WO2019162911A1 - Activateurs fnew de l'enzyme sirt1 pour le traitement de pathologies cardiovasculaires et cardiométaboliques - Google Patents

Activateurs fnew de l'enzyme sirt1 pour le traitement de pathologies cardiovasculaires et cardiométaboliques Download PDF

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WO2019162911A1
WO2019162911A1 PCT/IB2019/051489 IB2019051489W WO2019162911A1 WO 2019162911 A1 WO2019162911 A1 WO 2019162911A1 IB 2019051489 W IB2019051489 W IB 2019051489W WO 2019162911 A1 WO2019162911 A1 WO 2019162911A1
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nmr
ppm
jax
yield
ddd
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WO2019162911A8 (fr
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Vincenzo Calderone
Filippo Minutolo
Tiziano Tuccinardi
Lara TESTAI
Carlotta Granchi
Alma MARTELLI
Valentina CITI
Virginia DE LORENZO GARDINAL
Giulia LENZI
Francesca LEO
Giulia MALLOGGI
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Universita' Di Pisa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
    • C07C215/82—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of another six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
    • C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/295—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • This invention describes a class of compounds able to activate the human SIRT1 enzyme and regulate many metabolic functions.
  • This invention relates to compounds that can be employed in medical applications, specifically for the treatment or prevention of cardiometabolic diseases, such as diabetes, and of cardiovascular disorders, such as coronaropathy, heart failure and atherosclerosis.
  • Sirtuins are a conserved family of deacetylase enzymes deeply involved in cellular physiological processes. To date, seven types of enzymes have been described, classified from SIRT1 to SIRT7 on the basis of their different cellular localization. SIRT1 is biosynthesized in the nucleus and - on the basis of cellular needs - transferred into the cytosol through a shuttling system. In the cytosol SIRT1 , influences mitochondrial activity and the metabolism of the whole cell through the modulation of different transcription cofactors which are essential for the maintenance of cellular homeostasis.
  • SIRT1 was first described in the yeast Saccharomyces cerevisiae and then in worms and flies, where it modulates the lifespan.
  • the reduction of SIRT 1 expression / activity due to physiological aging and also observed in mammals, may explain the worsening of age-related cellular functions and may be linked to cardiovascular and non-cardiovascular pathologies.
  • Recent studies have shown that SIRT 1 is less effective in patients with heart failure and coronary heart disease; furthermore, pre-clinical studies have demonstrated that SIRT1 activity is reduced after ischemia-reperfusion injury.
  • SIRT1 is also involved in insulin resistance, suggesting that it may represent a novel and interesting target in the management of type II diabetes mellitus.
  • Cardiovascular diseases are still today the main cause of morbidity and mortality in Western countries and aging represents one of the main risk factors.
  • resveratrol represents the reference activator of SIRT1 .
  • SRT501 polyphenol microemulsion formulations
  • SRT1720 is one of the most studied compounds: it has shown to be able to prolong life expectancy, control glucose homeostasis in different animal models of diabetes and protect the myocardium from ischemia / reperfusion injury.
  • SRT2104 is a very promising SIRT1 activator, as it showed high tolerability when administered for 28 days to elderly volunteers; moreover, an assessment of its pharmacodynamic profile in humans gave promising results in respect of lipid parameters.
  • the compound SRT2104 is well tolerated by diabetic patients and promotes a reduction in body weight; however, it exerts no significant cardiometabolic and vascular effect.
  • the compound SRT3025 another SIRT1 activator, has also been included in a phase I clinical trial; however, the prolongation of the QT interval (time of depolarization and repolarization of the ventricular cells) that was observed discouraged the researchers and no further study was conducted.
  • SIRT1 plays a key role in the regulation of cellular physiological processes, there is a great interest in identifying and developing novel SIRT1 activators to be employed in the treatment/prevention of cardiovascular diseases. Such compounds may provide novel ways to treat age-related diseases.
