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WO2024170727A1 - Combinaisons d'agonistes du récepteur bêta 2-adrénergique et de metformine destinées à être utilisées dans le traitement de l'obésité et la réduction de la graisse corporelle - Google Patents

Combinaisons d'agonistes du récepteur bêta 2-adrénergique et de metformine destinées à être utilisées dans le traitement de l'obésité et la réduction de la graisse corporelle Download PDF

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Publication number
WO2024170727A1
WO2024170727A1 PCT/EP2024/053959 EP2024053959W WO2024170727A1 WO 2024170727 A1 WO2024170727 A1 WO 2024170727A1 EP 2024053959 W EP2024053959 W EP 2024053959W WO 2024170727 A1 WO2024170727 A1 WO 2024170727A1
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Prior art keywords
fluorophenyl
methanol
ethanol
pyridyl
methyl
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PCT/EP2024/053959
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English (en)
Inventor
Anastasia KALINOVICH
Tore Bengtsson
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Atrogi AB
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Atrogi AB
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Priority to EP24706052.8A priority Critical patent/EP4665321A1/fr
Publication of WO2024170727A1 publication Critical patent/WO2024170727A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to methods for the treatment or prophylaxis of obesity and the reduction of body fat.
  • the invention relates to methods for the treatment or prophylaxis of obesity and therapeutic and non-therapeutic methods of reducing body fat, involving treatment with a combination of a ⁇ 2 -adrenergic receptor agonist and metformin, and to compositions and kits-of-parts for use in such methods.
  • ⁇ -adrenergic receptors are divided into the subtypes, ⁇ 1 , ⁇ 2 , and ⁇ 3 , of which ⁇ 2-AR is the major isoform in skeletal muscle cells.
  • ARs are G protein coupled receptors (GPCRs) which signal through classical secondary messengers, such as cyclic adenosine monophosphate (cAMP).
  • E2- adrenoceptor agonists dose-dependently increase resting metabolic rate by 10–50% and increases muscle mass and reduces fat mass in young healthy individuals (see Hostrup and Onslev, J Physiol, 600, 1209 (2022)).
  • E 2 -adrenoceptor agonist clenbuterol improves skeletal muscle glucose uptake implying that E 2 -adrenoceptor agonists are beneficial for the treatment of type 2 diabetes (see Beak et al., Nat Commun, 14, 179 (2023)).
  • a ⁇ 2-adrenergic receptor agonist for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
  • a ⁇ 2- adrenergic receptor agonist in the manufacture of a medicament for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin.
  • a ⁇ 2- adrenergic receptor agonist in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of metformin.
  • the compound metformin for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.
  • the use of the compound metformin in the manufacture of a medicament for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.
  • the use of the compound metformin in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, wherein the use further comprises administration of a ⁇ 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.
  • treatments of the invention may be referred to herein as the “treatments of the invention”, or the like.
  • references to the “treatment of” a particular condition take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.
  • the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.
  • references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients.
  • the treatment is in a mammal (e.g. a human).
  • therapeutically effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • prophylaxis includes references to the prevention of (and, similarly, preventing) the disease or disorder (and vice-versa).
  • references to prevention may also be references to prophylaxis, and vice versa.
  • the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
  • references to use in and methods for the treatment or prophylaxis of diseases and disorders as specified herein will refer in particular to uses in and methods for treatment of such diseases and disorders.
  • the term “obesity” as used herein will be understood by those skilled in the art to refer to a condition characterised by abnormal or excessive fat accumulation that may impair health, which conditions will be readily identified by those skilled in the art.
  • obesity may be understood to be a condition characterised by abnormal or excessive fat accumulation that may impair health in which the subject (e.g. an adult subject) has a body mass index (BMI) of 30.0 or higher (e.g. 30.0 to 39.9).
  • BMI body mass index
  • the treatments and prophylactic methods and uses as described herein may be characterised by the lowering of body fat composition (i.e. the reduction of body fat; in particular, body fat in the form of adipose tissue) in the patient.
  • references to the lowering of body fat composition will refer to reducing levels of body fat in the form of adipose tissue.
  • references to the treatment or prophylaxis of obesity may refer to the treatment or prophylaxis of obesity by reducing levels of body fat in the form of adipose tissue.
  • references to the treatment or prophylaxis of obesity may include references to the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue) and/or reducing body weight.
