WO2018189679A1 - Dérivés d'isoindoline destinés à être utilisés en tant qu'activateurs d'ampk - Google Patents

Dérivés d'isoindoline destinés à être utilisés en tant qu'activateurs d'ampk Download PDF

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Publication number
WO2018189679A1
WO2018189679A1 PCT/IB2018/052509 IB2018052509W WO2018189679A1 WO 2018189679 A1 WO2018189679 A1 WO 2018189679A1 IB 2018052509 W IB2018052509 W IB 2018052509W WO 2018189679 A1 WO2018189679 A1 WO 2018189679A1
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WO
WIPO (PCT)
Prior art keywords
dioxoisoindolin
cyanomethyl
benzamide
carboxamide
biphenyl
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PCT/IB2018/052509
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English (en)
Inventor
Edoardo PAOLINI
Luca QUATTRINI
Vito COVIELLO
Luca ANTONIOLI
Matteo FORNAI
Corrado Blandizzi
Won Keun Oh
Concettina LA MOTTA
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Universita' Di Pisa
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Publication date
Application filed by Universita' Di Pisa filed Critical Universita' Di Pisa
Publication of WO2018189679A1 publication Critical patent/WO2018189679A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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

  • the present invention relates in general to the pharmaceutical field, and more precisely it refers to isoindoline derivatives of formula (I) reported in the following, that are activators of an enzymatic complex, the protein kinase activated by adenosine monophosphate (abbreviated in the following as AMPK, acronym for the whole English term 5' Adenosine MonoPhosphate-activated protein Kinase). They are useful for the prophylaxis and treatment of metabolic disorders, such as diabetes and obesity, and of immune-mediated inflammatory diseases and cancer.
  • AMPK adenosine monophosphate
  • the present invention also relates to a process for the preparation of these compounds.
  • AMPK is a heterotrimeric kinase of the serine / threonine kinase family, known to be involved in the regulation of metabolic pathways of the energy demand / consumption, and plays a key role in maintaining adequate levels of ATP in the cells in conditions that deplete these levels, such as exercise, hunger, hypoxia and rapid cell growth.
  • the AMPK kinase activates the pathways that generate ATP, such as glucose transport in muscles, fatty acid oxidation, and autophagy, while inhibiting the pathways consuming ATP, such as the synthesis of cholesterol and fatty acids, and the protein synthesis.
  • the AMPK enzyme complex is also known to regulate co-activators and transcription factors such as PGC1a, FOXO proteins, HDAC, p300 and CREB. It moreover regulates the activity of another key metabolic element, mTOR, with which it allows cells to respond appropriately to metabolic stress and to regulate cell growth and differentiation, as well as autophagy.
  • this enzymatic complex represents a very attractive target for the treatment of various metabolic diseases.
  • the discovery that physical activity activates AMPK in skeletal muscles leading to increased glucose uptake indicates a therapeutic potential of compounds that are AMPK activators to treat type 2 diabetes.
  • AMPK activators to treat type 2 diabetes.
  • a reduced AMPK activity in adipose tissue was observed, together with an increased expression of genes associated with inflammation compared to what was observed in control subjects, suggesting also in this case that a reduced activity of AMPK could play a role in the causes of the disease.
  • AMPK Activation of AMPK in hepatic and adipose tissue modulates different biochemical pathways that balance lipogenesis and lipolysis to maintain ATP.
  • the enzyme complex AMPK inhibits the lipid synthesis through the phosphorylation and inhibition of ACC1 and HMG-CoA reductase, together with the transcriptional regulation of lipogenic transcription factors involved in the synthesis of fatty acids and cholesterol, SREBP-1C and SREBP-2, respectively.
  • this enzyme complex critically contributes to the modulation of immune / inflammatory cell functions (i.e. macrophages, neutrophils, lymphocytes, dendritic cells), such as the production of cytokines, chemotaxis, cytotoxicity, apoptosis and proliferation.
  • immune / inflammatory cell functions i.e. macrophages, neutrophils, lymphocytes, dendritic cells
  • AMPK AMPK-mediated inflammatory diseases characterized by abnormal functions of immune cells, such as psoriasis, inflammatory bowel disease, rheumatoid arthritis, atherosclerosis and some neurodegenerative diseases (i.e. of Huntington, Alzheimer's syndrome and Parkinson's disease), thus confirming the relevance of this protein in the modulation of immune / inflammatory responses.
  • the AMPK enzyme complex is also involved in blocking carcinogenesis, by counteracting most of the metabolic changes that occur in rapidly proliferating cells by acting on their metabolic state.
  • AMPK can rightly be considered a relevant molecular target for the treatment of metabolic diseases, including type 2 diabetes and obesity, as well as of immune-mediated inflammatory diseases and cancer, thus making strongly felt the need to provide powerful and effective AMPK activator compounds.
