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WO2016001224A1 - Nouveaux activateurs de protéines kinases activées par l'amp - Google Patents

Nouveaux activateurs de protéines kinases activées par l'amp Download PDF

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WO2016001224A1
WO2016001224A1 PCT/EP2015/064848 EP2015064848W WO2016001224A1 WO 2016001224 A1 WO2016001224 A1 WO 2016001224A1 EP 2015064848 W EP2015064848 W EP 2015064848W WO 2016001224 A1 WO2016001224 A1 WO 2016001224A1
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salt
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Mathilde Muzerelle
Robert Lysek
Nathalie Bellocq
Marc Lang
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Debiopharm International SA
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Debiopharm International SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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

Definitions

  • Metabolic disorders such as diabetes, insulin resistance, dyslipidemia, hypertension, overweight, obesity, etc. are well recognized as factors increasing the cardiovascular risk.
  • diabetes is a complex metabolic disorder with many risk factors and implications.
  • hyperglycemia is the major risk factor for microvascular complications, and 70% to 80% of such patients will die of macrovascular disease.
  • Type 2 diabetes patients with atherogenic dyslipidemia which includes elevated plasma triglycerides, low HDL-C and a preponderance of small dense LDL particles, have a higher risk of atherosclerosis. Therefore, treatment of type 2 diabetes should address both hyperglycemia to prevent microvascular disease (such as retinopathy, neuropathy, nephropathy) and atherogenic dyslipidemia to prevent macrovascular complications (Reasner CA. J Cardiovasc Pharmacol. 2008, 52 (2): 136-44).
  • AMP-activated protein kinase acts as an intracellular metabolic sensor in a variety of ceils, where it monitors and responds to variations in the AMP:ATP ratio (Hardie et al, Annu. Rev. Biochem. 67:821-855, 1998). AMPK is switched on by any cellular stress that causes a rise in the AMP:ATP ratio, either by interfering with ATP production (e.g. hypoxia, glucose deprivation or ischemia), or increasing ATP consumption (e.g. muscle contraction) (Hardie DG, Ross FA, Hawley SA., Nat Rev Mol Cell Biol. 13(4):251-62, 2012).
  • ATP production e.g. hypoxia, glucose deprivation or ischemia
  • ATP consumption e.g. muscle contraction
  • AMPK Upon activation of AMPK, the enzyme phosphorylates a number of protein substrates to decrease further ATP usage by the ceil. Besides its function as a sensor of cellular energy status, AMPK also plays a critical role in the energy balance of the whole organism.
  • AMPK fatty acid synthesis in adipose cells, fatty acid and cholesterol synthesis as well as gluconeogenesis in liver
  • anabolic (biosynthetic) pathways fatty acid synthesis in adipose cells, fatty acid and cholesterol synthesis as well as gluconeogenesis in liver
  • AMPK may be involved in blood flow regulation through endothelial nitric oxide synthase stimulation (Buhl et al, Diabetes 2002, 51 , 2199-206).
  • AMPK is activated, for example, by hormones and cytokines, including leptin and adiponectin, which increase AMPK signalling.
  • AMPK activity is found in all tissues, including liver, kidney, muscle, lung, and brain (Cheung et al., Biochem. J. 346:659-669, 2000).
  • AMPK is a heterotrimeric complex consisting of a catalytic subunit (a) and two regulatory subunits ( ⁇ and ⁇ ).
  • the AMPK complex is evolutionarity conserved and can also be found in yeast and plants.
  • Mammalian AMPK is composed of different isoforms of subunits: ⁇ 1 , a2, ⁇ 1 , ⁇ 2, ⁇ 1 , y2, and ⁇ 3 (Hardie and Hawley, BioEssays 23:11 12-1 1 19, 2001) leading to 12 possible heterotrimeric combinations.
  • the a2 isoform is predominately found in skeletal and cardiac muscle AMPK; both the a1 and a2 isoforms are found in hepatic AMPK; while in pancreatic islet ⁇ -celts the a1 isoform AMPK predominates (Quentin T et al., Histol Histopathol. 201 1 , 26(5):589-96). While the ⁇ 1 isoform is abundant in rodent liver, the ⁇ 2 isoform is highly expressed in human liver and skeletal muscle (Wu J et al., Journal of Biological Chemistry 2013, 288, 50: 35904-12).
  • metformin activates AMPK by an indirect mechanism, i.e. inhibition of complex I of the respiratory chain (Owen MR et al. Biochemical Journal, 2000, 348, 607-614), suggesting that it may activate AMPK by increasing cellular AMP:ATP ratio.
  • Thiazolidinediones (TZD) can also activate AMPK by an indirect effect via the adiponectin release (Hardie DG. Annual Review of Pharmacology and Toxicology, 2007, 47: 185-210), which may account for many of the long term effects of TZD, and by an adiponectin-independent effect, probably the inhibition of complex I of the respiratory chain, and thus increase of cellular AMP:ATP ratio, as metformin does.
  • WO 2009/100130 A1 discloses 2,3-benzopyrrole derivatives acting as AMPK modulators.
  • the AMPK activity of the corresponding compounds was evaluated in vitro by phosphorylation of the amino-termina! fragment of human acetyl CoA carboxylase-type 1 , amino acids 1 -120.