  • references to the treatment or prophylaxis of obesity may include references to the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue).
  • references to lowering body fat composition and/or reducing body weight may refer to therapeutic methods and uses (e.g. in patients in need thereof) and non-therapeutic methods and uses (e.g. cosmetic methods and uses).
  • references to lowering body fat composition and/or reducing body weight may refer to therapeutic methods and uses in the lowering body fat composition and/or reducing body weight, such as uses and methods performed in an obese patient.
  • metabolic syndrome as used herein will be understood by those skilled in the art to refer to a condition characterised by a clustering of at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides and low high-density lipoprotein (HDL) levels, such that the conditions occur together, which conditions will be readily identified by those skilled in the art.
  • the treatment or prophylaxis of metabolic syndrome as described herein will include the treatment or prophylaxis (e.g. treatment) of abdominal obesity (e.g. by reducing levels of abdominal body fat in the form of adipose tissue).
  • dislipidaemia as used herein will be understood by those in skilled in the art to refer to a condition characterised by being defined as an abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood (often due to diet and lifestyle), which condition will be readily identified by those skilled in the art.
  • lipids e.g. cholesterol and/or fat
  • the uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and/or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, and (iv) the treatment or prophylaxis of dyslipidaemia, as described herein may each be in a patient who does not have (for example, has not been diagnosed with and/or is not experiencing symptoms associated with) hyperglycaemia or a disorder characterized by hyperglycaemia, such as in a patient who does not have diabetes (e.g. type 2 diabetes), which may be referred to as a non- diabetic (e.g. non-type 2 diabetic) patient.
  • a non- diabetic e.g. non-type 2 diabetic
  • references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and/or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia will refer in particular to (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and/or reducing body weight.
  • references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and/or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia, will refer in particular to (i) the treatment or prophylaxis of obesity.
  • references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and/or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia will refer in particular to (i) the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue).
  • references to uses and methods for (i) the treatment or prophylaxis of obesity, (ii) lowering body fat composition and/or reducing body weight, (iii) the treatment or prophylaxis of metabolic syndrome, or (iv) the treatment or prophylaxis of dyslipidaemia will refer in particular to (i) the treatment or prophylaxis of obesity by lowering body fat composition (e.g. by reducing levels of body fat in the form of adipose tissue) in a patient who does not have (for example, has not been diagnosed with and/or is not experiencing symptoms associated with) hyperglycaemia or a disorder characterized by hyperglycaemia, such as in a patient who does not have diabetes (e.g.
  • treatment of the first to third aspects of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
  • compounds referred to herein, such as compounds referred to as agonists may be provided in the form of a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts, each of which may be in the form of salts in varying ratios of compound to counter ion (e.g. including hemi salts).
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound comprised in the formulations of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. by rotary evaporation under reduced pressure, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound comprised in the formulations of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Particular acid addition salts that may be mentioned include carboxylate salts (e.g.
  • sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxyethanesulphonate, 1,2-ethanedisulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalenedisulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.
  • sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphon
  • base addition salts include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.
  • compounds as described herein may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils.
  • references to an agonist will refer to compounds suitable for acting as such when administrated to a subject to be treated (i.e. a patient, e.g. a human, in need thereof).
  • Suitable compounds may include compounds which provide the required effect and compounds which are converted to compounds providing the required effect after administration (i.e. in vivo), which compounds may be referred to as pro-drugs.
  • pro-drugs Particular compounds that may be mentioned are compounds which elicit the required effect.
  • the term “agonist” may be understood to indicate an agent (i.e.
  • Agonists may display, for example, half maximal effective concentration (EC50) values of less than about 100 ⁇ M, such as less than about 10 ⁇ M, or less than about 1 ⁇ M (e.g. less than about 200, about 150 or about 120 nM).
  • EC50 half maximal effective concentration
  • references herein to agonists will also include pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds which may not possess the relevant activity per se, but may be administered (e.g. parenterally or orally) to a patient and thereafter be metabolised in the body to form compounds possessing the required activity, which compounds may be referred to as prodrugs.
  • suitable prodrugs of compounds as described herein will be known to those skilled in the art, such as suitable esters (e.g. methyl or ethyl esters, and the like).
  • references to compounds that are agonists, and pharmaceutically acceptable salts thereof will include compounds that are prodrugs of such agonists, and pharmaceutically acceptable salts thereof.