  • the compounds covered by this patent have been developed with the aim of improving the activity, selectivity and bioavailability of the SIRT1 activators discovered so far, and our preliminary data confirm their potential usefulness as SIRT1 activators. Indeed, novel molecules have been synthetized and they have shown SIRT1 activating properties; some of these compounds have been found to be more potent than resveratrol. Furthermore, they have shown interesting cardioprotective properties in an experimental model of acute myocardial infarction.
  • This invention relates to a compound having the structural formula (I):
  • R1 , R2, R3 e R4 are independently selected from -OFI and -H;
  • X is selected from: -NH, O, S;
  • R5 is selected from among the following groups:
  • R6 is selected from -H or a non-substituted phenyl group
  • R2 and R3 are never simultaneously -OH.
  • the compound of this invention is used as a medicament for the treatment or prevention of ischemic pathologies, cardio-metabolic pathologies, including diabetes, and cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
  • Figure 1 shows the effects of compounds 1 -36 on SIRT1 ; data are expressed as a % vs resveratrol.
  • Figure 2 shows the effects of different concentrations of compounds 14-17 on SIRT1 ; data are expressed as a % vs resveratrol.
  • Figure 3 shows the effects of compounds 14 and 15 in reducing the ischemic area after an ischemia/reperfusion injury. Ischemic areas are expressed as a % of the whole left ventricle area.
  • This invention relates to a compound having the structural formula (I):
  • R1 , R2, R3 e R4 are independently selected from -OH and -H;
  • X is selected from: -NH, O, S;
  • R5 is selected from among the following groups:
  • R6 is selected from -H or a non-substituted phenyl group
  • R2 and R3 are never simultaneously -OH.
  • X is selected from -NH and -O.
  • X is -NH
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is selected from -NH and -O and R5 is
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is selected from the groups: In one embodiment of the invention, R1 , R2, R3 and R4 are independently selected from -OH and -H, X is selected from -O and -NH and R5 is
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is
  • R1 , R2, R3 and R4 are independently
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -S and R5 is
  • R1 , R2, R3 and R4 are independently
  • R1 , R2, R3 and R4 are independently
  • the compound according to this invention is selected from:
  • the compounds of the invention activate the SIRT1 enzyme and regulate cell metabolism and the transcription of numerous factors that are important for cell survival.
  • the compounds are capable of activating the SIRT1 enzyme and favoring cell survival following an insult, for example following an ischemic insult.
  • a further aspect of this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the invention and pharmaceutically acceptable excipients, adjuvants and/or carriers.
  • the pharmaceutical composition is formulated for enteral use, preferably oral or sublingual; for example, the composition is prepared in the form of pills, capsules, tablets, granular powder, hard-shelled capsules, orally dissolving granules, sachets or lozenges.
  • the pharmaceutical composition is formulated for parenteral use, for example intravenous, subcutaneous or intramuscular, preferably intravenous.
  • parenteral use for example intravenous, subcutaneous or intramuscular, preferably intravenous.
  • a further aspect of this invention relates to the compound as described above or the pharmaceutical composition comprising the compound for use as a medicament, preferably for use in the treatment or in the prevention of cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
  • a further aspect of this invention relates to the compound as described above or the pharmaceutical composition comprising the compound used in association or in combination with other molecules.
  • Said molecules are selected from: ACE inhibitors, statins, sartans, calcium channel blockers, beta-blockers, vasodilators, digitalin, antianginal, anti-ischemic, antiarrhythmic, antihypertensive and hypocholesterolemic drugs and combinations thereof.
  • a further aspect of this invention relates to a method for the treatment or prevention of cardio-metabolic pathologies, including diabetes, and cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
  • Said method comprises at least a step of administering an effective dose of the compound of this invention or of the pharmaceutical composition comprising said compound to a patient who has a need for said compound.