  • US 2013/0184240 A1 describes a library of 3H-imidazolo[4,5-b]pyridines and 2,3-benzopyrroles. The activity of some compounds of US 2013/0184240 A1 was evaluated using a human AMPK ⁇ 1 ⁇ 1 ⁇ 1 as well as human AMPK ⁇ 2 ⁇ 2 ⁇ 1. Further examples of structurally similar compounds are disclosed in WO 2014/069426 A1 , Also this document primarily focusses on activation of AMPK ⁇ 2 ⁇ 2 ⁇ 1 as a target protein kinase.
  • WO 2014/031468 discloses a library of benzimidazole hexahydrofuro[3,2-b]furan derivatives for use as activators of AMP-protein kinases. Activation of human recombinant AMPK complex 1 (containing ⁇ 1 ⁇ 1 ⁇ 1) or AMPK complex 7 (containing ⁇ 2 ⁇ 1 ⁇ 1) for some of the disclosed compounds was tested in an in vitro AMPK activation assay.
  • the present invention aims to provide novel AMPK activators having a high activity towards human AMPK.
  • the first aspect of the present invention relates a compound of general Formula (I):
  • R2 is represented by Formula (II)
  • X is represented by -0-, -S-, -S ⁇ 0)-, -S(0)2- -NH- or -CH2-;
  • R3 and R 5 are independently represented by a hydrogen atom, a halogen atom, a hydroxyl group, or by one of the following: a C-j.g saturated aliphatic group, a Cj.g alkoxy group, a C- .Q alkylamino group, a C3.Q cycloalkoxy group, a 03.5 cycloalky!amino group, a
  • R 4 is an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one substituent selected from -OR 6 , -NHR 6 -NR 6 R 7 and -S(0)R 6 ; wherein if R 4 is an aliphatic or a heteroaliphatic group, the substituent selected from -OR 6 , -NHR 6 , -NR 6 R 7 , and -S(0)R 6 is directly linked to a primary carbon atom; and
  • R 4 is an aromatic or a heteroaromatic group, the substituent selected from -OR 6 ,
  • -NHR 6 , -NR 6 R 7 , and -S(0)R 6 is directly linked to a carbon atom or a heteroatom of the aromatic or heteroaromatic moiety;
  • R 1 , R 6 and R 7 are independently represented by a C-
  • a further aspect of the present invention relates to the use of the compound of general Formula (I) or a salt or solvate thereof for the treatment of a human or animal body, in particular, the present invention relates to the use of the compound of the general Formula (I) or a salt or a solvate thereof for use in the treatment or prophylaxis of a disorder responsive to AMPK activation.
  • the disorder responsive to AMPK activation is a metabolic disorder such as e.g. diabetes, dyslipidemia, hyperglycemia or hypertension.
  • compositions comprising a therapeutically effective amount of the compound of general Formula (I), or a salt or solvate thereof as active ingredient.
  • said pharmaceutical composition may be an oral dosage form.
  • the present invention relates to a compound of the general Formula (I):
  • the substituent R 2 possesses four stereogenic centres and, therefore, the Formula (II) describes 16 distinct stereoisomers. Accordingly, the compound of the present invention may be present in the form of a substantially pure stereoisomer or as a mixture of two or more diastereomers and/or enantiomers.
  • the substituent R 2 can be represented by the Formula (Ila):
  • the Formula (lla) describes 2 distinct stereoisomers.
  • the compound of the present invention may be present in the form of a substantially pure stereoisomer or as a mixture of two diastereomers.
  • the substituent R 2 is represented by the 1 ,4-3,6-dianhydromannitol residue i.e. by the Formula (lib):
  • the substituent X in the general Formula (I) can be represented by -0-, -S-, -S(O)- -S(0)2- -NH- or -CH2-
  • X in the general Formula (I) is represented by -0-, -S-, -NH- or -CH2-.
  • X in the general Formula (I) is represented by -0-.
  • the corresponding aromatic or heteroaromatic moiety comprising the substituents Y and Z may be a phenylene, a pyridinylene or a pyridazilene group.
  • the substituents R 3 and R 5 in the general Formula (I) are independently represented by a hydrogen atom, a halogen atom, a hydroxyl group, or by one of the following: a C-j .g saturated aliphatic group, a C-j.g alkoxy group, a C-j.g alkylamino group, a C ⁇ -Q cycloalkoxy group, a
  • halogen atom may refer to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a fluorine atom or a chlorine atom being particularly preferred.
  • saturated aliphatic group refers to a straight chain or a branched alkyi group, a cycloa!kyl group, an alkylcycloalkyl group or a cycloaikylalkyl group.
  • Cf-6 saturated aliphatic group includes C- ⁇ .g aikyl C3-6 cyc!oalkyl groups, C4..5 alkylcycloalkyl groups and C4. Q cycloalkyiaikyl groups.
  • C - ⁇ aikyl groups include but are not limited to methyl, ethyl, /i-propyl, /-propyl, n-butyl, sec. -butyl, ferf.-butyl, n-pentyl and n-hexyl groups.
  • the C-j.g aikyl group is a straight chain or branched aikyl group having 1 to 4 carbon atoms.
  • the term "Cf.g aikyl group” refers to methyl, ethyl or n-propyl.