  • Suitable ⁇ 2 -adrenergic receptor agonists (which may also be referred to as ⁇ 2 -agonists) may include those known to those skilled in the art.
  • suitable ⁇ 2-adrenergic receptor agonists will include those that are selective, which term will be known to those skilled in the art (i.e. compounds that are agonists of the relevant receptor(s) but which do not cause significant activation of other ⁇ -adrenergic receptors).
  • Suitable ⁇ 2-adrenergic receptor agonists can be identified using techniques known to those skilled in the art, including those as described in the examples provided herein.
  • Suitable ⁇ 2 -adrenergic receptor agonists that may be employed in the various aspects of the invention include, but are not limited to, those described in: WO 2004/071388, EP 0 272 976, FR 2647310, DE 2 157 040, DE 2212600, DE 2015573, ZA 6705591, DE 2128258, WO 91/09596, GB 1199630, DE 4209989, BE 611502, NL 7804582, EP 0 043 807, WO 2008/022038, DE 2413102, US 2,308,232, BE 823841, BE 660244, WO 2000/075114, WO 2005/102350, WO 2005/110990, JP 56055355, AT 285583, US 4,223,137, US 3,056,836, FR 1324914, DE 6
  • ⁇ 2 -adrenergic receptor agonists that may be employed in the various aspects of the invention (which compounds may be identified as also being suitable ⁇ 2- adrenergic receptor agonists) include those described in the following publications, the contents of which are hereby incorporated herein in their entirety (in particular, the biological examples, the generic compound definitions, including all embodiments thereof and associated definitions, and the example compounds provided therein, including pharmaceutically acceptable salts thereof, and associated methods of preparation): WO 2017/153737 WO 2019/053429 WO 2019/053426 WO 2019/053425 WO 2020/188301 WO 2022/063895 WO 2022/063889 WO 2023/046885 WO 2023/046882 WO 2023/105035 WO 2023/203223 WO 2020/198466
  • a particular ⁇ 2 -adrenergic receptor agonist that may be mentioned is the following compound: and pharmaceutically acceptable salts thereof.
  • a particular ⁇ 2 -adrenergic receptor agonist that may be mentioned is (R)-2-(tert- butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol, and pharmaceutically acceptable salts thereof.
  • Particular pharmaceutically acceptable salts of the above-mentioned compound i.e. (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol
  • Particular pharmaceutically acceptable salts of the above-mentioned compound i.e. (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethan-1-ol
  • include the hemi-tartrate and dihydrochloride salts such as the hemi-tartrate salt).
  • references to a specific steroisomer of a compound may refer to the specific stereoisomer being present (e.g. in a composition or formulation comprising the same) in the substantial absence of the corresponding opposite stereoisomer.
  • references to the substantial absence of the corresponding opposite stereoisomer may refer to the desired stereoisomer being present at a purity of at least 80% (e.g. at least 90%, such as at least 95%) relative to the opposite stereoisomer.
  • compounds may be indicated to be present in the substantial absence of the compound in the other configuration, which may indicate that the compound in the relevant configuration is present in an enantiomeric excess (e.e.) of at least 80% (such as at least 90%, at least 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%).
  • the compound in the relevant configuration is present in an enantiomeric excess (e.e.) of at least 90% (such as at least 95%, at least 98% or, particularly, at least 99%, for example at least 99.9%).
  • the ⁇ 2 -adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetarine, zinterol, bamethane, (R)- bamethane, clencyclohexerol, tulobuterol, BRL-47672, trantinterol, clen
  • the ⁇ 2 -adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetarine, zinterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol, BRL-47672 and trantinterol, and pharmaceutically
  • the ⁇ 2 -adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol, trantinerol and abediterol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, (R)-bamethane, clencyclohexerol, tulobuterol and trantinerol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane, tulobuterol and (R)-tulobuterol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane and tulobuterol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, clenbuterol, (R)-clenbuterol, bamethane, (R)-bamethane and tulobuterol, and pharmaceutically acceptable salts thereof.
  • formoterol arformoterol
  • clenbuterol clenbuterol
  • R)-clenbuterol bamethane
  • bamethane CAS: 912804-58-1
  • the structure should prevail.