  • AICAR adenosine analogue 5-aminoimidazole-4-carboxamide riboside
  • AMPK activators have also been described, the thienopyridone derivative A769662 developed by Abbott Laboratories, and the benzoimidazole derivative 991 developed by Merck Sharp and Dohme. They both bind to the allosteric binding site for drug and metabolite (ADaM) of AMPK, therefore they do not work in the presence of mutations in the enzyme AMPK complex that stabilize the ADaM site. Furthermore, both these compounds are characterized by a modest oral bioavailability.
  • ADaM drug and metabolite
  • a further product developed by Metabasis Pharmaceutics as a direct activator of AMPK is the isoxazolyl-furan-2-phosphonic acid C2 that promotes the activity of AMPK mimicking AMP.
  • this product does not meet the requirements for the development of an effective drug: because of its high hydrophilicity, the cell walls are in fact impermeable to C2, which has already been set aside in favour of one of its prodrugs, the corresponding isopropyl phosphoester C13, which exhibits better bioavailability.
  • derivatives having a isoindoline-1 ,3-dionic nucleus are able to significantly stimulate the AMPK enzymatic complex activity, involved in particular, as illustrated above, in the regulation of metabolic pathways for the production and consumption of cellular energy.
  • A is selected from the group consisting of C1-C6 alkyl, cyano C1-C4 alkyl, aryl, heteroaryl, heterocycle, aryl C1-C4 alkyl, heteroaryl C1-C4 alkyl, and heterocycle C1- C4 alkyl, wherein each aryl, heteroaryl or heterocycle group is optionally substituted with one or more substituents, equal or different from each other and selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, methoxy, hydroxy, methyl- thio, mercapto, amino, carboxy, formyl, carbamoyl, alkylcarbonyl, arylcarbonyl, sulphamoyl, alkylamido, arylamido, alkylureido, arylureido, alkylsulphonamido, arylsulphonamido, aryl, heteroaryl, and heterocycle;
  • B is absent or is selected from among O, S, SO, S02, NH, and N(H)CO;
  • R is selected from the group consisting of aryl, heteroaryl, heterocycle, wherein each aryl, heteroaryl or heterocycle group is optionally substituted by one or more substituents equal or different between each other and selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, methoxy, hydroxy, methyl-thio, mercapto, amino, carboxy, formyl, carbamoyl, alkylcarbonyl, arylcarbonyl, sulphamoyl, alkylamido, arylamido, alkylureido, arylureido, alkylsulphonamido, arylsulphonamido, aryl, heteroaryl, and heterocycle,
  • AMPK enzymatic complex for use in the prophylaxis and treatment of diseases or disorders that benefit from activation of the AMPK enzymatic complex, for example metabolic disorders, such as diabetes and obesity, immune-mediated inflammatory pathologies and cancer.
  • FIG. 1 illustrates the level of activation of AMPK in the C2C12 cell line after 30 minutes of exposure to the isoindoline-1 ,3-dionic compound 1 obtained as disclosed in Example 2 below and to berberine (BBR), reference compound, both tested at concentration 10 microM;
  • FIG. 2 illustrates the level of AMPK activation in the C2C12 cell line after 30 minutes of exposure to isoindoline-1 ,3-dionic compounds 1 and 25 described below, tested at concentration 20 microM, and to acadesine (ACA), reference compound, tested at concentration 200 microM.
  • ACA acadesine
  • halogen refers to fluorine, chloro, bromo or iodo, if not defined otherwise.
  • alkyl refers to a monovalent saturated hydrocarbon radical bearing a linear or branched residue, if not indicated otherwise.
  • the "alkyl” group in the present invention when consisting of 2 or more carbon atoms, may comprise double or triple carbon-carbon bonds or, when consisting of 3 or more carbon atoms, may form cyclic residues.
  • aryl refers to a cyclic or bicyclic aromatic group, consisting of a minimum of 6 to a maximum of 10 carbon atoms, for example phenyl or naphthyl, except differently defined.
  • heteroaryl and heterocycle refer respectively to heteroaromatic compounds and to non-aromatic heterocyclic compounds, formed by a minimum of 5 to a maximum of 12 members and containing from 1 to 3 heteroatoms, selected from the group consisting of N, O, S, SO and S02.
  • the term "pharmaceutically acceptable salt” refers to derivatives of the isoindoline-1 ,3-dionic compounds of general formula (I) wherein the compound has been suitably modified by conversion of any basic or acid group, if present, into the corresponding addition salt with any acid or base conventionally considered as acceptable for pharmaceutical uses.
  • the isoindoline-1 ,3- dionic derivatives for use have general formula (I) wherein A is cyanomethyl, B is N(H)CO and R is phenyl optionally substituted with one or more substituents selected from hydroxy or methoxy.
  • Non-limitative examples of isoindoline-1 ,3-dionic derivatives of general formula (I) for the use according to the present invention are selected from the following:
  • step i) the starting reagent 5-aminoisoindoline-1 ,3-dione of formula (II) is converted into the desired compounds of general formula (I) according to the different alternative procedures of step i) illustrated in the Scheme 1 below as a), b), c) and d) wherein the amino group on the benzo- fused ring can be functionalized or converted into hydroxyl or sulfhydryl, as explained above, depending on the kind of spacer B and of substituent R that is wanted in compounds (I), before alkylation at the isoindoline nitrogen on position 2 of the ring.