  • C ⁇ Q cycloalkyl group may refer to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C4.Q alkylcycloalkyl group may, for instance, refer to a cyciopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl or to cyclopentylmethyi group.
  • a "C4.5 cycloalkylalkyi group" in the general Formula (I) may be represented inter alia by methylcyclopropy!, methylcyclobutyl or methylcyclopentyl groups, which may be (E) or (Z) isomers.
  • alkoxy refers to substituents comprising aikyl, cycloalkyl, alkylcycloalkyl and cycloalkylalkyi groups, respectively, singularly bonded to an oxygen atom.
  • alkylamino refers to substituents comprising aikyl, cycloalkyl, alkylcycloalkyl and cycloalkylalkyi groups, respectively, singularly bonded to -NH-.
  • the C ⁇ .Q saturated aliphatic group may be optionally substituted with at least one halogen atom.
  • the corresponding substituent may be a perfluorated C .Q alky! group such as, for instance, trifluoromethyi, pentafluoroethyl or n-heptafluoropropyl.
  • C ⁇ .g saturated aliphatic group optionally substituted with at least one halogen atom refers to a trifluoromethyi group.
  • the saturated aliphatic group may contain one or several heteroatoms such as O, S, N etc.
  • the term "saturated aliphatic group” includes substituents such as -CH2OCH3, -CH2 (CH3)2 etc.
  • R1 , R6 and R? in the general Formula (I) are independently represented by a C _Q saturated aliphatic group or by a hydrogen atom.
  • R R 6 and R 7 are hydrogen atoms or C ⁇ .g a!kyl groups, hydrogen atoms being particularly preferred.
  • R 4 may be an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one substituent selected from -OR 6 , a hydroxyl group, -NHR 6 -NR 6 R 7 and -S(0)R 6 .
  • the "aliphatic group” is non-aromatic moiety that may be saturated (e.g. only comprise single bond) or contain one or more units of unsaturation, (e.g. double and/or triple bonds).
  • An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen and may be substituted or unsubstituted.
  • the term "aliphatic group” as used herein includes alicyclic groups.
  • An aliphatic group preferably contains between about 1 and about 24 carbon atoms, more preferably between about 4 to about 24 carbon atoms, more preferably between about 4-12 carbon atoms, more typically between about 4 and about 8 carbon atoms.
  • the aliphatic group is a C-
  • heteroaliphatic group refers to a non-aromatic moiety containing at least one atom different from hydrogen and carbon.
  • the heteroaliphatic group may be saturated (e.g. only comprise single bond) or contain one or more units of unsaturation, (e.g. double and/or triple bonds).
  • the heteroaliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen and may be substituted or unsubstituted.
  • heteroaliphatic group as used herein includes heteroalicyclic groups.
  • a heteroaliphatic group preferably contains between about 1 and about 24 carbon atoms, more preferably between about 4 to about 24 carbon atoms, more preferably between about 4-12 carbon atoms, more typically between about 4 and about 8 carbon atoms.
  • heteroaliphatic groups include saturated 3 to 6- membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazotidiny!, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.
  • heteroaliphatic groups include inter alia optionally substituted pyrroiidino groups and an optionally substituted morpholino groups.
  • the aliphatic group or the heteroaliphatic group comprises at least one primary carbon atom which is substituted with at least one substituent selected from - OR 6 , -NHR 6 , -NR 6 R 7 , and -S(0)R 6 .
  • _s(0)R6 is directly bound to a methylene group.
  • aromatic group means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • the aromatic group may contain carbon and hydrogen atoms and may be substituted or unsubstituted.
  • aromatic group embraces aromatic substituents such as phenyl, naphthyl, and biphenyl. In a preferred embodiment, the term “aromatic group” refers to an optionally substituted phenyl group.
  • heteroatom group embrace partially unsaturated and unsaturated heteroatom-containing cyclic substituents, where the heteroatoms may be selected from nitrogen, sulphur and oxygen.
  • partially unsaturated heteroaromatic groups include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • Heteroaromatic groups may include a pentavalent nitrogen, such as in tetrazoiium and pyridinium radicals.
  • the term “heteroaromatic group” also embraces substituents where heteroaromatic moieties are fused with aryl or cycloalkyl moieties. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
  • heteromatic group further embraces unsaturated heteroatom-containing cyclic substituents.
  • unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrtdazinyl, triazolyl (e.g. 4/--1 ,2,4-triazolyl, f H-1 ,2,3-triazolyl, 2H-1 ,2,3- triazoiyi, etc.) tetrazolyt (e.g.
  • the aromatic or the heteroaromatic group is directly substituted by at least one substituent selected from -OR 6 , -NHR 6 , -NR 6 R 7 , and -S(0)R 6 .
  • at least one substituent selected from -OR 6 , -NHR 6 , -NR 6 R 7 , and -S(0)R 6 is directly bound to a carbon atom or to a heteroatom of the aromatic or heteroaromatic moiety of
  • R 4 bears at least one phenolic group, at least one aromatic amino group or at least one aromatic ether group.
  • the substituent R 4 in the general Formula (I) is substituted with at least one, preferably with at least two substituents selected from -OR 6 , a hydroxyl group, -NHR 6 , -NR 6 R 7 and -S(0)R 6 .
  • R 4 in the general Formula (!) may be substituted with at least one, preferably with at least two hydroxyl groups.