  • the ⁇ 2 -adrenergic receptor agonist is selected from the group consisting of formeterol, arformeterol, salmeterol, clenbuterol, tulobuterol, bambuterol vilanterol, indacaterol, olodaterol, carmoterol and abediterol, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2-adrenergic receptor agonist is selected from the group consisting of salbutamol, ritodrine, colterol, hexaprenaline, tulobuterol and isoxsuprine, and pharmaceutically acceptable salts thereof.
  • the ⁇ 2 -adrenergic receptor agonist is clenbuterol or (R)- clenbuterol, or a pharmaceutically acceptable salt thereof.
  • the compound clenbuterol may be understood to have the following structure:
  • the ⁇ 2-adrenergic receptor agonist is tulobuterol or (R)- tulobuterol, or a pharmaceutically acceptable salt thereof.
  • the compound tulobuterol may be understood to have the following structure:
  • the international nonpropriety name (INN) or developmental drug code e.g.
  • BRL-47672 for a compound generally indicates the stereochemical configuration of the compound, or a particular mixture of stereoisomers (e.g. a racemate).
  • a racemate e.g. a racemate
  • names may also be considered to encompass separate stereoisomers that display the relevant biological activity, and which have not presently been assigned an alternative INN or developmental drug code.
  • the INN or developmental drug code should be understood to represent the compound to which the relevant name or code has been assigned only. Where no INN or developmental drug code is available for a compound, the compound may be identified by its Chemical Abstracts Service Registry Number (CAS number).
  • the indication “CAS: XXXXXX-XX-X” (wherein the number of figures in the first group may vary) is used to identify such compounds.
  • the CAS number for a compound may also be considered to encompass other stereoisomers, or mixtures thereof, that display the relevant biological activity, and which have not presently been assigned alternative CAS numbers (as described above for INNs and developmental drug codes).
  • the CAS number should be understood to represent the compound to which the relevant name or code has been assigned only.
  • the ⁇ 2 -adrenergic receptor agonist is selected from the group consisting of (R)-bamethane, bamethane, clencyclohexerol, radopamine, tulobuterol, and (R)-tulobuterol.
  • the present invention also embraces pharmaceutical formulations comprising isotopically-labelled compounds, which are identical to the compounds recited herein but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • the invention also encompasses pharmaceutical formulations comprising deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • deuterated compounds i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • certain compounds acting as ⁇ 2 - adrenergic receptor agonists are able to activate the ⁇ 2-adrenergic receptor without inducing significant cAMP production.
  • particular ⁇ 2 -adrenergic receptor agonists that may be mentioned include those able to activate the ⁇ 2 -adrenergic receptor without (or with only a minimal effect in) inducing cAMP production.
  • the methods and uses as described herein may be performed without inducing (or without inducing significant levels of) cAMP production.
  • the ⁇ 2-adrenergic receptor agonist as described herein may be further described as being a ⁇ 2-adrenergic receptor agonist that does not induce significant cAMP (i.e. levels and/or production thereof).
  • the skilled person will be able to determine the level of cAMP production provided by compounds, such as those referred to herein, using techniques known to those skilled in the art, such as those described in the examples as provided herein.
  • the level of cAMP production induced by a given compound can be determined by reference to the amount induced by a defined concentration of that compound relative to that induced by the same concentration of a reference compound, such as isoprenaline, using techniques known to those skilled in the art (e.g. following the protocol as described in the biological examples provided in WO 2019/053427, i.e. in cells, such as differentiated L6-myotubes, having been stimulated with isoprenaline or the compound with a final concentration of 1x10 -5 M, for 15 min in stimulation buffer, such as HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, at pH 7.4).
  • stimulation buffer such as HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, at pH 7.4
  • compounds that do not induce significant cAMP may be defined as being compounds that induce less than 50% (or, in some embodiments, less than 25%) of the cAMP induced by isoprenaline (e.g. in accordance with the protocol described above).
  • Particular compounds acting as ⁇ 2 -adrenergic receptor agonists which are able to activate the ⁇ 2 -adrenergic receptor without (or with only a minimal effect in) inducing cAMP production include those described in the following publications, the contents of which are incorporated herein in their entirety (in particular, the biological examples, the generic compound definitions, including all embodiments thereof and associated definitions, and the example compounds provided therein, including pharmaceutically acceptable salts thereof, and associated methods of preparation): WO 2017/153737 WO 2019/053429 WO 2019/053426 WO 2019/053425 WO 2019/053427 WO 2020/188299 WO 2020/188301 WO 2022/063895 WO 2022/063889 WO 2023/046885 WO 2023/046882 WO 2023/105035 WO 2023/203223 Compounds described in publications referenced and incorporated herein were screened in accordance with the procedures outlined in Biological example 1 and Biological example 2 of WO 2019/053427.
