WO2019053428A1 - Bêta-hydroxyéthylamines pour utilisation dans le traitement ou la prévention des stéatoses hépatiques non alcooliques - Google Patents

Bêta-hydroxyéthylamines pour utilisation dans le traitement ou la prévention des stéatoses hépatiques non alcooliques Download PDF

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WO2019053428A1
WO2019053428A1 PCT/GB2018/052596 GB2018052596W WO2019053428A1 WO 2019053428 A1 WO2019053428 A1 WO 2019053428A1 GB 2018052596 W GB2018052596 W GB 2018052596W WO 2019053428 A1 WO2019053428 A1 WO 2019053428A1
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compound
use according
optionally substituted
represent
alkyl optionally
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PCT/GB2018/052596
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Benjamin Pelcman
Tore Bengtsson
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Atrogi Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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

Definitions

  • the present invention relates to compounds and compositions for use in the treatment or prevention of a fatty liver disease.
  • it relates to the use of such compounds and compositions in the treatment of or prevention of conditions such as non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • such compounds are thought to have a beneficial side-effect profile as they do not exert their effect through significant cAMP release.
  • Fatty liver disease is a condition which is defined by the accumulation of fat, in particular triglycerides, in the cells of the liver.
  • a healthy liver should contain no more than 5% of the liver's weight in fat.
  • fat accounts for greater than around 5 to 10 % of a liver's weight it is considered to be 'fatty'.
  • Early-stage fatty liver disease is often harmless; however, if not treated, it can lead to serious liver damage, including cirrhosis. High levels of liver fat have also been associated with an increased risk of diabetes, heart attack and stroke.
  • alcohol-related fatty liver disease i.e. alcoholic steatosis
  • NAFLD nonalcoholic fatty liver disease
  • both of these types of fatty liver disease can eventually lead to serious conditions, such as cirrhosis.
  • Non-alcoholic fatty liver disease is defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver (designated as an accumulation of greater than 5% of hepatocytes histologically). It is the most common liver disorder in developed countries (for example, affecting around 30% of US adults) and most patients are asymptomatic. If left untreated, the condition may progressively worsen and may ultimately lead to cirrhosis of the liver. NAFLD is particularly prevalent in obese patents, with around 80% thought to have the disease. A sub-group of NAFLD patients (for example, between 2 and 5% of US adults) exhibit liver cell injury and inflammation in addition to excessive fat accumulation.
  • NASH non-alcoholic steatohepatitis
  • NASH NASH-related hypertension
  • diabetes mellitus type 2 insulin resistance
  • central (truncal) obesity hyperlipidaemia
  • low high-density lipoprotein (HDL) cholesterol hypertriglyceridemia
  • hypertension hypertension
  • not all patients with these conditions have NASH, and not all patients with NASH suffer from one of these conditions. Nevertheless, given that NASH is a potentially fatal condition, leading to cirrhosis, liver failure and hepatocellular carcinoma, there exists a clear need for an effective treatment.
  • NAFLD Newcastle disease virus
  • agonists at the receptor such as certain ⁇ -hydroxyethylamines, act as are useful in the treatment or prevention of a nonalcoholic fatty liver disease (NAFLD), such as non-alcoholic steatohepatitis (NASH).
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • agonist may be understood to indicate an agent that binds to a receptor and activates the receptor to produce a biological response.
  • the term also comprises partial agonists.
  • Agonists (and partial agonists) may display, for example, half maximal effective concentration (EC50) values of less than about 1 mM, such as less than about 100 ⁇ , or less than about 10 ⁇ , such as less than about 1 ⁇ (e.g. less than about 100, about 10 or about 1 nM).
  • EC50 half maximal effective concentration
  • receptor agonists that may be employed in the various aspects of the invention include 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 1 199 630, DE 4209989, BE 611502, NL 7804582, EP 0 043 807, WO 2008/022038, DE 2413102, US 2,308,232, BE 823841 , BE 660244, WO 2000/0751 14, WO 2005/102350, WO 2005/1 10990, JP 56055355, AT 285583, US 4,223,137, US 3,056,836, FR 1324914, DE 638650, DD 45721 , US 3,801 ,631 , DE 2259282, DE 2300614, EP 0 290 122, US 2004/0266867, US 2010/0022658, US 2010
  • the receptor agonist is selected from the group consisting of 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, clencyclohexerol, tulobuterol, BRL-47672 trantinterol, clenproperol, clenpenterol, brombuterol, rac
  • the receptor agonist is selected from group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, clencyclohexerol, tulobuterol, trantinterol, mabuterol and abediterol, and pharmaceutically acceptable salts thereof.
  • the receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, clenbuterol, (R)- clenbuterol, bamethane, mabuterol and abediterol, and pharmaceutically acceptable salts thereof.
  • bamethane CAS: 3703-79-5
  • R- bamethane CAS: 912804-58-1
  • the international non-proprietary 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 stereosiomers (e.g. a racemate).
  • INN international non-proprietary name
  • developmental drug code e.g. BRL-47672
  • a compound generally indicates the stereochemical configuration of the compound, or a particular mixture of stereosiomers (e.g. a racemate).
  • such 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.
  • a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a non-alcoholic fatty liver disease, wherein:
  • R 1 represents C4-12 alkyl optionally substituted by one or more halo
  • R 2 and R 3 each independently represent H or C1-3 alkyl optionally substituted by one or more halo; or R 2 and R 3 may be linked together to form, together with the carbon atom to which they are attached, a 3- to 6-membered ring, which ring optionally is substituted by one or more groups independently selected from halo and Ci alkyl optionally substituted by one or more halo; each X independently represents halo, R a , -CN, -N 3 , -N(R b )R c , -NO2, -ONO2, -OR d , -S(0)pR e or -S(0) q N(R f )R 9 ; R a represents C1-6 alkyl optionally substituted by one or more groups independently selected from G; each R b , R c , R d , R e , R f and R 9 independently represents H or C1-6 alkyl optionally substituted by one or more groups independently selected from G; or alternative
  • a method of treating or preventing a non-alcoholic fatty liver disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • references herein to compounds of particular aspects of the invention will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments.
  • Medical uses As described herein, the compounds of the first aspect of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds that possess pharmacological activity.