  • R 4 is an aromatic group substituted with at least one, preferably with at least two phenolic hydroxyl groups or a heteroaromatic group substituted with at least one, preferably with at least two hydroxy! groups.
  • the compounds of the present invention may also exist as several tautomeric forms.
  • R 4 is a pyridyi group substituted with one or several hydroxyl groups
  • R 4 and the corresponding compound of the Formula (I) may exist in a corresponding pyridone form.
  • AMPK ⁇ 2 activators and, in particular, activators of the ⁇ 2 ⁇ 2 ⁇ 1 AMPK isoform can be expected to have beneficial effects on glycemia and muscle insulin resistance. Accordingly, it is preferred that the compounds of the present invention act as potent AMPK ⁇ 2 activators and, in particular, as potent activators of the ⁇ 2 ⁇ 2 ⁇ 1 AMPK isoform.
  • the compounds represented by the general Formula (I) generally act as more potent activators of human AMPK, in particular as more potent activators of the isoform ⁇ 1 ⁇ 2 ⁇ 1 when compared to the corresponding compounds lacking a group selected from a hydroxyl group, -OR 6 , -NHR 6 , -NR 6 R 7 and -S(0)R 6 on R 4 .
  • the presence of at least one, preferably of least two hydroxyl groups on R 4 shows an advantageous impact on the activity of the compounds of the present invention. If R 4 is an aromatic or a heteroaromatic group, it may advantageously have at least one, preferably at least two phenolic hydroxyl groups. If R 4 is an aliphatic or a heteroaliphatic group, it can advantageously have at least one, preferably at least two primary alcoholic hydroxy! groups.
  • the compound of the present invention is represented by the general Formula (I), wherein
  • R1 is a hydrogen atom or a C ⁇ .Q alkyl group
  • R2 is represented by Formula (II)
  • R3 is a hydrogen atom, a halogen atom, a C-
  • X is represented by -0-, -S-, -NH- or -CH2-;
  • R 4 is an aliphatic, a heteroaliphatic, an aiicyciic, a heteroalicyclic, an aromatic or a heteroaromatic group, each being substituted with at least one hydroxyl group.
  • the compound of the present invention is represented by the general Formula (I), wherein
  • R1 is a hydrogen atom
  • R2 is represented by Formula (lla)
  • R3 is a hydrogen atom, or a halogen atom
  • R4 is an aromatic group substituted with at least one hydroxyl group or a heteroaromatic group substituted with at least one hydroxy! group
  • the compound of the present invention is represented by the general Formula (I), wherein
  • X is represented by -0-;
  • R2 is represented by Formula (li
  • R3 is a fluorine atom, a chlorine atom, or a hydrogen atom
  • R ⁇ is a substituted phenyl group being represented by Formula (III)
  • R ⁇ to R 1 2 are independently represented by substituents selected from the group consisting of a hydrogen atom, a hydroxyl group, a A/,A/-dimethylaminomethyl group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group.
  • the aromatic and heteroaromatic groups R ⁇ to R "12 may be substituted by at least one hydroxyl group or a di-C-i _Q-alkylamino group.
  • R ⁇ may be represented by e.g. one of the following Formulae (Ilia)
  • the compound of the present invention may be represented by the general Formula (I), wherein
  • X is -0-
  • R2 is represented by Formula (lib)
  • R3 is a fluorine atom, a chlorine atom or a hydrogen atom
  • R 4 is represented by one of Formulae (Va) to (Vf):
  • Y and Z are both represented by
  • Examples of the corresponding compounds include inter alia those represented by the following structures (17) to (29):
  • the compound of the present invention may be represented by the general Formula (I), wherein
  • X is represented by -0-;
  • R2 is represented by Formula (lib)
  • R3 is a fluorine atom, a chlorine atom or a hydrogen atom
  • R 4 is represented by one of Formulae (Vc), (Vd) or (Ve):
  • Preferred embodiments of the present invention include the following ⁇ 1 ⁇ to ⁇ 7 ⁇ : ⁇ 1 ⁇ A compound of general Formula (I)
  • X is represented by -0-, -S-, -S ⁇ 0)-, -S(0) 2 - -NH- or -CH2-;
  • R 3 are independently represented by a hydrogen atom, a halogen atom, a hydroxy! group, or by one of the following: a C-i_6 saturated aliphatic group, a C-1.5 alkoxy group, a C-j.g alkylamtno group, a C3.Q cycloalkoxy group, a C3.Q cycioalkylamino group, a C4.5 alkyicycloalkoxy group, a C4.5 alkylcycioalkylamino group, a C4.5 cycloaikylaikoxy group, or a C4.5 cycloaikylaikylamino group, each being optionally substituted with at least one halogen atom;
  • R 4 is an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one substituent selected from -OR 6 , -NHR 6 , -NR 6 R 7 , -S(0)R 6 , and -S(0) 2 R 6 ; and
  • Ri , R 6 and R 7 are independently represented by a C .Q saturated aliphatic group or by a hydrogen atom.