  • Test results are given in Table 1. If a compound at 10 ⁇ M shows activity of more than 75 % of that of isoproterenol at 10 ⁇ M, the activity is denoted with +++; if it is between 75 and 50 % it is denoted with ++; if it is between 50 and 25 % it is denoted with +; if it less than 25 % it is denoted with -.
  • Compounds are drawn as salt-free molecules in Table 1, but the tested compounds might have been containing additional salt or solvent components that do not contribute to the biological activity.
  • metformin will refer to the INN of the compound 1,1-dimethylbiguanide monohydrochloride.
  • all references to metformin herein may be replaced with references to 1,1-dimethylbiguanide monohydrochloride.
  • other salts of 1,1-dimethylbiguanide may be used without departing from the teaching of the present invention.
  • references to metformin may be replaced with references to 1,1-dimethylbiguanide and pharmaceutically acceptable salts thereof.
  • both the ⁇ 2 -adrenergic receptor agonist, or pharmaceutically acceptable salt thereof, and metformin may be administered in the form of a pharmaceutical formulation, which may further comprise one or more pharmaceutically acceptable excipient.
  • Suitable pharmaceutical formulations may be commercially available or otherwise are described in the literature, such as, Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995), and Martindale – The Complete Drug Reference (35 th Edition), and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference in their entirety.
  • suitable formulations and in particular combined preparations including both a ⁇ 2 -adrenergic receptor agonist, or pharmaceutically acceptable salts thereof, and metformin may be achieved by the skilled person using routine techniques.
  • References to pharmaceutically acceptable excipient(s) may be understood to include pharmaceutically acceptable, diluents, carriers and/or adjuvants, as known to those skilled in the art.
  • Various formulations comprising metformin are known to those skilled in the art, including oral solutions and tablets (including film-coated, standard release and extended release formulations).
  • Example formulations comprising metformin include Riomet TM (manufactured by Ranbaxy TM ), Fortamet TM (Shionogi Pharma TM ) and Glumetza TM (Depomed TM ).
  • the skilled person will understand that the invention may also relate to combination products comprising a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and metformin, and uses thereof.
  • a pharmaceutical formulation comprising: (a) a ⁇ 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient, which formulations may be referred to hereinafter as the “formulations of the invention”, or the like.
  • a pharmaceutical formulation comprising: (a) a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient, for use in: (i) the treatment or prophylaxis of obesity; (ii) a therapeutic method of lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, which formulations may be referred to hereinafter as the “formulations of the invention”, or the like, and which treatments (and associated prophylaxis) may be referred to herein after as the “treatments of in the invention”, or the like.
  • a method for: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation comprising: (a) a ⁇ 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) metformin, and optionally one or more pharmaceutically acceptable excipient.
  • the formulations of the second and third aspects of the invention may have any of the particular features described above for the first aspect of the invention, including all combinations thereof.
  • the skilled person will understand that the combination of a ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and metformin may also be provided in the form of a kit-of-parts comprising the same.
  • kits-of-parts comprising components: (A) a pharmaceutical formulation comprising a ⁇ 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, optionally in admixture with one or more pharmaceutically acceptable excipient, and (B) a pharmaceutical formulation comprising metformin, optionally in admixture with one or more pharmaceutically acceptable excipient, wherein components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.
  • the kit-of-parts is for use in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia.
  • the kits-of-parts of the invention may be referred to herein as the “kits-of-parts of the invention”.
  • kit-of-parts of the fourth aspect of the invention further comprises instructions to use each component in conjunction with the other in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia.
  • kits-of-parts comprising: (I) one of components (A) or (B) as defined hereinabove, and (II) instructions to use that component in conjunction with the other of the two components in: (i) the treatment or prophylaxis of obesity; (ii) lowering body fat composition and/or reducing body weight; (iii) the treatment or prophylaxis of metabolic syndrome; or (iv) the treatment or prophylaxis of dyslipidaemia.