  • compounds of the first aspect of the invention are useful in the treatment of a non-alcoholic fatty liver disease, which term will be readily understood by one of skill in the art (as described herein).
  • compounds of the invention are for use in the treatment of a non-alcoholic fatty liver disease (or useful in the manufacture of a medicament for such treatment, or useful in a method for such treatment, as described herein).
  • steatosis i.e. hepatic steatosis
  • the term "steatosis” encompasses the abnormal retention of fat (i.e. lipids) within a cell.
  • the treatment or prevention is of a fatty liver disease which is characterized by steatosis.
  • lipids During steatosis, excess lipids accumulate in vesicles that displace the cytoplasm of the cell. Over time, the vesicles can grow large enough to distort the nucleus, and the condition is known as macrovesicular steatosis. Otherwise, the condition may be referred to as microvesicular steatosis.
  • Steatosis is largely harmless in mild cases; however, large accumulations of fat in the liver can cause significant health issues. Risk factors associated with steatosis include diabetes mellitus, protein malnutrition, hypertension, obesity, anoxia, sleep apnea and the presence of toxins within the cell.
  • fatty liver disease is most commonly associated with alcohol or a metabolic syndrome (for example, diabetes, hypertension, obesity or dyslipidemia). Therefore, depending on the underlying cause, fatty liver disease may be diagnosed as alcohol-related fatty liver disease or non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • Particular diseases or conditions that are associated with fatty liver disease that are not related to alcohol include metabolic conditions such as diabetes, hypertension, obesity, dyslipidemia, abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, acute fatty liver of pregnancy, and lipodystrophy.
  • Other non-alcohol related factors related to fatty liver diseases include malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, polycystic ovary syndrome and diverti culosis.
  • the compounds of the invention have been found to be particularly useful in the treatment or prevention of NAFLD, which may be referred to as a fatty liver disease which is not alcohol related.
  • a fatty liver disease which is "not alcohol related” may be diagnosed wherein alcohol consumption of the patient is not considered to be a main causative factor.
  • a typical threshold for diagnosing a fatty liver disease as "not alcohol related" is a daily consumption of less than 20 g for female subjects and less than 30 g for male subjects.
  • the treatment or prevention is of a NAFLD which is associated with inflammation.
  • Non-alcoholic steatohepatitis is the most aggressive form of NAFLD, and is a condition in which excessive fat accumulation (steatosis) is accompanied by inflammation of the liver. If advanced, NASH can lead to the development of scar tissue in the liver (fibrosis) and, eventiually, cirrhosis.
  • the compounds of the invention have been found to be useful in the treatment or prevention of NAFLD, particularly when accompanied by inflamation of the liver. It follows that the compounds of the invention are also useful in the treatment or prevention of NASH. Therefore, in a further embodiment of the first aspect of the invention, the treatment or prevention is of non-alcoholic steatohepatitis (NASH).
  • treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
  • treatment with compounds of the invention may be combined with other means for the treatment of a fatty liver disease, as described herein, such as treatment with one or more other therapeutic agent that is useful in the treatment of a fatty liver disease as known to those skilled in the art; for example, therapies comprising requiring the patient to undergo a change of diet and/or undertake exercise regiments, and/or surgical procedures designed to promote weight loss (such as gastric band surgery).
  • treatment with compounds of the invention may be performed in combination with (e.g. in a patient who is also being treated with) one or more (e.g. one) additional compounds (i.e. therapeutic agents) that are capable of reducing the level of fat (e.g. triglycerides) in the liver.
  • references to the treatment of a particular condition take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the condition.
  • the term may refer to achieving a therapeutically significant reduction of fat (e.g. triglycerides levels) in liver cells (such as a reduction of at least 5% by weight, e.g. a reduction of at least 10%, or at least 20% or even 25%).
  • prevention includes references to the prophylaxis of the disease or disorder (and vice versa).
  • references to prevention may also be references to prophylaxis, and vice versa.
  • the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
  • references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients.
  • the treatment is in a mammal (e.g. a human).
  • the term therapeutically effective amount will refer to an amount of a 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).
  • compounds of the first aspect of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the active compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
  • references to prodrugs will include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the first aspect of the invention are included within the scope of the invention.
  • enteral or parenteral administration e.g. oral or parenteral administration
  • salts include acid addition salts and base addition 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 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. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • carboxylate salts e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or ter
  • sulphonate salts e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxyethanesulphonate, 1- or 2- naphthalene-sulphonate or 1 ,5-naphthalenedisulphonate salts
  • 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 of the first aspect of the invention 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. Where compounds of the first aspect of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention. Compounds of the first aspect of the invention may also exist in solution.
  • Compounds of the first aspect of the invention may contain double bonds and may thus exist as E (ent ought) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention. Compounds of the first aspect of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
  • Compounds of the first aspect of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers i.e. enantiomers
  • the desired optical isomers may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution); for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • references to halo and/or halogen groups will each independently refer to fluoro, chloro, bromo and iodo (for example, fluoro (F) and chloro (CI)).
  • Ci -Z alkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3- z -cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
  • Part cyclic alkyl groups that may be mentioned include cyclopropylmethyl and cyclohexylethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g.
  • alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C2 alkenyl or a C2 alkynyl group).
  • Particular alkyl groups that may be mentioned include saturated alkyl groups.
  • references to heteroatoms will take their normal meaning as understood by one skilled in the art.
  • Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulphur (e.g. oxygen, nitrogen and sulphur).
  • references to polycyclic (e.g. bicyclic or tricyclic) groups e.g. when employed in the context of cycloalkyi groups
  • references to polycyclic (e.g. bicyclic or tricyclic) groups will refer to ring systems wherein at least two scissions would be required to convert such rings into a straight chain, with the minimum number of such scissions corresponding to the number of rings defined (e.g. the term bicyclic may indicate that a minimum of two scissions would be required to convert the rings into a straight chain).
  • bicyclic e.g.
  • alkyl groups when employed in the context of alkyl groups may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, and may also refer to groups in which two non-adjacent atoms are linked by an alkylene group, which later groups may be referred to as bridged.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those 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 compounds of the invention also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.
  • the compounds of the invention i.e. the compound of formula I
  • R d represents H
  • the compounds of the invention wherein, when n represents at least 1 and an X substituent is present in the 4-position of the benzene ring (i.e. the 4-position of the essential benzene ring relative to the point of substitution by the essential substituent), the X substituent in the 4-position represents -N(R b )R c or -OR d , wherein R b , R c and R d represents H.