  • Ri is a hydrogen atom or a C ⁇ Q alkyl group
  • R2 is represented by Formula (II)
  • R3 is a hydrogen atom, a halogen atom, a C .Q a!kyl group being optionally substituted with at least one halogen atom, or a C ⁇ .g alkoxy group being optionally substituted with at least one halogen atom;
  • X is represented by -O- -S-, -NH- or -CH2-;
  • R 4 is an aliphatic, a heteroaliphatic, an aromatic or a heteroaromatic group, each being substituted with at least one hydroxyl group.
  • R 2 is represented by Formula (lla)
  • R3 is a hydrogen atom, or a halogen atom
  • R 4 is an aromatic group substituted with at least one hydroxyl group or a heteroaromatic group substituted with at least one hydroxyl group;
  • X is represented by ⁇ 0 ⁇ ;
  • R 2 is represented by Formula (lib)
  • R 3 is a fluorine atom, a chlorine atom, or a hydrogen atom
  • R4 is a substituted phenyl group ing represented by Formula (III)
  • R ⁇ to R ⁇ 2 are independently represented by substituents selected from the group consisting of a hydrogen atom, a hydroxy! group, a W,/V-dimethylaminomethyl group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group.
  • X is represented by -0-;
  • R2 is represented by Formula (Mb)
  • R 3 is a fluorine atom, a chlorine atom or a hydrogen atom; and represented by one of Formulae (Va) to (Vd):
  • R2 is represented by Formula (lib)
  • R3 is a fluorine atom, a chlorine atom or a hydrogen atom
  • R3 is a hydrogen atom, a halogen atom
  • R4 is represented by one of Formulae (Vc), (Vd) or (Ve):
  • a further aspect of the present invention relates to use of the compound of general Formula (I) or a salt or solvate thereof for the treatment of a human or animal body.
  • the present invention relates to the use of the compound of general Formula (I) or a salt or a solvate thereof for use in the treatment or prophylaxis of a disorder responsive to AMPK activation.
  • the present invention further relates to a method for treatment or prophylaxis of a disorder responsive to AMPK activation comprising administering a compound of general Formula (!) to a patient in need thereof.
  • AMPK activator refers to a compound that either increases the phosphorylation of downstream substrates of (phosphorylated or not) AMPK, and/or that increases the phosphorylation of AMPK, in particular of the human ⁇ 2 isoform.
  • a "direct AMPK activator” refers to a compound that activates AMPK via direct interaction with at least one of its subunits.
  • the compounds of the present invention are capable of activating 2-containing rA PK heterotrimers at EC 0 ⁇ 150 ⁇ and/or activating ⁇ 1 -containing rAMPK heterotrimers at
  • the compounds of the present invention are capable of activating ⁇ 2- ⁇ 3 ⁇ rAMPK heterotrimers at EC50 ⁇ 3000 nM and/or activating ⁇ 1 -containing rAMPK heterotrimers at EC50
  • the compounds of the present invention are capable of activating 2-containing rAMPK heterotrimers at EC50 ⁇ 150 nM and/or activating ⁇ 1 -containing rAMPK heterotrimers at EC 0 ⁇ 500 nM.
  • the corresponding in vitro recombinant human AMPK (rAMPK) activation assay is described in Example 2 below.
  • a disorder responsive to AMPK activation refers to a disorder, the symptoms of which would be alleviated, or the course of which would be beneficially modified, through activation of AMPK, including without limitation, metabolic disorder, diabetes, dyslipidemia and hypertension. Additionally, a “disorder responsive to AMPK activation” as used herein may be obesity, fatty liver disease, cardiovascular disease, inflammation and cancer.
  • diabetes includes insulin-dependent diabetes mellitus ⁇ i.e. !DDM, also known as type 1 diabetes), non-insulin-dependent diabetes mellitus ⁇ i.e. NIDDM, also known as type 2 diabetes), and pre-diabetes.
  • Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization.
  • Type 2 diabetes often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the type 2 diabetic patients are also overweighed or obese.
  • One of the criteria for diagnosing diabetes is the fasting plasma glucose level.
  • a diabetic subject has a fasting plasma glucose level of greater than or equal to 126 mg/dl.
  • a pre-diabetic subject is someone suffering from pre-diabetes. Pre-diabetes is characterized by an impaired fasting plasma glucose level of greater than or equal to 100 mg/dl and less than 126 mg/di; or impaired glucose tolerance; or insulin resistance.
  • a pre-diabetic subject is a subject with impaired fasting glucose (a fasting plasma glucose level of greater than or equal to 100 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (a 2-hour plasma glucose level of > 140 mg/dl and ⁇ 200 mg/dl); or insulin resistance, resulting in an increased risk of developing diabetes.
  • Dyslipidemia encompasses abnormal levels of any lipid fractions as well as specific lipoprotein abnormalities. For example, it refers to elevation of plasma cholesterol and/or elevation of triglycerides and/or elevation of free fatty acids and/or low high- density lipoprotein (HDL) level and/or high low-density lipoprotein (LDL) level and/or high very low-density lipoprotein (VLDL) level.
  • Dyslipidemia may for example contribute to the development of atherosclerosis and ultimately symptomatic vascular disease including coronary heart disease. Dyslipidemia may or may not be associated with diabetes.
  • metabolic disorder encompasses any abnormal chemical reaction disrupting normal metabolism, leading to excessive levels or deficiency of certain substances.
  • Non-limiting examples of metabolic disorders include diabetes, dyslipidemia, hypertension, overweight, obesity, and any combination thereof.