  • kits-of-parts of the fourth aspect of the invention may have any of the particular features described above for the first aspect of the invention, including all combinations thereof.
  • kits-of-parts described herein may comprise more than one formulation including an appropriate quantity/dose of a ⁇ 2 -adrenergic receptor agonist, or pharmaceutically acceptable salt and/or pro drug thereof, and/or more than one formulation including an appropriate quantity/dose of metformin, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s). With respect to the treatments, formulations and kits-of-parts of the invention as described herein, references to treatment with or administration of each component will refer to said component being administered in conjunction with the other.
  • body fat may refer in particular to body fat in the form of adipose tissue.
  • pharmaceutical formulations, kits-of-parts, compounds for use, uses and methods of treatment of the invention as defined herein may be useful in lowering body fat composition and/or reducing body weight in a patient (or subject) in need thereof, e.g. a patient who has an above-normal body weight or BMI (e.g. a BMI of 30 or greater), such as in an obese patient, which may be referred to as therapeutically lowering body fat composition and/or reducing body weight.
  • BMI body weight indicator
  • compositions, kits-of-parts, compounds for use, uses and methods of treatment of the invention may also be useful in lowering body fat composition and/or reducing body weight in a patient (or subject) who has a normal body weight or who is overweight (in each case, with a corresponding BMI).
  • such subjects e.g. adult subjects
  • will be non-obese e.g. having a BMI of less than 30.0
  • subjects being overweight BMI 25.0 to 29.9
  • BMI 18.5 to 24.9 a healthy weight
  • kits-of-parts, uses and methods of treatment of the invention may be useful in lowering body fat composition and/or reducing body weight in a patient (or subject) who is overweight.
  • references to non-therapeutic uses and methods will refer to uses and methods in patients that are not directed to the treatment of a medical condition but which provide the relevant effects for other purposes, such as for cosmetic purposes.
  • other uses in medical treatment as described herein may be understood to be further characterised by lowering body fat composition and/or reducing body weight.
  • the treatment or prophylaxis of obesity as described herein may be achieved by lowering body fat composition and/or reducing body weight (e.g. lowering body fat composition).
  • Methods of administration i.e. the pharmaceutical formulations, kits-of-parts, compounds for use, uses and methods of treatment as described herein, including all embodiments and preferred features thereof
  • the present invention relates to two components, namely a ⁇ 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin, being administered in conjunction with each other.
  • References to each component being administered in conjunction with the other will include the components being administered, sequentially, separately or simultaneously, as part of a medical intervention directed towards treatment of the relevant condition.
  • references may include the components being administered sufficiently close in time to enable a beneficial effect for the patient that is greater, over the course of the treatment of the relevant condition, than if administered in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of, treatment of a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
  • references to the components i.e. the ⁇ 2 - adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin
  • references to the components being administered simultaneously will include the components being administered (i.e. taken by the patient, such as being taken orally) at substantially the same time.
  • the components are administered (i.e. taken by the patient, such as being taken orally) sequentially (and, therefore, as separate doses).
  • the components are administered sequentially at least 2 hours apart (i.e. the interval between the administration of each component to the patient, e.g.
  • the components are administered sequentially at least 4 hours apart, such as between 4 hours and 48 hours apart, or between 4 hours and 24 hours apart, or between 4 hours and 12 hours apart.
  • the components are administered sequentially at least 6 hours apart, such as between 6 hours and 48 hours apart, or between 6 hours and 24 hours apart, or between 6 hours and 12 hours apart (e.g. between 6 hours and 10 hours apart).
  • the components are administered sequentially at least 7 hours apart, such as between 7 hours and 48 hours apart, or between 7 hours and 24 hours apart, or between 7 hours and 12 hours apart (e.g. between 7 hours and 9 hours apart).
  • the components are administered sequentially at least 8 hours apart, such as between 8 hours and 48 hours apart, or between 8 hours and 24 hours apart, or between 8 hours and 12 hours apart (e.g. between 8 hours and 9 hours apart).
  • the components are administered sequentially at about 8 hours apart.
  • references to the components as the ⁇ 2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and the compound metformin will include references to the respective components (a) and (b) of the third aspect of the invention, and the respective components (A) and (B) of the fourth aspect of the invention.
  • compounds and pharmaceutical formulations as defined herein will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, transdermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • compounds and pharmaceutical formulations as described herein are administered orally.