  • the compounds of the invention wherein, when n represents at least 1 and an X substituent is present in the 4-position of the benzene ring (i.e. the 4-position of the essential benzene ring relative to the point of substitution by the essential substituent), the X substituent in the 4-position represents -OR d , particularly wherein R d represents H.
  • n represents at least 1 and an X substituent is present in the 4-position of the benzene ring (i.e. the 4-position of the essential benzene ring relative to the point of substitution by the essential substituent), the X substituent in the 4-position does not represent halo.
  • n represents at least 1 and an X substituent is present in the 4-position of the benzene ring (i.e. the 4- position of the essential benzene ring relative to the point of substitution by the essential substituent), the X substituent in the 4-position does not represent chloro.
  • n represents at least 1 and an X substituent is present in the 4-position of the benzene ring (i.e. the 4-position of the essential benzene ring relative to the point of substitution by the essential substituent), wherein the X substituent in the 4-position represents -OH.
  • the compounds of the invention i.e. the compound of formula I wherein when n represents 1 and the X substituent is located in the 3-position of the benzene ring (i.e. the 3-position of the essential benzene ring relative to the point of substitution by the essential substituent) and represents halo (e.g. CI) or -OR d , wherein R d represents H.
  • the compounds of the invention wherein, when n represents at least 1 and an X substituent is present in the 3-position of the benzene ring (i.e. the 3-position of the essential benzene ring relative to the point of substitution by the essential substituent), the X substituent in the 3-position represents halo (e.g. CI) or -OR d , wherein R d represents H.
  • X represents -OH and may be located in the 3-position or the 4-position of the benzene ring.
  • R 1 represents C4-10 alkyl optionally substituted by one or more F, such as C4-8 alkyl optionally substituted by one or more F.
  • R 1 represents C4-8 alkyl optionally substituted by two or three F, such as C4-6 alkyl optionally substituted by three F (e.g. where the three F are attached to the terminal carbon of the C4-6 alkyl, e.g. 4,4,4-trifluorobutyl).
  • R 1 represents C4-10 alkyl, such as C4-8 alkyl.
  • R 1 represents C4-12 alkyl.
  • R 1 represents C4-7 alkyl (e.g. C4-5 alkyl).
  • the R 1 represents C4-12 alkyl (e.g. C4-7 alkyl, such as C4-5 alkyl) wherein the carbon bound to the essential -NH- group is unbranched, e.g. represented by a -CH2- moiety.
  • Particular R 1 groups that may be mentioned include those in which the alkyl group (for example, the C4-12 alkyl group e.g. the C4-10 alkyl, such as C4-8 alkyl) is linear or part-cyclic (particularly part-cyclic such that the carbon bound to the essential -NH- group is unbranched, e.g. -CH2-).
  • Other particular R 1 groups that may be mentioned include those in which the alkyl group (e.g. the C4-10 alkyl, such as C4-8 alkyl) is linear (e.g. n-butyl, n-hexyl or n-octyl).
  • R 1 groups that may be mentioned include those in which the alkyl group represents C4-12 alkyl (e.g. C4-7 alkyl, such as C4-5 alkyl) wherein the carbon bound to the essential -NH- group is substituted by one substituent, e.g. represented by a -CH(R 2 )- moiety, wherein R 2 represents C1-2 alkyl (e.g. methyl), e.g. wherein R 2 represents 2-pentyl.
  • C4-12 alkyl e.g. C4-7 alkyl, such as C4-5 alkyl
  • R 2 represents C1-2 alkyl (e.g. methyl)
  • R 2 represents 2-pentyl.
  • R 1 represents n-butyl, sec-butyl, te/f-butyl, 2-pentyl, cyclopentyl, -CH2-cyclopropyl, -(CH2)2-cyclopropyl, n-hexyl, -(CH2)3-cyclopropyl, -CH2-cyclohexyl, n-octyl, -(CH2)2-cyclohexyl, -(CH2)3-cyclohexyl, 4,4,4-trifluorobutyl or 1-adamantyl (e.g. n-butyl, tert-butyl or cyclopropylmethyl).
  • 1-adamantyl e.g. n-butyl, tert-butyl or cyclopropylmethyl.
  • R 1 represents n-butyl, sec-butyl, fe/f-butyl, 2-pentyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclohexyl or 1-adamantyl (e.g. n-butyl, ferf-butyl or cyclopropylmethyl).
  • R 1 represents n-butyl, sec-butyl, 2-pentyl, cyclopentyl, -CH2-cyclopropyl, -(CH2)2-cyclopropyl, n-hexyl, -(CH2)3-cyclopropyl, -CH2-cyclohexyl or n- octyl, -(CH2)2-cyclohexyl, -(CH2)3-cyclohexyl or 1-adamantyl (e.g. n-butyl or cyclopropyl methyl).
  • R 1 represents n-butyl, 2-pentyl, -CH2-cyclopropyl, -(CH2)2- cyclopropyl, n-hexyl, -(CH2)3-cyclopropyl, -CH2-cyclohexyl, n-octyl, -(CH2)2-cyclohexyl or -(CH2)3-cyclohexyl.
  • R 1 may represent -Chb-cyclopropyl, -(CH2)2-cyclopropyl, -(CH2)3-cyclopropyl, -CH2-cyclohexyl, -(CH2)2-cyclohexyl or -(CH2)3-cyclohexyl.
  • R 1 may represent n-butyl or 2-pentyl.
  • R 1 represents n-butyl, -CH2-cyclopropyl, or -CH2- cyclohexyl. In a particular embodiment, R 1 may represent -Chb-cyclopropyl. In a further embodiment, R 1 may represent n-butyl.
  • R 1 does not represent te/f-butyl.
  • each R 2 and R 3 independently represents H or C1-2 alkyl (e.g. methyl).
  • n- indicates a linear alkyl group where the point of attachment of the group to the rest of a molecule is through a carbon atom at the end of the carbon chain and thus that that carbon atom is bound to one other carbon atom.
  • secondary indicates that the point of attachment of the rest of the molecule to the alkyl group is through a carbon atom adjacent to the end of the carbon chain and thus that that carbon is itself bound to two other carbon atoms.
