- Oxadiazolopyridine Derivates for Use as Ghrelin O-Acyl Transferase (GOAT) Inhibitors
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The present invention relates to compounds of general formula I, wherein the groups R1, R2 and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to ghrelin O-acyl transferase (GOAT) and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular obesity.
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Paragraph 0311-0314; 0371-0373
(2018/03/01)
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- Direct metalation of heteroaromatic esters and nitriles using a mixed lithium-cadmium base. Subsequent conversion to dipyridopyrimidinones
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(Chemical Equation Presented) All pyridine nitriles and esters were metalated at the position next to the directing group using (TMP) 3CdLi in tetrahydrofuran at room temperature. The 2-, 3-, and 4-cyanopyridines were treated with 0.5 equiv of base for 2 h to afford, after subsequent trapping with iodine, the corresponding 3-iodo, 2-iodo, and 3-iodo derivatives, respectively, in yields ranging from 30 to 61%. Cyanopyrazine was similarly functionalized at the 3 position in 43% yield. Ethyl 3-iodopicolinate and -isonicotinate were synthesized from the corresponding pyridine esters in 58 and 65% yield. Less stable ethyl 4-iodonicotinate also formed under the same conditions and was directly converted to ethyl 4-(pyrazol-1-yl)nicotinate in a two-step 38% yield. All three ethyl iodopyridinecarboxylates were involved in a one-pot palladium-catalyzed cross-coupling reaction/cyclization using 2-aminopyridine to afford new dipyrido[1,2-a:3′,2′-d]pyrimidin-11- one, dipyrido[1,2-a:4′,3′-d]pyrimidin-11-one, and dipyrido[1,2-a:3′,4′-d]pyrimidin-5-one in yields ranging from 50 to 62%. A similar crosscoupling/ cyclization sequence was applied to methyl 2-chloronicotinate using 2-aminopyridine, 2-amino-5-methylpyridine, and 1-aminoisoquinoline to give the corresponding tricyclic or tetracyclic compounds in 43-79% yield. Dipyrido[1,2-a:4′,3′-d]pyrimidin-11-one and dipyrido[1,2-a:3′,4′-d]pyrimidin-5-one showed a good bactericidal activity against Pseudomonas aeroginosa. Dipyrido-[1,2-a:2′,3′-d] pyrimidin-5-one and pyrido[2′,3′:4,5]pyrimidino[2,1-a]isoquinolin-8- one showed a fungicidal activity against Fusarium and dipyrido[1,2-a:4′, 3′-d]pyrimidin-11-one against Candida albicans. Ethyl 4-(pyrazol-1-yl) nicotinate and dipyrido[1,2-a:2′,3′-d]pyrimidin-5-one have promising cytotoxic activities, the former toward a liver carcinoma cell line (HEPG2) and the latter toward a human breast carcinoma cell line (MCF7).
- Bentabed-Ababsa, Ghenia,Ely, Sidaty Cheikh Sid,Hesse, Stephanie,Nassar, Ekhlass,Chevallier, Floris,Nguyen, Tan Tai,Derdour, Aicha,Mongin, Florence
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experimental part
p. 839 - 847
(2010/08/20)
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