  • pharmaceutical formulations as described herein may be described as oral pharmaceutical formulations.
  • the pharmaceutical formulation(s) is/are provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, transdermal patches, plasters, inhalants (e.g. to be applied intranasally).
  • compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.
  • the pharmaceutical formulation(s) is/are provided in a pharmaceutically acceptable oral dosage form, including tablets or capsules, which forms may be prepared using techniques known to those skilled in the art.
  • the compound in the preparation of pharmaceutical formulations for oral administration, may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the mixture may then be processed into granules or compressed into tablets.
  • Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g.
  • hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g.
  • solutions or suspensions containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol.
  • liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials.
  • Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the skilled person will understand that the compounds described herein, and formulations and kits-of parts comprising the same, may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art.
  • the skilled person e.g. the physician
  • treatments (and methods of prophylaxis) described herein may be combined with other means for the treatment of excess body weight or a disoder characterized by excess body weight (as defined herein, such as obesity), such as treatment with one or more other therapeutic agent that is useful in the treatment of excess body weight or a disorder characterized by excess body weight (as defined herein, such as obesity).
  • agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).
  • Preparation of formulations and kits-of-parts Pharmaceutical formulations and kits-of-parts as described herein may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a process for the preparation of a pharmaceutical composition/formulation comprises bringing into association a ⁇ 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and metformin, with one or more pharmaceutically-acceptable excipients (e.g. an adjuvant, diluent and/or carrier).
  • a method of preparing a kit-of-parts as defined hereinbefore which method comprises bringing component (A) into association with component (B), thus rendering the two components suitable for administration in conjunction with each other.
  • references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
  • kits-of-parts as hereinbefore defined, by bringing the two components “into association with” each other, it is contemplated that the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.
  • pharmaceutical formulations, kits-of-parts, methods and uses described herein may have the advantage that, in the treatment of the conditions mentioned hereinbefore, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar methods (treatments) known in the prior art whether for use in the above-stated indications or otherwise.
  • such pharmaceutical formulations, kits of parts, methods and uses may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.
  • ⁇ 2-adrenergic receptor agonist provides complementary biological effects which combine to improve energy expenditure/energy intake balance (e.g. by increasing energy expenditure above basal levels for a given patient), which in turn results in a reduction in lipid storage in adipose tissue due to lipolysis.
  • certain of the compounds acting as ⁇ 2-adrenergic receptor agonists such as those described herein, are able to activate the ⁇ 2 -adrenergic receptor without (or with only a minimal effect in) inducing cAMP production. It is thought that this allows for therapeutic effects as described herein to be obtained with lower levels of side effects than would result from other treatments.
  • Figure 4 shows the change in body weight in the experiment of Biological Example 2.
  • Figure 5 shows the change in lean mass in the experiment of Biological Example 2.
  • Figure 6 shows the food intake over time in the experiment of Biological Example 3.
  • Figure 7 shows the change in fat mass in the experiment of Biological Example 3.
  • Figure 8 shows the change in body weight in the experiment of Biological Example 3.
  • Figure 9 shows the change in lean mass in the experiment of Biological Example 3. Examples
  • the present invention is illustrated by way of the following examples, which are not intended to be limiting on the overall scope of the invention. For the avoidance of doubt, in the case of a discrepancy between the name of the compound and the structure drawn in this specification, the structure should prevail.
  • Compound A The following compound, which be referred to herein as Compound A, was used in the biological examples provided herein in the salt form as specified (and, in the context of which, references to Compound A will refer to that salt form).
  • Compound A The synthesis of Compound A is described in WO 2019/053427 (see Example 17 therein), the contents of which are incorporated herein by reference.
  • Biological Example 1 Compound A was used in the form of the dihydrochloride (2HCl) salt; in Biological Examples 2 and 3, Compound A was used in the form of the hemi-tartrate salt.
  • Biological example 1 Glucose uptake in the presence of a selective E 2 -adrenergic receptor inhibitor L6-myoblasts were grown in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 1 g/L glucose supplemented with 10 % fetal bovine serum (FBS), 2 mM L-glutamine, 50 U/mL penicillin, 50 Pg/mL streptomycin and 10 mM HEPES.