  • tertiary indicates that the point of attachment of the alkyl group to the rest of a molecule is through a carbon atom that is bound to three other carbon atoms.
  • each R 2 and R 3 independently represents H, methyl or ethyl (e.g. methyl).
  • R 2 represents H and R 3 represents H or methyl.
  • R 2 and R 3 each represent H.
  • each X independently represents halo, R a , -CN, -N 3 , -N(R b )R c , -N0 2 or -OR d , wherein R a represents Ci -4 alkyl optionally substituted by one or more F, and wherein R b , R c and R d each independently represent H or Ci -4 alkyl optionally substituted by one or more F.
  • each X may independently represent halo, R a , -CN, -IM3, -N(R b )R c , -NO2 or -OR d , wherein R a represents Ci -4 alkyl optionally substituted by one or more F, and R b , R c and R d each independently represent H or Ci -4 alkyl optionally substituted by one or more F.
  • each X may independently represent halo, R a , -CN, -N3, -NO2 or -OR d , wherein R a represents Ci -4 alkyl optionally substituted by one or more F, and R d each independently represent H or Ci -4 alkyl optionally substituted by one or more F.
  • each X independently represents F, CI, R a , -NH2, -CN or -OH, wherein R a represents Ci -4 alkyl (e.g. C1-2 alkyl) optionally substituted by one or more F (for example R a represents -CHF2 or -CF3 ( e.g. -CF3)).
  • each X independently represents F, CI, R a , -NH2 or -OH, wherein R a represents C1-2 alkyl optionally substituted by one or more F (for example R a represents -CHF 2 or -CF 3 (e.g. -CF 3 )).
  • each X independently represents F, CI, R a , or -OH, wherein R a represents C1-2 alkyl optionally substituted by one or more F.
  • each X independently represents CI, -NH2, -CF3 or -OH. In a further embodiment, each X independently represents -OH.
  • n 0, 1 , 2 or 3 (for example 1 or 2, e.g. 1).
  • n 0, 1 or 2 (e.g. 0 or 1). In other embodiments of the compounds of the invention, n represents 1 , 2 or 3 (e.g. 1 or 2). In particular embodiments of the compounds of the invention, n represents 1.
  • each X independently represents halo (e.g. F or CI, such as F), -NH2, -CF3 or -OH.
  • X independently represents CI, -NH2, -CF3 or -OH.
  • X groups may be located in the 3-, 4- and 5- positions of the essential benzene ring.
  • each X independently represents F, CI, -CF3, -IMH2 or -OH.
  • the X groups may be located in the 3- and 4- positions, or the 3- and 5- positions of the essential benzene ring.
  • each X independently represents F, CI, -NH2, or -OH.
  • the X groups may be located in the 3- and 4- positions, or the 3- and 5- positions of the essential benzene ring.
  • each X independently represents CI or -OH. In such embodiments, the X groups may be located in the 3- and 4-positions, or the 3- and 5- positions of the essential benzene ring. In certain embodiments, wherein n represents 2, each X independently represents F, CI, - CF3 or -NH2. In such embodiments, the X groups may be located in the 3- and 4-positions, or the 3- and 5- positions of the essential benzene ring.
  • n 2 or 3 and/or (e.g. and)
  • each X independently represents halo (e.g. F or CI, such as F), -NH2, -CF3 or -OH, particularly where such X groups are located in the 3-, 4- and 5-positions of the essential benzene ring.
  • halo e.g. F or CI, such as F
  • -NH2, -CF3 or -OH particularly where such X groups are located in the 3-, 4- and 5-positions of the essential benzene ring.
  • a compound of formula I, or a pharmaceutically acceptable salt thereof wherein the essential benzene ring is unsubstituted in the 2- and 6-positions.
  • each X independently represents halo, R a or -OR d ;
  • R a represents C1-4 alkyl optionally substituted by one or more F;
  • R d represents H or C1-4 alkyl optionally substituted by one or more F; and/or (e.g. and) n represents 0, 1 , 2 or 3.
  • each X independently represents F, CI, R a or -OH;
  • R a represents C1-2 alkyl optionally substituted by one or more F; and/or (e.g. and) n represents 0, 1 or 2 (e.g. 1 or 2).
  • each X independently represents F, CI, methyl or -OH;
  • n 1 or 2 (e.g. 1); and/or (e.g. and)
  • At least one X is in the 3- or in the 4-position on the phenyl group to which it is attached.
  • X independently represents CI or -OH which substituents are in the 3- and 4-position on the phenyl group to which they are attached;
  • n 2.
  • X represents F, CI, R a or -OH in the 3-position on the phenyl group to which it is attached, wherein R a represents C1-2 alkyl optionally substituted by one or more F (for example, R a may represent -CF3 or -CHF2 (e.g. -CHF2)); and
  • n 1.
  • X represents CI or -OH (e.g -OH) in the 3-position on the phenyl group to which it is attached;
  • n 1.
  • X represents F, CI, R a or -OH in the 4-position on the phenyl group to which it is attached, wherein R a represents C1-2 alkyl optionally substituted by one or more F (for example R a may represent -CF3 or -CHF2 (e.g. -CHF2)); and
  • n 1
  • n 1
  • X represents CI or -OH (e.g. -OH) in the 4-position on the phenyl group to which it is attached; and n represents 1.
  • R 1 represents n-butyl or cyclopropylmethyl
  • R 2 and R 3 represent H
  • n 1 ;
  • X represents -OH and is in the 4-position on the phenyl group to which it is attached.
  • a compound of formula I or a pharmaceutically acceptable salt thereof, wherein when n represents 1 and X is located in the 4-position of the essential benzene ring and represents -OR d , then R d represents H.
  • the compound of formula I is a compound of formula IA wherein R 1 , R 2 and R 3 are as defined herein (for the avoidance of doubt, including all embodiments thereof), and X 1 , X 2 , X 3 , X 4 and X 5 each independently represent H or X, wherein X is as defined herein (for the avoidance of doubt, including all embodiments thereof).
  • X 1 and X 5 each independently represent H, F, CI or methyl
  • X 2 , X 3 and X 4 each independently represent H, halo, R a , -CN, -N 3 , -N(R b )R c , -N0 2 or -OR d , wherein R a represents Ci- 4 alkyl optionally substituted by one or more F, and wherein R b , R c and R d each independently represent H or Ci- 4 alkyl optionally substituted by one or more F.