  • a "patient” refers to a mammal, preferably a human.
  • a further aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of general Formula (I), or a salt or solvate thereof as active ingredient.
  • said pharmaceutical composition may be an oral dosage form.
  • oral dosage form refers to any form of a pharmaceutical composition that is suitable for oral administration such as tablets, capsules and the like.
  • the salts of the compound of the general Formula (I) are salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, W,W-dibenzylethylenediamine, diethylamine, 2-diethyl- aminoethanol, 2-dimethylaminoethano, ethanolamine, ethylenediamine, W-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • pharmaceutically acceptable salf further includes all acceptable salts derived from acids such as quaternary salt, acetate, carbonate, carbamate, sulfonate, strong inorganic acids and the like.
  • pharmaceutically acceptable salts may be used for modifying the solubility or hydrolysis characteristics of a compound, or in sustained release formulations. It will be understood that, as used herein, references to the compound of Formula (I) are meant to also include the pharmaceutically acceptable salts.
  • the term “prophylaxis” means prohibiting, restraining, or inhibiting the incidence, occurrence or recurrence of a symptom, disorder, condition, or disease.
  • prevention of diabetes such as diabetes associated with obesity, refers to the administration of a compound of the present invention to prevent the onset of diabetes in a subject in need thereof.
  • a subject in need of preventing diabetes is, for example, a pre-diabetic subject that is overweight or obese.
  • the expression "therapeutically effective amount' means the amount of the compound of Formula (I) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Such response includes, in comparison with a non-treated tissue, system, animal or human; alleviation of the symptoms of the disorder being treated; improved treatment; prevention, elimination or reduction of progress of a disease, condition or disorder.
  • the expression "therapeutically effective amount' also encompasses the amounts which are effective for increasing normal physiological function, upon single or multiple administration of the compound.
  • the therapeutically effective amount can, for example, comprise an amount of about 0.1 to 30 mg/kg per single administration.
  • treating means slowing, stopping, reducing, alleviating or reversing the progression or severity of a symptom, disorder, condition or disease.
  • the compounds of Formula (I) present advantageous properties in decreasing fasting blood glucose, decreasing all fractions of liver lipids and improving circulating lipid profile. These properties can be beneficially used for treating or preventing a variety of disorders related to glucose and/or lipid metabolism in patients in need thereof. Compounds of Formula (I) are thus particularly advantageous as none of the currently available drugs directly affects all of these parameters. In addition, the combined effects of the compounds of structural Formula (I) could not be predicted from previously known structures.
  • the present invention further relates to uses of the compounds of Formula (I) in the treatment or prevention of disorders responsive to AMPK activation, such as metabolic disorders.
  • the present invention relates to the use or method of use of the compounds of Formula (I) in the treatment or prevention of diabetes.
  • the present invention relates to the use or method of use of the compounds of the present invention in the treatment or prevention of dyslipidemia. It is to be understood that prevention or treatment of several of these disorders may be combined while using the compounds of Formula (I).
  • the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as active ingredient, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, it relates to pharmaceutical compositions comprising a therapeutically effective amount of an ammonium salt, a calcium salt, a magnesium salt, a potassium salt or a sodium salt of compound of Formula (I) and a pharmaceutically acceptable carrier.
  • compositions of the present invention may comprise the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof in form of one or several polymorphs.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient, and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the pharmaceutically acceptable carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing the compound of Formula (I) and pharmaceutically acceptable excipients.
  • Any suitable route of administration may be employed for providing a patient, with an effective dosage of a compound of the present invention, including without limitation oral and parenteral (such as intravenous bolus or infusion, injection, intraperitoneal, subcutaneous or intramuscular administration).
  • oral and parenteral such as intravenous bolus or infusion, injection, intraperitoneal, subcutaneous or intramuscular administration.
  • compositions of the present invention that are suitable for oral administration (oral dosage forms) may be presented in solid or liquid form.
  • suitable solid oral dosage forms include discrete units such as capsules, pills, cachets, powders (such as effervescent), granules or tablets, and the like, each containing a predetermined amount of the compound of Formula (I) as active ingredient.
  • Suitable liquid oral dosage forms include solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions.
  • Pharmaceutical compositions of the present invention may also be in the form of sustained release formulations.
  • any inert ingredient that is commonly used as a carrier or diluent may be used in the formulations of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof.
  • a preferred diluent is microcrystaliine cellulose.
  • compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • a disintegrating agent e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • compositions of the present invention may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-ftowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent
  • each tablet, cachet or capsule contains from about 0.1 to 1 ,000 mg, particularly 0.1 , 0.2, 0.5, 1.0, 5, 10, 25, 50, 75, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 175, 180, 200, 225, 250, 300, 350, 400, 450, 500, 750 and 1 ,000 milligrams of the active ingredient, for the symptomatic adjustment of the dosage to the patient to be treated.
  • R 1 , R 2 , R 3 , R 4 , X, Y or Z have the meaning indicated under the Formula (i) unless expressly stated otherwise.
  • the compounds of Formula (I) may be prepared following the synthetic pathway described in the General Scheme 1 where each symbol has the same meaning as described earlier, Hal represents a halogen atom such as bromine or chlorine, PG represents a protecting group such as a SEM, PMP, Boc, Fmoc group and the B(W)2 group represents either a boronic acid or a boronic ester.