  • the process for preparing the compound according to this invention is exemplified in the experimental part.
  • Azide B1 or B2 (0.523 mmol, 100 mg) was dissolved in anhydrous 1 ,4- dioxane (2 ml_) and commercially available 3- or 4-methoxyphenyl isothiocyanate (0.436 mmol) was added, followed by PPh3 (0.523 mmol). The mixture was stirred at 100 °C for 30 min. The cooled solution was concentrated and the resulting crude product was purified by column chromatography over silica gel using n- hexane/EtOAc mixtures as the eluent, to yield intermediate C1 (83% yield); C2 (57% yield); C3 (35% yield) or C4 (74% yield).
  • a vial was loaded with K3PO4 (1.62 mmol) and intermediate F1 or F2 (1.62 mmol, 324 mg). Then, in an inert atmosphere, copper (I) iodide (0.081 mmol) in DMSO (0.6 ml_) and commercially available 4-bromoanisole (0.81 mmol) were added. The vial was sealed, and the reaction mixture was stirred at 130 °C. After the reaction mixture was heated for 24 h, it was cooled to rt and the workup consisted of filtration of the reaction mixture through a Celite pad and washing with EtOAc.
  • N8 (22% yield), N9 (2% yield), N10 (57% yield) or N1 1 (63% yield).
  • a commercially available enzyme kit was used to perform a preliminary screening of the original compounds developed and synthetized as SIRT1 activators. The enzyme activity was monitored through a spectrofluorimetric approach.
  • the enzyme substrate (comprising a polypeptide conjugated with a fluorophore through an acetyl bond (Arg-His-Lys-Lys (e-acetyl)- AMC)) is incubated with the SIRT1 enzyme and NAD+ as a cofactor.
  • the deacetylation of the polypeptide leads to the formation of the acetylated fluorophore (acetyl-AMC), which releases the fluorophore and emits fluorescence, after the addition of a developer.
  • the fluorescence which is directly proportional to the enzyme’s activity, was analyzed using a spectrofluorimetric plate (Aex 350-360 nm, Aem 450-465 nm) and the data obtained were expressed as a % of the fluorescence evoked by 100 mM resveratrol, used as the reference activator of SIRT1.
  • Many of the tested compounds showed higher activity when compared with the reference compound.
  • compounds 14, 15, 16 and 17 showed a markedly higher effectiveness in activating the purified enzyme than resveratrol 100 mM ( Figures 1 and 2, table 2).
  • all the pyridine derivatives showed concentration-dependent SIRT 1 activation.
  • Table 2 the table shows the effects of the synthetized compounds on SIRT1 (expressed as a % vs the reference compound resveratrol 100 mM). Negative values indicate that the compound reduced the activity of the enzyme.
  • SIRT1 activators were selected for the purpose of evaluating their cardioprotection properties in an in vivo rat model of ischemia / reperfusion injury.
  • Wistar albino rats males, 300-350 g
  • the rats were anesthetized with pentobarbital sodium (70mg / kg i.p.) and connected to an electrocardiograph to monitor cardiac activity. Following tracheotomy, respiratory activity was kept constant by means of an artificial respirator (70 breaths / min, 1 ml of air blown / 10Og) for the whole duration of the experimental procedure. After partial thoracotomy, the heart was exposed and reversible occlusion of the left coronary artery was performed for 30 minutes by means of a ligature with a surgical needle (13mm, C1 , 3/8 circular, 6-0). After the removal of the occlusion, reperfusion was maintained for 120 min. The animals were then sacrificed by administration of an anesthetic overdose and a morphometric evaluation of the heart was performed.
  • the left ventricle was transversally cut into slices about 2 mm thick and each slice was incubated for 20 min at 37 ° C in triphenyl-tetrazolium chloride in order to distinguish the ischemic areas, which appeared pale pink or white, from the vital areas, which appeared red in colour.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
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  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une classe de composés capables d'activer l'enzyme SIRT1 humaine et de réguler de nombreuses fonctions métaboliques. La présente invention concerne des composés qui peuvent être utilisés dans des applications médicales, en particulier pour le traitement ou la prévention de maladies cardiométaboliques, telles que le diabète, et de troubles cardiovasculaires, tels que la coronaropathie, l'insuffisance cardiaque et l'athérosclérose.
PCT/IB2019/051489 2018-02-26 2019-02-25 Activateurs fnew de l'enzyme sirt1 pour le traitement de pathologies cardiovasculaires et cardiométaboliques WO2019162911A1 (fr)