  • R a represents Ci- 4 alkyl optionally substituted by one or more F
  • R b , R c and R d each independently represent H or Ci- 4 alkyl optionally substituted by one or more F.
  • X 1 represents H.
  • X 5 represents H, F, CI or methyl
  • X 2 , X 3 and X 4 each independently represent H, halo, R a , -CN, -N 3 , -N(R b )R c , -NO2 or -OR d , wherein R a represents Ci- 4 alkyl optionally substituted by one or more F, and wherein R b , R c and R d each independently represent H or Ci- 4 alkyl optionally substituted by one or more F.
  • R a represents Ci- 4 alkyl optionally substituted by one or more F
  • R b , R c and R d each independently represent H or Ci- 4 alkyl optionally substituted by one or more F.
  • X 1 , X 2 and X 5 each represent H ;
  • X 3 and X 4 each independently represent H, halo, R a , -CN, -NH2, or -OH, wherein R a represents C1-2 alkyi optionally substituted by one or more F (for example, R a may represent -CF3 or -CHF2).
  • X 1 , X 2 and X 5 each represent H ;
  • X 3 and X 4 each independently represent H, halo, -NH2, -CN or -OH.
  • X 1 , X 2 and X 5 each represent H ;
  • X 3 and X 4 each independently represent H, F, CI, -CN, -NH 2 or -OH.
  • X 1 , X 2 and X 5 each represent H;
  • X 3 and X 4 each independently represent H, halo (e.g. F, CI), -CN or -OH.
  • halo e.g. F, CI
  • X 1 , X 2 and X 5 each represent H;
  • X 3 and X 4 each independently represent H, CI or -OH.
  • X 1 , X 2 and X 5 each represent H;
  • X 3 represent -NH2 or -OH; and/or (e.g. and)
  • X 4 represents H or CI.
  • X 1 , X 2 , X 3 , X 4 and X 5 each represent H ; or
  • X 1 , X 2 , X 3 and X 5 represent H and X 4 represents CI; or
  • X 1 , X 2 , X 4 and X 5 represent H and X 3 represents -OH.
  • X 1 and X 5 each represent H.
  • X 2 and X 4 each independently represent halo, R a , -CN, -N 3 , -N(R b )R c , -NO2 or -OR d ; wherein R a represents C1-4 alkyi optionally substituted by one or more F, and wherein R b , R c and R d each independently represents H or C1-4 alkyl optionally substituted by one or more F; and
  • X 3 represents H, halo, R a , -CN, -N 3 , -N(R b )R c , -NO2 or -OR d ; wherein R a represents C1.4 alkyl optionally substituted by one or more F, and wherein R b , R c and R d each independently represents H or C1-4 alkyl optionally substituted by one or more F.
  • X 1 and X 5 each represent H
  • X 2 and X 4 each independently represent F, CI, R a or OR d ; wherein R a represents C1-2 alkyl optionally substituted by one or more F, and wherein R d represents H or C1-2 alkyl optionally substituted by one or more F; and
  • X 3 represents H, -N(R b )R c or -OR d ; wherein R b , R c and R d each independently represent H or C1-2 alkyl optionally substituted by one or more F.
  • R b , R c and R d each independently represent H or C1-2 alkyl optionally substituted by one or more F.
  • X 1 and X 5 each represent H
  • X 2 and X 4 each independently represent F, CI, -CF3 or -OH;
  • X 3 represents H, -NH 2 or -OH.
  • X 1 and X 5 each represent H
  • X 2 and X 4 each independently represent CI, -CF3 or -OH;
  • X 3 represents H, -NH 2 or -OH. In certain embodiments:
  • X 1 , X 3 and X 5 each represent H ;
  • X 2 and X 4 each represent -OH.
  • X 1 and X 5 represent H
  • X 2 and X 4 each independently represent CI or -CF3
  • X 3 represents -NH2 or -OH.
  • X 1 represents -CI and X 3 represents -CF3.
  • X groups and the positions and number thereof, such as may correspond to X 1 to X 5 groups in compounds of formula IA) that may be mentioned include those present in the examples provided herein.
  • R 1 , R 2 and R 3 groups that may be mentioned include those present in the examples provided herein.
  • R 1 represents n-butyl or cyclopropylmethyl
  • R 2 and R 3 represent H
  • n 1 ;
  • X represents -OH and is in the 4-position on the phenyl group to which it is attached (i.e. in a compound of formula IA, X 1 , X 2 , X 4 and X 5 represent H and X 3 represents -OH).
  • Particular compounds of the first aspect of the invention that may be mentioned include the compounds of the examples provided herein, and pharmaceutically acceptable salts thereof.
  • compounds of formula I that may be mentioned include:
  • Certain particular compounds of formula I include:
  • compounds of the first aspect of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Moreover, it has been found that certain such optical and/or diastereoisomers may show increased utility in the treatment or prevention of a fatty liver disease (such as non-alcoholic steatohepatitis (NASH)), as described herein.
  • a fatty liver disease such as non-alcoholic steatohepatitis (NASH)
  • the compound of formula I is such that the carbon substituted with the essential -OH group is in the R configuration, as understood by those skilled in the art.
  • the compound of formula I is a compound of formula IB
  • n, X, R 1 , R 2 and R 3 are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof).
  • n 1 ;
  • X represents -OH
  • R 1 represents C 4 -s alkyl (e.g. C 4 alkyl, such as n-butyl); and/or (e.g. and)
  • R 2 and R 3 both represent H.
  • R 1 represents C 4 -s alkyl (e.g. C 4 alkyl, such as n-butyl);
  • R 2 and R 3 both represent H.
  • the compound of formula I (or the compound of formula IA or IB) is a compound of formula IC
  • X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 and R 3 are as described herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof).
  • X 1 , X 3 , X 4 and X 5 each represent H;
  • X 3 represents -OH
  • R 1 represents C4-8 alkyl (e.g. C 4 alkyl, such as n-butyl); and/or (e.g. and)
  • R 2 and R 3 both represent H.
  • compounds of the first aspect of the invention include the compounds of the examples provided herein, and pharmaceutically acceptable salts thereof.
  • compounds of formula IB or IC that may be mentioned include:
  • references to a specific steroisomer of a compound of formula I e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the R configuration, as represented by compounds of formula IB and formula IC
  • references to a specific stereoisomer present in the substantial absence of the corresponding opposite stereoisomer e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the S configuration).