  • General Scheme 1 illustrates preparation of the compounds of Formula (I) in which ⁇ is a hydrogen atom.
  • the instant compound is generally isolated in the form of a pharmaceutically acceptable salt, such as those previously described herein, or of a solid.
  • MS mass spectra
  • Step 1 4'-Formyl-2',6'-dimethoxy-[1, 1'-biphenyl]-4-yl trifluoromethanesulfonate
  • Step 2 4'-((Dimethylamino)methyl)-2',6' ⁇ dimethoxy-[1, 1 '-biphenyt]-4-yl trifluoromethanesulfonate
  • reaction mixture was stirred for 6 h and cooled to 10 °C in an ice bath after which NaBH4 (352 mg, 9.24 mmol, 3.0 eq.) was added portion wise over a period of 30 min and the reaction mixture was stirred at RT for about 1 h. After this time, the reaction mixture was cooled to 0 °C and quenched with NH4OH solution
  • Step 3 4'-((Dimethylamino)methyl)-2',6'-dihydroxyl-[1, 1 '-biphenyl]-4-yl trifluoromethanesulfonate
  • BBr3 1.0 mL, 1.43 mmol, 6.0 eq.
  • Step 1 4'-Bromo-[1, 1 '-biphenyl]-2,6-diol
  • the compounds 1 - 6 and 17 - 18 of the present invention were assayed in vitro to determine their EC50 against five different rAMPK heterotrimers (two containing the ⁇ 1 subunit and three containing the ⁇ 2 subunit). As reference examples, the corresponding EC50 values were also determined for the compounds 31 - 37, which do not fall under the definition of the general Formula (I). The structures of the compounds 31 - 37 are shown below:
  • AMPK activity was measured by the phosphorylation at Ser79 of the amtno-terminal fragment of human acetyl CoA carboxylase-type 1 , amino acids 1 -120 (ACC1/1-120). The fragment was expressed as a biotinylated fusion protein in E. colt. Human rAMPK genes were expressed in the monkey COS7 ceil expression system. The compounds were tested in triplicate at one or both of the following concentration ranges (pM): (A) 45, 15, 5, 1.67, 0.56, 0.185, 0.06, 0.02 and 0.00685, or (B) 1.67, 0.56, 0.185, 0.06, 0.02, 0.00685, 0.002286, 0.0007621 and 0.000254.
  • concentration ranges pM
  • the enzyme assay was conducted in a 5 pL reaction mixture containing compounds of Formula (I) at the indicated concentrations in 80 mM HEPES, pH 7.0, 160 mM NaCI, 2.5 mM MgCl2,
  • the reaction mixture was further incubated overnight at room temperature and analyzed on a Perkin Elmer Fusion-Alpha microplate analyzer.
  • the AlphaScreen readout for this assay is based on an excitation with laser-stimulated visible light at 680 nm and emission at 520-620 nm.
  • EC50 is calculated with the GraphPadPrism software and is defined as the compound concentration at which the half maximum rAMPK activation is reached.
  • the fold activation equals the ratio of the maximum rAMPK activation that is reached at any compound concentration divided by the rAMPK activation obtained in the absence of compound.
  • HepG2 cells ATCC, HB-8065
  • MEM Minimum Essential Medium with GlutaMAXTM
  • FBS heat inactivated fetal bovine serum
  • Peptomycin Gibco, 15070-063
  • HepG2 cells were then seeded in 96 well tissue culture plates (Jet Biofil, TCP01 1096) at 40,000 cells/well or, in other cases, 60,000 cells/well in complete medium, incubated 1 hour at room temperature and grown overnight at 37 °C and 5% CO2. The day after, complete medium was removed and cells were rinsed once with PBS 1x (Gibco, 7001 -036) supplemented with 10% FBS for 15 minutes prior to treatment.
  • PBS 1x Gibco, 7001 -036
  • C2C12 myoblasts (ATCC, CRL- 772) at 0.7 x 10 6 cells/mL were thawed in a
  • DMEM Dulbecco's Modified Eagle Medium with high glucose and pyruvate
  • FBS heat inactivated fetal bovine serum
  • penicillin 50 units/mL of penicillin and 50 pg/mL of streptomycin (Gibco, 15070- 063) in a humidified atmosphere of 95% air and 5% CO2 at 37 °C for 7 days, by changing complete medium and splitting cells three times a week.
  • C2C12 myoblasts were then seeded in 96 well tissue culture plates (Jet Biofil, TCP011096) at 30,000 cells/well or, in other cases, 45,000 cells/well in complete medium, incubated 1 hour at room temperature and grown overnight at 37 °C and 5% CO2.
  • the differentiation medium was replaced 3 days after and then every day. After 6 days differentiation, medium was removed and cells were rinsed once with Hank's balanced salt solution (HBSS; Gibco, 14025-050) for 15 minutes prior to treatment.
  • HBSS Hank's balanced salt solution
  • Cells were treated in triplicate with increasing concentrations of compound (tested ranges of concentrations were 0.01 , 0.03, 0.1 , 0.3, 1 , 3, 10, 30, 100, 300, 1000 ⁇ , and vehicle (2% DMSO) for control cells, in PBS 1x supplemented with 10% FBS (for HepG2) or HBSS (for C2C12).