  • DMEM Dulbecco’s Modified Eagle’s Medium
  • Cells were plated at 1x 10 5 cells per mL in 24-well plates. After reaching 90 % confluence the cells were grown in medium containing 2 % FBS for 7 days where upon cells differentiated into myotubes. The differentiated L6-myotubes were serum-starved overnight in medium containing 0.5 % fatty-acid free BSA and stimulated with Compound A at a final concentration of 1x10 -5 M in the presence of the selective E2-adrenergic receptor antagonist ICI-118551. After 1 h 40 min the cells were washed with warm, glucose free medium twice and another portion of agonist was added to the glucose free medium.
  • the cells were exposed to 50 nM 3 H-2-deoxyglucose for 10 min before washed in ice cold glucose free medium three times and lysed in 400 ⁇ l/well 0.2 M NaOH for 1 h at 60 °C.
  • the cell lysate was mixed with 4 ml scintillation buffer (Emulsifier Safe, Perkin Elmer) and the radioactivity was detected in a E-counter (Tri- Carb 4810TR, Perkin Elmer).
  • Figure 1 shows that the glucose uptake promoted by Compound A is inhibited in a dose-dependent manner by the selective E2-adrenergic receptor antagonist ICI- 118551, which proves that the glucose uptake promoted by Compound A is mediated through the E 2 -adrenergic receptor.
  • adrenergic receptor inhibitor Compound A
  • metformin Prior to treatment 2.5-month-old male C57Bl/6 mice were kept on a high-fat high- sucrose diet (45 % fat) at 30 °C for 5 months. The mice had similar body weight and body composition and were divided into four groups (11-12/group).
  • mice were treated by oral gavage in the morning with water, 150 mg/kg/day metformin, 1 mg/kg/day Compound A, or 150 mg/kg/day metformin + 1 mg/kg/day Compound A (in one gavage).
  • Five mice from the mixed group became sick and were euthanised during the first 10 days of the experiment, and were excluded from fat mass, weight, and lean mass analysis, but could not be excluded from the food intake analysis. These five mice ate the least, which explains the very low food intake during the first 10 days of the experiment.
  • Biological example 3 Effects on body weight and food intake of a selective E2- adrenergic receptor inhibitor (Compound A) and metformin when Compound A is administered 8 h after metformin
  • a selective E2- adrenergic receptor inhibitor Compound A
  • metformin When Compound A is administered 8 h after metformin
  • mice Prior to treatment 2.5-month-old male C57Bl/6 mice were kept on a high-fat high- sucrose diet (45 % fat) at 30 °C for 7 months. The mice had similar body weight and body composition and were divided into four groups (10/group) and were kept grouped caged (2-3 mice per cage). Three groups were treated by two oral gavages, one in the morning and one in the afternoon, with 8 hours apart.
  • Morning and afternoon gavages were, respectively, either water and water (the control), or 150 mg/kg/day metformin and water, or 150 mg/kg/day metformin and 0.3 mg/kg/day Compound A.
  • Food intake, body weight and body composition were measured weekly.
  • the fourth group was treated with 150 mg/kg/day metformin and 0.3 mg/kg/day Compound A in the same gavage. Some of these mice did not fare well and the whole group was removed from the experiment.
  • As mice were grouped-caged collective food intake was measured in each cage. Mice in each cage were from the same treatment group.
  • Figures 6-9 Figure 6 shows the food intake over time; Figure 7 shows the change in fat mass; Figure 8 shows the change in body weight; Figure 9 shows the change in lean mass.

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Abstract

L'invention concerne un agoniste du récepteur Pz-adrénergique, ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé dans : (i) le traitement ou la prophylaxie de l'obésité ; (ii) l'abaissement de la composition de graisse corporelle et/ou la réduction du poids corporel ; (iii) le traitement ou la prophylaxie du syndrome métabolique ; ou (iv) le traitement ou la prophylaxie de la dyslipidémie, l'utilisation comprenant en outre l'administration de metformine.
PCT/EP2024/053959 2023-02-16 2024-02-16 Combinaisons d'agonistes du récepteur bêta 2-adrénergique et de metformine destinées à être utilisées dans le traitement de l'obésité et la réduction de la graisse corporelle Ceased WO2024170727A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025238248A1 (fr) * 2024-05-17 2025-11-20 Atrogi Ab UTILISATION D'AGONISTES DU RÉCEPTEUR β2-ADRÉNERGIQUE DANS LE TRAITEMENT DE L'ATROPHIE MUSCULAIRE

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