  • references to a compound of formula IC being present in the substantial absence of the corresponding opposite steroisomer will refer to the substantial absence of the corresponding compound as depicted below.
  • references to the substantial absence of the corresponding opposite stereoisomer will refer to the desired stereoisomer (e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the (R) configuration) being present at a purity of at least 80% (e.g. at least 90%, such as at least 95%) relative to the opposite stereoisomer (e.g. in the case of compounds of formula I, where the carbon substituted by the essential -OH group is in the S configuration).
  • compounds may be indicated to be present in the substantial absence of the compound in the other configuration (i.e.
  • (S) configuration which may indicate that 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%).
  • compounds referred to as having a specific stereochemistry at a defined position may also have stereochemistry at one or more other positions, and so may exist as mixtures of enantiomers or diastereoisomers in relation to the stereochemistry at those positions.
  • compositions As described herein, compounds of the first aspect of the invention are useful as pharmaceuticals. Such compounds may be administered alone or may be administered by way of known pharmaceutical compositions/formulations.
  • references herein to compounds of the first aspect of the invention being for particular uses (and, similarly, to uses and methods of use relating to compounds of the invention) may also apply to pharmaceutical compositions comprising compounds of the invention as described herein.
  • a pharmaceutical composition for use in the treatment or prevention of a non-alcoholic fatty liver disease comprising a compound as defined in the first aspect of the invention (i.e. a compound of the invention), and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • compositions of the first aspect of the invention may act systemically and/or locally (i.e. at a particular site).
  • compounds and compositions as described in the first and second aspects of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Pharmaceutical compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • pharmaceutical compositions may be formulated for topical administration.
  • the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration.
  • a pharmaceutically acceptable dosage form including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration.
  • 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 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.
  • the mixture may then be processed into granules or compressed into tablets.
  • Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules.
  • active compounds e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents
  • hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready- made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such 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.
  • compositions as described hereinabove may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art.
  • Oral, pulmonary and topical dosages may range from between about 0.01 ⁇ g/kg of body weight per day ⁇ g/kg/day) to about 200 ⁇ g/kg/day, preferably about 0.01 to about 10 ⁇ g/kg/day, and more preferably about 0.1 to about 5.0 ⁇ g/kg/day.
  • treatment with such compounds may comprise administration of a formulations typically containing between about 0.01 ⁇ g to about 2000 mg, for example between about 0.1 ⁇ g to about 500 mg, or between 1 ⁇ g to about 100 mg (e.g. about 20 ⁇ g to about 80 mg), of the active ingredient(s).
  • the most preferred doses will range from about 0.001 to about 10 ⁇ g/kg/hour during constant rate infusion.
  • treatment may comprise administration of such compounds and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g.
  • the skilled person e.g. the physician
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • treatment with compounds of the first aspect of the invention may further comprise (i.e. be combined with) further (i.e. additional/other) treatment(s) for the same condition.
  • treatment with compounds of the invention may be combined with other means for the treatment of NAFLD (as defined herein, such as non-alcoholic steatohepatitis (NASH)), such as treatment with one or more other therapeutic agent that is useful in the treatment of NAFLD (as defined herein, such as non-alcoholic steatohepatitis (NASH)).
  • NAFLD non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • the pharmaceutical composition may further comprise one or more additional (i.e. other) therapeutic agent.
  • a combination product comprising: (A) a compound as defined in the first aspect of the invention.
  • each of components (A) and (B) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • kit-of-parts comprising:
  • the additional therapeutic agent is a therapeutic agent that is useful for the treatment or prevention of a non-alcoholic fatty liver disease (e.g. NASH), as known to those skilled in the art (such as those described herein).
  • a non-alcoholic fatty liver disease e.g. NASH
  • the additional therapeutic agent is an agent that is capable of reducing the level of fat (e.g. triglycerides) in the liver.
  • agents will be readily identified by those skilled in the art and include, in particular, such therapeutic agents that are commercially available (e.g. agents that the subject of a marketing authorization in one or more territory, such as a European or US marketing authorization).
  • references to therapeutic agents capable of reducing the level of fat (e.g. triglycerides) in the liver may refer to compounds capable of reducing the level of fat (e.g. triglycerides) in the liver by at least 10% by weight (such as at least 20%, at least 30% or at least 40%, for example at least 50%, at least 60%, at least 70% or at least 80%, e.g. at least 90%) when compared to the level of fat (e.g. triglycerides) in the liver prior to treatment with the relevant compound.
  • compositions/formulations, combination products and kits as described herein may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a process for the preparation of a pharmaceutical composition/formulation comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable adjuvant, diluent or carrier.
  • a process for the preparation of a combination product or kit-of-parts as hereinbefore defined comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of a non-alcoholic fatty liver disease (e.g. NASH), and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • a non-alcoholic fatty liver disease e.g. NASH
  • 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, we include that the two components of the kit of parts may be:
  • n, X, R 2 , R 3 and n are as defined hereinabove, with a compound of formula III
  • n, X, R 1 , R 2 , R 3 and n are as defined hereinabove and Y 1 represents H or PG 1 wherein PG 1 is a suitable protecting group as known to those skilled in the art (e.g. -C(0)OfBu or -SO2CH3) with a suitable reduction agent as known to those skilled in the art, such as NaBhU or UAIH4, or by hydrogenation in the presence of a suitable catalyst;
  • PG 1 is a suitable protecting group as known to those skilled in the art (e.g. -C(0)OfBu or -SO2CH3) with a suitable reduction agent as known to those skilled in the art, such as NaBhU or UAIH4, or by hydrogenation in the presence of a suitable catalyst;
  • n, X, R 1 , R 2 and R 3 are as defined hereinabove
  • Y 3 represents H or PG 5
  • PG 5 represents a suitable protecting group as known to those skilled in the art
  • Y 4 represents H or PG 6
  • PG 6 represents a suitable protecting group as known to those skilled in the art
  • PG 4 represents a suitable protecting group as known to those skilled in the art (e.g.
  • carbamate protecting groups such as te/f-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc) and carboxybenzyl (Cbz) and amide protecting groups (such as acetyl and benzoyl)) under conditions known to those skilled in the art (for example in the case of Boc, in the presence of a suitable acid (e.g. trifluoroacetic acid or HCI).