  • concentrations were employed: 0.001 , 0.003, 0.01 , 0.03, 0.1 , 0.3, 1 , 3, 10, 30, 100 ⁇ .
  • ice-cold cell lysis buffer 1x (20 mM Tris-HCi (pH 7.5), 150 mM NaCI, 1 mM Na2EDTA, 1 mM EGTA, 1 % Triton, 2.5 mM sodium pyrophosphate, 1 mM beta- glycerophosphate, 1 mM Na3V04, 1 ⁇ g/ml leupeptin; Cell Signaling Technology, 9803) freshly supplemented with protease inhibitors 1x (Thermo Scientific, 78437) was added. Cells were lysed by incubation on ice for 10 minutes.
  • Celt lysates obtained were used for AMPK activity analysis by direct measurement of the level of phosphorylation of the AMPK substrate acetyl-CoA carboxylase (ACC) on Ser79 by using the bead-based assay technology Alphascreen® (Amplified Luminescent Proximity Homogeneous Assay).
  • ACC acetyl-CoA carboxylase
  • This assay approach takes advantage of the biotin group which is found naturally conjugated to ACC.
  • the reaction mixture was incubated overnight (approx. 16 hours) at room temperature in the dark. After overnight incubation, quantification of ACC phosphorylation was achieved by reading plates with an Alpha-enabled, p!ate multimode reader (Perkin Elmer, EnSpire, 2300-001 M), with an excitation at 680 nm and reading emission at 520-620 nm.
  • Nonlinear regression analysis was used to calculate relative EC50 for each compound by using GraphPad Prism software
  • Compounds 1 - 4 of the present invention are particularly efficient activators of at least five human rAMPK heterotrimers. They have been shown to have an EC50 equal or less than 135 nM on at least three 2-containing heterotrimers and an EC50 equal or less than 479 nM on at least two ⁇ 1 -containing heterotrimers. Furthermore, compounds 1 - 4 of the present invention activate AMPK expressed by celts, with an EC50 equai or less than 14.1 ⁇ in HepG2 cells and an EC50 equal or less than 10.1 ⁇ in C2C12 celts.
  • the compounds 31 - 37 i.e. compounds lacking R 4 with at least one substituent selected from a hydroxyl group, -NHR6 -NR6R7 and -S(0)R6, showed significantly higher values of EC50 for the corresponding isoforms. Thus, the activity of these compounds was considerably lower.
  • the collected data indicate that e.g. a replacement of the morpholine moiety in the compound 32 (Comparative Example) by a substituent R 4 having at least one, preferably at least two hydroxyl groups (cf. e.g. Compound 2) allows a significant improvement of the activity.
  • ADMET properties of selected compounds of the present invention were investigated using a prediction model. Thus, in the following, so called eADMET values are given.
  • the compounds of the present invention display advantageous ADMET properties.

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Abstract

La présente invention concerne un composé de formule structurelle (I) ou un sel de celui-ci, qui est utile en tant qu'activateur direct de l'AMPK. Un autre aspect de la présente invention concerne l'utilisation dudit composé pour le traitement de maladies associées à l'AMPK et une composition pharmaceutique contenant ledit composé.
PCT/EP2015/064848 2014-06-30 2015-06-30 Nouveaux activateurs de protéines kinases activées par l'amp Ceased WO2016001224A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9980948B2 (en) 2014-08-27 2018-05-29 Shionogi & Co., Ltd. Azaindole derivative having AMPK-activating activity
US10478425B2 (en) 2016-02-26 2019-11-19 Shionogi & Co., Ltd. 5-phenylazaindole derivative having AMPK-activating activity
WO2021263039A1 (fr) * 2020-06-26 2021-12-30 Kallyope, Inc. Activateurs d'ampk
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012116145A1 (fr) * 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014031468A1 (fr) * 2012-08-22 2014-02-27 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole hexahydrofuro[3,2-b] furane
WO2014069426A1 (fr) * 2012-10-31 2014-05-08 塩野義製薬株式会社 Benzimidazole ayant pour effet d'activer l'ampk et dérivé d'azabenzimidazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012116145A1 (fr) * 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014031468A1 (fr) * 2012-08-22 2014-02-27 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole hexahydrofuro[3,2-b] furane
WO2014069426A1 (fr) * 2012-10-31 2014-05-08 塩野義製薬株式会社 Benzimidazole ayant pour effet d'activer l'ampk et dérivé d'azabenzimidazole

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9980948B2 (en) 2014-08-27 2018-05-29 Shionogi & Co., Ltd. Azaindole derivative having AMPK-activating activity
US10478425B2 (en) 2016-02-26 2019-11-19 Shionogi & Co., Ltd. 5-phenylazaindole derivative having AMPK-activating activity
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
WO2021263039A1 (fr) * 2020-06-26 2021-12-30 Kallyope, Inc. Activateurs d'ampk
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
CN116390925A (zh) * 2020-06-26 2023-07-04 卡尔优普公司 Ampk活化剂
JP2023531726A (ja) * 2020-06-26 2023-07-25 キャリーオペ，インク． Ａｍｐｋアクチベーター
EP4172162A4 (fr) * 2020-06-26 2024-08-07 Kallyope, Inc. Activateurs d'ampk

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