  • step ii' second step of alkylation at the isoindoline nitrogen, wherein the benzamidic derivative obtained in step i') is converted into the compound of general formula
  • the 5-aminoisoindoline- 1 ,3-dione of formula (II), a commercial product is reacted preferably with an amount of benzoylchloride in the presence of a base, such as trimethylamine in the solvent toluene, to form the N-(1 ,3-dioxoisoindolin-5-yl)benzamide of formula (IV), following a procedure previously disclosed in the literature (Zhou, W. et al. MedChemComm, 2016, 7(2), 292-296).
  • the N-(1 ,3- dioxoisoindolin-5-yl)benzamide of formula (IV) is converted into the activator of AMPK having formula (I) by reaction with an amount of chloroacetonitrile in the presence of a base, such as potassium carbonate in solvent DMF, to form N-(2-(cyanomethyl)-1 ,3- dioxoisoindolin-5-yl)benzamide.
  • a base such as potassium carbonate in solvent DMF
  • the compounds of general formula (I) defined above according to the invention are useful in the prophylaxis and/or treatment of diseases or disorders that benefit from the activation of the enzymatic complex AMPK, in particular metabolic diseases, immuno-mediated inflammatory diseases and cancer. They can be used, alone or in combination of two or more compounds, in pharmaceutical compositions with pharmaceutically acceptable vehicles, excipients and/or diluents, and possible further active principles having known activity, such as antidiabetic agents, anti-inflammatory agents, and anticancer agents, chemotherapeutic or not-chemotherapeutic agents, in order to increase their therapeutic efficacy.
  • the present compounds can be present in the compositions as such or in the form of pharmaceutically acceptable salts.
  • compositions can be formulated in various pharmaceutical forms, for different administration routes, for example as oral, topical or injectable compositions, according to the conventional methods, in the form of tablets, granules, powder, capsules, syrup, aqueous solution, aqueous suspension, oily solution, oily suspension, emulsion or microemulsion, to be used for the oral, intramuscular, intravenous, subcutaneous or topical administration.
  • TLC Thin Layer Chromatography
  • Example 3 Preparation of 4-chloro-N-(1,3-dioxoisoindolin-5-yl)benzamide 1.00 mmol of 5-aminoisoindoline-1 ,3-dione, commercial product, was solubilized in 1.0 ml_ of toluene and added with 1.20 mmol of commercial 4- chlorobenzoylchloride and 1.20 mmol of triethylamine, then heated at reflux for 10 hours. After cooling, the solid that separates was collected by filtration, dried under vacuum and purified by crystallization in methanol. 285.5 mg of the desired product of the title were so obtained (yield 95%). It was characterized by chemical-physical and spectroscopical data. M.p.
  • the functional efficacy of the present isoindoline-1 ,3-dionic derivatives of general formula (I) was verified by in vitro assays, carried out on cell lines of C2C12 murine myoblasts. The cells were treated with the isoindoline-1 ,3-dionic derivatives under examination, used at concentration of 10 microM. After 30 minutes, the level of phosphorylation of the AMPK protein at the Thr172 residue was determined, using the Western Blot method. The results obtained, expressed in terms of ratio between the phosphorylated protein and the native protein, were compared with the analogous data acquired in the presence of berberine (BBR), an AMPK activator of natural origin used as reference product.
  • BBR berberine
  • Figure 1 illustrates the level of activation of AMPK in the C2C12 cell line after 30 minutes of exposure to the isoindoline-1 ,3-dionic compound 1 obtained as described above in Example 2 and to berberine, reference product, both tested at concentration of 10 microM.
  • Figure 2 illustrates the level of AMPK activation in the C2C12 cell line after 30 minutes of exposure to the isoindoline-1 ,3-dionic derivatives 1 and 25 obtained as described above in Examples 2 and 4, tested at concentration of 20 microM, and by comparison to acadesine (ACA), only AMPK agonist product put on the market until today, tested at concentration of 0.2 milliM.
  • the tested isoindoline-1 ,3-dionic derivatives 1 and 25 significantly activate the target protein with respect to the vehicle group and they do not show a significantly different efficacy with respect to the reference product ACA, which was however used at a concentration 10 times higher than the derivatives tested.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des dérivés d'isoindoline-1,3-dionique, capables d'activer de manière efficace le complexe enzymatique AMPK, et qui sont destinés à être utilisés dans la prophylaxie et le traitement thérapeutique de maladies et de troubles en particulier des troubles métaboliques, tels que le diabète et l'obésité, les pathologies inflammatoires à médiation immunitaire et le cancer.
PCT/IB2018/052509 2017-04-10 2018-04-10 Dérivés d'isoindoline destinés à être utilisés en tant qu'activateurs d'ampk WO2018189679A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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