  • PG 4 , PG 5 (if present) and PG 6 (if present) may each represent the same protecting group, and therefore may be deprotected under a single set of conditions;
  • the substituents X, R 1 , R 2 and R 3 may be modified one or more times, after or during the processes described above for preparation of compounds of formula I by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, dehydrogenations, alkylations, dealkylations, acylations, hydrolyses, esterifications, etherifications, halogenations and nitrations.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • the skilled person may also refer to "Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W.
  • processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention (e.g. isolation and optionally purification of the compound of formula I or la).
  • compounds of formula IB and IC may be provided by reacting compounds having the required stereochemistry in processes as described in step (i) or step (iii) in the processes described herein above.
  • suitable starting materials having the required stereochemistry such as suitable compounds of formula II and V wherein the carbon substituted with the essential oxygen is the R configuration, as required for the preparation of compounds of formula IB and IC
  • suitable starting materials having the required stereochemistry may be prepared by analogy with the process described in step (iib) herein above.
  • Protecting groups may be applied and removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).
  • Compounds as described herein may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
  • such compounds may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.
  • compounds as described herein are thought to be potent agonists of the receptor, and are useful for reducing in the level of fat (e.g. triglycerides) in the liver.
  • fat e.g. triglycerides
  • BBr3 (0.22 mL, 2.2 mmol) was added to a solution of 2-(butylamino)-1-(4-methoxy- phenyl)ethan-1-ol (200 mg, 0.90 mmol) in 10 mL CH 2 CI 2 at 0 °C.
  • the cooling bath was removed and the mixture was stirred for 1 h and poured onto ice.
  • the mixture was extracted with CH2CI2 and the pH of the aqueous layer was adjusted to 6-7 with NaHCC>3 (aq, sat), extracted with CH2CI2 and concentrated.
  • the residue was suspended in EtOAc, dried (IS ⁇ SCU) and filtered trough Celite and concentrated.
  • the sub-title compound was prepared in accordance with the procedure in Example 3, steps (c) and (d) from 4-benzyloxyphenacyl bromide and cyclopentylamine.
  • the sub-title compound was prepared in accordance with the procedure in Example 3, Steps (c) and (d) from 4-benzyloxyphenacyl bromide and 1-adamantylamine.
  • the title compound was purchased from Vitas M-Laboratory
  • step b A solution of 4-benzyloxyphenacyl bromide (3.0 g, 10 mmol, see Example 3, step b) in CH2CI2 (75 mL) was added to a solution of n-butylamine (3 mL, 30 mmol) in CH2CI2 (75 mL) at -30 °C. The mixture was stirred at -30 °C for 1 h and kept at -20 °C for 15 h. Di- te/f-butyl dicarbonate (3.4 mL, 15 mmol) was added and the mixture was stirred at rt for 2 h.
  • a transfer hydrogenation catalyst was prepared by dissolving (1S, 2S)- ⁇ +)-N- (4-toluenesulphonyl)-1 ,2-diphenylethylene diamine (36.9 mg, 0.10 mmol) and [Ru(cymene)Cl2]2 (30.8 mg, 0.05 mmol) in formic acid/EtsN (5:2, 2 mL), as described in Kawamato, A.M. and Wills, M., J. Chem. Soc. Perkin 1, 1916 (2001).
  • Example 18 4-(1-Hydroxy-2-(octylamino)ethyl) henol acetate
  • DIPEA (0.24 mL, 1.36 mmol) was added dropwise to a mixture of (3-bromopropyl)- cyclohexane hydrobromide (303 mg, 1.36 mmol) and CH2CI2 (4 mL) at 0 °C.
  • a solution of 4-benzyloxyphenacyl bromide (208 mg, 0.68 mmol, see Example 3, Step (b)) in CH2CI2 (3 mL) was added over 15 min to the stirred mixture at 0 °C. The mixture was stirred at 0 °C for 1 h and at 5 °C overnight.
  • the sub-title compound was prepared from 3,5-dibenzyloxyacetophenone in accordance with the procedures in Example 12, Steps (d) and (e).
  • Acetyl chloride (2.1 mL, 2.3 g, 29.4 mmol) was added dropwise to a mixture of 2, 6-dichlorophenol (3.7 mL, 4 g, 24.5 mmol), Et 3 N (8.6 mL, 6.2 g, 61.3 mmol) and CH2CI2 (30 mL) at 0 °C.
  • the mixture was stirred at rt for 2.5 h, treated with Na2CC>3 (aq, sat) and extracted with CH2CI2.
  • the combined extracts were washed with brine, dried over Na2S0 4 and concentrated to give the sub-title compound (4.75 g, 23.1 mmol, 94 %).
  • Boc 2 0 (1.35 g, 6.2 mmol) and DMAP (51 mg, 0.4 mmol) was added to a solution of N,N- bis(te/f-butoxycarbonyl)-2,6-dichloro-4-acetylaniline (1.67 g, 4.1 mmol) in THF (20 mL) at rt.
  • the mixture was stirred at rt and four additional portions of B0C2O (1.35 g, 6.2 mmol) and DMAP (51 mg, 0.4 mmol) were added over 5 days.
  • the mixture was diluted with EtOAc and washed with citric acid (aq, 2 M). The phases were separated and the aq layer was extracted with EtOAc.
  • the sub-title compound was prepared from A/,A/-bis(te/f-butoxycarbonyl)-2,6-dichloro-4- (bromoacetyl)aniline and 2-aminopentane in accordance with the procedure in Example 12, Step (e). (e) 1-(4-Amino-3,5-dichlorophenyl)-2-(pentan-2-ylamino)ethan-1-ol trifluoroacetate
  • TFA (0.46 mL, 5.9 mmol) was added to a solution of A/,A/-bis(te/f-butoxycarbonyl)-2,6- dichloro-4-(1-hydroxy-2-(2-pentylamino)ethyl)aniline in CH2CI2 (4 mL) at rt.
  • the mixture was stirred at rt for 1 h and an additional portion of TFA (0.23 mL, 3.0 mmol) was added. After stirring at rt for 1 h, the mixture was concentrated and purified by chromatography to give the title compound (10 mg, 0.025 mmol, 17 %).
  • the compound is a 1 :1 mixture of diastereomers.