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IT102018000003040A IT201800003040A1 (it) 2018-02-26 2018-02-26 Nuovi attivatori dell’enzima SIRT1 per il trattamento delle patologie cardiovascolari e cardiometaboliche
IT102018000003040 2018-02-26

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024794A1 (fr) * 1996-12-03 1998-06-11 Eli Lilly And Company PHENYLE GLYOXAMIDES UTILES EN TANT QU'INHIBITEURS DE sPLA¿2?
WO2005003101A2 (fr) * 2003-07-02 2005-01-13 Biofocus Discovery Limited Composes se liant au site actif d'enzymes proteine kinases
WO2006010637A2 (fr) * 2004-07-30 2006-02-02 Gpc Biotech Ag Pyridinylamines
WO2009146358A1 (fr) * 2008-05-29 2009-12-03 Sirtris Pharmaceuticals, Inc. Imidazopyridine et analogues liés en tant que modulateurs de la sirtuine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024794A1 (fr) * 1996-12-03 1998-06-11 Eli Lilly And Company PHENYLE GLYOXAMIDES UTILES EN TANT QU'INHIBITEURS DE sPLA¿2?
WO2005003101A2 (fr) * 2003-07-02 2005-01-13 Biofocus Discovery Limited Composes se liant au site actif d'enzymes proteine kinases
WO2006010637A2 (fr) * 2004-07-30 2006-02-02 Gpc Biotech Ag Pyridinylamines
WO2009146358A1 (fr) * 2008-05-29 2009-12-03 Sirtris Pharmaceuticals, Inc. Imidazopyridine et analogues liés en tant que modulateurs de la sirtuine

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BECERRA-CELY ET AL.: "Insights into Pummerer synthesis of oxazolines", ORG. BIOMOL. CHEM., vol. 14, 2016, pages 8474 - 8485, XP002782527 *
BUTLER D E ET AL: "Novel Pharmacological Activity of a Series of Substituted Pyridines", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 14, no. 7, 1971, pages 575 - 579, XP002321162, ISSN: 0022-2623, DOI: 10.1021/JM00289A005 *
CHEN TAIJIE ET AL: "Cu-mediated selective O-arylation on C-6 substituted pyridin-2-ones", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 54, no. 11, 10 January 2013 (2013-01-10), pages 1401 - 1404, XP028577991, ISSN: 0040-4039, DOI: 10.1016/J.TETLET.2012.12.126 *
DAHLGREN ET AL.: "Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor", J. MED. CHEM., vol. 55, 15 October 2012 (2012-10-15), pages 10148 - 10159, XP002782531 *
JEANNE L. BOLLIGER ET AL: "Access to 2-Aminopyridines - Compounds of Great Biological and Chemical Significance", ADVANCED SYNTHESIS & CATALYSIS, vol. 353, no. 6, 18 April 2011 (2011-04-18), DE, pages 945 - 954, XP055422594, ISSN: 1615-4150, DOI: 10.1002/adsc.201000942 *
KIREN ET AL.: "A benzannulation protocol to prepare substituted aryl amines using a Michael-Aldol reaction of beta-keto sulfones", J. ORG. CHEM., vol. 74, 24 September 2009 (2009-09-24), pages 7781 - 7789, XP002782525 *
LIANG ET AL.: "Palladium-catalyzed C(sp2)-H pyridocarbonylation of N-aryl-2-aminopyridines: dual function of the pyridyl moiety", ORGANIC LETTERS, vol. 16, 7 May 2014 (2014-05-07), pages 2748 - 2751, XP002782530 *
MOR M ET AL: "Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: Synthesis, quantitative structure-activity relationships, and molecular modeling studies", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 47, no. 21, 2 September 2004 (2004-09-02), pages 4998 - 5008, XP002386388, ISSN: 0022-2623, DOI: 10.1021/JM031140X *
SMITH ET AL.: "The reaction of pyrite with diphenyl ether", TETRAHEDRON LETTERS, vol. 25, no. 28, 1984, pages 2949 - 2952, XP002782526 *
SUN T AL.: "Synthesis of N-heterocyclic carbene-Pd(II)-2-methyl-4,5-dihydrooxazole complexes and their application toward highly chemoselective mono-Suzuki-Miyaura coupling of dichlorobenzenes", ASIAN J. ORG. CHEM., vol. 7, 10 February 2018 (2018-02-10), pages 781 - 787, XP002782528 *
TONSON ABRAHAM: "Metalation of 2-methyl-N-phenylbenzamide with n-butyllithium. Formation of N,3-diphenyl-1-isoquinolin-amine by subsequent reaction with benzonitrile", MONATSHEFTE FÜR CHEMIE, vol. 113, 1982, pages 371 - 374, XP002782529 *

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WO2019162911A8 (fr) 2019-11-28

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