However, the change in lean body mass for the combination of liraglutide and Compound B was significantly lower compared to administration of liraglutide alone.

[0319] Biological Example 8: Combination of Compound C with Liraglutide Male C57Bl / 6N mice, 2.5 months old, were housed in cages (4-5 mice per cage) at 30°C and fed a high-fat, high-sucrose diet (45% fat) for 5 months. Mice were divided into four groups (2-3 mice per cage) based on fasting blood glucose level, glucose tolerance, body weight, body fat, and lean body mass. They were treated daily for 2 weeks with subcutaneous administration of either vehicle, liraglutide (0.1 mg / kg), Compound C (5 mg / kg), or a mixture of liraglutide (0.1 mg / kg) and Compound C (5 mg / kg). Food intake and body weight were measured every other day, and body fat and lean body mass were measured weekly.

[0320] The results obtained during the experimental period are shown as follows: Figure 9b shows cumulative food intake, Figure 10b shows the change in body weight, Figure 11b shows the change in fat mass, and Figure 12b shows the change in lean body mass.

[0321] These data confirm that administration of liraglutide and the combination of liraglutide and Compound C each reduced food intake compared to the control group. Furthermore, all three treatments significantly reduced body weight and fat mass. However, the changes in lean body mass for the combination of liraglutide and Compound C and Compound C alone were significantly lower than those for administration of liraglutide alone.

Claims

1. β-Glucocorticoids for use in the treatment or prevention of diseases or disorders characterized by muscle wasting ２ - an adrenergic receptor agonist or a pharmaceutically acceptable salt thereof.

2. A method for treating or preventing a disease or disorder characterized by muscle wasting, comprising administering a therapeutically effective amount of β ２ - a method comprising administering an adrenergic receptor agonist or a pharmaceutically acceptable salt thereof to a patient in need thereof.

3. In the manufacture of a medicament for the treatment or prevention of a disease or disorder characterized by muscle wasting, ２ - Use of an adrenoceptor agonist or a pharmaceutically acceptable salt thereof.

4. β for use in the treatment or prevention of a disease or disorder characterized by muscle wasting ２ - A pharmaceutical formulation comprising an adrenoceptor agonist or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

5. β for use according to any one of claims 1 to 4, wherein the disease or disorder characterized by muscle wasting is a muscular dystrophy, such as Duchenne muscular dystrophy. ２ - Adrenergic receptor agonists, methods, uses or formulations for use.

6. β for use according to any one of claims 1 to 5, wherein the treatment and / or prevention of muscle wasting is treatment and / or prevention of muscle atrophy in patients undergoing weight loss. ２ - Adrenergic receptor agonists, uses, methods or formulations for use.

7. β for use according to claim 6, wherein the treatment and / or prevention of muscle atrophy is treatment and / or prevention of loss of lean body mass. ２ - Adrenergic receptor agonists, uses, methods or formulations for use.

8. 8. The use of any one of claims 6 and 7, wherein the weight loss is a weight loss treatment. ２ - Adrenergic receptor agonists, uses, methods or formulations for use.

9. The weight loss treatment comprises: (i) the treatment and / or prevention of obesity, and / or (ii) reduction of body fat composition and / or weight loss, comprising treatment and / or prevention with one or more therapeutic weight loss agents ２ - Adrenergic receptor agonists, uses, methods or formulations for use.

10. 10. The method of claim 9, wherein the weight loss treatment comprises treatment with one or more therapeutic weight loss agents, such as therapeutic weight loss agents for the treatment or prevention of obesity. ２ - Adrenergic receptor agonists, uses, methods or formulations for use.

11. The beta-glucan for use according to claim 10, wherein the therapeutic weight loss agent is a GLP-1 receptor agonist. ２ - Adrenergic receptor agonists, uses, methods or formulations for use.

12. β for use according to claim 11, wherein the GLP-1 receptor agonist is liraglutide. ２ - Adrenergic receptor agonists, uses, methods or formulations for use.

13. (a) β ２ an adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, (b) therapeutic weight loss agents; and optionally one or more pharmaceutically acceptable excipients; 10. A pharmaceutical formulation comprising:

14. Ingredients: (A) β ２ - a pharmaceutical formulation comprising an adrenoceptor agonist or a pharmaceutically acceptable salt thereof, optionally in admixture with one or more pharmaceutically acceptable excipients, and (B) a pharmaceutical formulation comprising a therapeutic weight loss agent, optionally in admixture with one or more pharmaceutically acceptable excipients; Including, Components (A) and (B) are each provided in a form suitable for administration in conjunction with the other; Combinations or parts kits.

15. 15. The formulation, combination or kit-of-parts according to claim 13 or 14, wherein said therapeutic weight loss agent is a GLP-1 receptor agonist.

16. 16. The formulation, combination or kit-of-parts according to claim 15, wherein said GLP-1 receptor agonist is liraglutide.

17. Said β ２ - β for use according to any one of claims 1 to 16, wherein the adrenoceptor agonist is a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof. ２ - Adrenergic receptor agonists, uses, methods, formulations for use, preparations, combinations or kits of parts.

18. Said β ２ -Adrenergic receptor agonists are 【Chemistry 1】 or a pharmaceutically acceptable salt thereof. ２ - Adrenergic receptor agonists, uses, methods, formulations for use, preparations, combinations or kits of parts.

19. Said β ２ -Adrenergic receptor agonists are 【Chemistry 2】 or a pharmaceutically acceptable salt thereof. ２ - Adrenergic receptor agonists, uses, methods, formulations for use, preparations, combinations, kits of parts.

20. Said β ２ -Adrenergic receptor agonists 【Transformation 3】 or a pharmaceutically acceptable salt thereof. ２ - Adrenergic receptor agonists, methods, formulations for use, preparations, combinations, kits of parts.

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