  • Example 31 1-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(pentan-2-ylamino)ethan- 1- o/
  • the title compound was prepared from 4-acetyl-2-chloro-6-trifluoromethylaniline and 2-aminopentane in accordance with the procedures in Example 29, Step (a), and Example 12, Step (e).
  • the compound is a 1 : 1 mixture of diastereomers.
  • MeMgBr (1 M in THF, 9.67 ml_, 9.67 mmol) was added to a solution of of 4-chloro-3- methoxybenzaldehyde (1.50 g, 8.79 mmol) in THF (10 ml_) at -78 °C. The mixture was stirred at -78 °C for 10 min and at rt for 3 h. NH 4 CI (aq, sat, 20 ml_) was carefully added and the mixture was extracted with EtOAc. The combined extracts were washed with H2O and brine, and dried over Na2S0 4 . Concentration and purification by chromatography gave the sub-title compound (1.10 g, 5.89 mmol, 67 %).
  • the title compound was prepared from 4-chloro-3-methoxybenzaldehyde and 2-aminopentane in accordance with the procedures in Example 32.
  • the compound is a 1 :1 mixture of diastereomers.
  • PdCl2(MeCN)2 (101.7 mg, 0.39 mmol) was added to a mixture of 2,6-difluoro-4-iodoaniline (2.0 g, 7.84 mmol), ZnO (830 mg, 10.2 mmol), Bu 4 NBr (3.79 g, 11.8 mmol), Et 3 N (372 ⁇ , 2.67 mmol) and DMSO (20 mL). The mixture was stirred at 100 °C for 16 h (not protected from air). EtzN (47.4 ⁇ , 0.34 mmol) was added and the mixture stirred for 6 h, cooled to rt, diluted with Et20 and washed with H2O.
  • L6- myoblasts were grown in Dulbecco's Modified Eagle's Medium (DMEM) containing 4,5 g/l glucose supplemented with 10% fetal bovine serum, 2 mM L-Glutamine, 50 U/ml penicillin, 50 ⁇ g/ml streptomycin and 10 mM HEPES. Cells were plated at 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 differentited into myotubes.
  • DMEM Dulbecco's Modified Eagle's Medium
  • Differentiated L6- myotubes were serum-starved overnight in medium containing 0,5 % fatty- acid free BSA and stimulated with agonist, final concentration 1x10 "5 . After 1 h 40 min cells were washed with warm, glucose free medium or PBS and another portion of agonist was added to glucose free medium. After 20 min the cells were exposed to 50 nM 3 H-2- deoxy- glucose for another 10 min before washed in ice cold glucose free medium or PBS and lysed in 0,2 M NaOH for 1 h in 60° C. Cell lysate was mixed with scintillation buffer (Emulsifier Safe, Perkin Elmer and radioactivity detected in a ⁇ -counter (Tri- Carb 2800TR, Perkin Elmer). The numerical values in the table are given as % increase over the basal level.
  • Differentiated cells were serum-starved overnight and stimulated with agonist, final concentration 1x10- 5 , for 15 min in stimulation buffer (HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, pH 7,4)
  • stimulation buffer HBSS supplemented with 1 % BSA, 5 mM HEPES and 1 mM IBMX, pH 7,4
  • the medium was then aspirated and to end the reaction 100 ⁇ _ of 95 % EtOH was added to each well of a 24- well plate and cells were kept in -20° C over night.
  • the EtOH was let to evaporate and 500 ⁇ _ of lysis buffer (1 % BSA, 5 mM HEPES and 0,3 % Tween- 20, pH 7,4) was added to each well before put in -80° C for 30 min and then kept in -20° C.
  • Intracellular cAMP levels were detected using an alpha screen cAMP kit (6760635D from Perkin Elmer). The numerical values in the table are given
  • Biological example 3 Effect of clenbuterol on liver lipid content 6 weeks old C57BI/6 mice (males and females) were put on a high-fat diet for 28 weeks. The mice were housed at thermoneutrality during the entire experiment. Treated mice were given 3 mg/L of clenbuterol in drinking water for 27 days. On the last experiment day the mice were fasted for 5 hours, killed by CO2, the heart was perfused with 10 ml of cold phosphate-buffered saline (PBS) and the liver were harvested cut in pieces and place in an Eppendorf tube containing isopentane and immediately dropped in liquid nitrogen. The tissues were kept at -80°C, until use.
  • PBS cold phosphate-buffered saline
  • BODIPY cell permeable lipophilic fluorescence dye
  • DAPI 4,6-diamidino-2-phenylindole

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Abstract

La présente invention concerne un composé de formule (I) ou un de ses sels de qualité pharmaceutique, pour utilisation dans le traitement d'une stéatose hépatique non alcoolique, telle que la stéatohépatite non alcoolique, formule (I) dans laquelle X, R1, R2, R3 et n sont tels que définis dans la description.
PCT/GB2018/052596 2017-09-13 2018-09-13 Bêta-hydroxyéthylamines pour utilisation dans le traitement ou la prévention des stéatoses hépatiques non alcooliques WO2019053428A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2023046882A1 (fr) * 2021-09-23 2023-03-30 Atrogi Ab Cyclohexyl bêta-hydroxy alkyl amines et leurs utilisations médicales

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2017049157A1 (fr) * 2015-09-18 2017-03-23 Duke University Méthodes et compositions pour le traitement de troubles associés à une stéatose

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Publication number Priority date Publication date Assignee Title
WO2017049157A1 (fr) * 2015-09-18 2017-03-23 Duke University Méthodes et compositions pour le traitement de troubles associés à une stéatose

Non-Patent Citations (1)

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Title
N W SHAPPELL ET AL: "Effects of clenbuterol on body stores of polychlorinated dibenzofurans (PCDF) and dibenzo-p-dioxins (PCDD) in rats 1,2 Introduction", ANIMAL SCIENCE J. ANIM. SCI, 1 January 2002 (2002-01-01), pages 2461 - 2475, XP055518492, Retrieved from the Internet <URL:https://pubag.nal.usda.gov/pubag/downloadPDF.xhtml?id=11764&content=PDF> *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023046882A1 (fr) * 2021-09-23 2023-03-30 Atrogi Ab Cyclohexyl bêta-hydroxy alkyl amines et leurs utilisations médicales

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