Imidazopyridines as VLA-4 integrin antagonists

A Trifluoromethylcarbene Source

“…As the incorporation of the CF 3 group into cyclopropanes represents important structural modifications which can improve the bioactivity of the target molecules, the synthesis of CF 3 -cyclopropanes has received a great deal of attention from the synthetic community. Traditional approaches such as intramolecular cyclization of CF 3 -substrates suffer from tedious procedures to prepare the starting materials. , Recently, Baran found that trifluoro­methyl­cyclo­propyl sulfinate salt is a good reagent for a radical reaction to afford CF 3 -cyclopropanes .…”

Bromo-Cyclobutenaminones as New Covalent UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors

“…The stability proves to be appropriate for biological investigations, as the t 1/2 value for the aqueous degradation was determined to be 36.5 h at room temperature. The stability and bioavailability of these structures is also supported by the fact that interestingly, the rather unique bromocyclobutenaminone core has been incorporated both in the α4β1/α4β7 integrin antagonist prodrug, Zaurategrast [24,25], which progressed to phase II clinical trials [26], as well as in related compounds [22].…”

“…The sequence furnished ethoxyenone (12) in moderate yield, which was transformed by acidic hydrolysis to 2,2-dimethylcyclobutane-1,3-dione (13) in high yield [18][19][20][21]. Next, dione 13 was condensed with various amines in the presence of AcOH as catalyst at 65 °C to generate the desired enaminones (14a-e) in moderate yields [18,22]. Bromination of all enaminones In continuation of our interests in finding new MurA inhibitors and in the use of the cyclobutyl motif in drug discovery [6,[15][16][17], here we describe cyclobutenaminone derivatives with carefully-modulated electrophilic character as new warheads for covalently targeting the Cys115 residue in the active site of MurA.…”

“…The sequence furnished ethoxyenone (12) in moderate yield, which was transformed by acidic hydrolysis to 2,2-dimethylcyclobutane-1,3-dione (13) in high yield [18][19][20][21]. Next, dione 13 was condensed with various amines in the presence of AcOH as catalyst at 65 • C to generate the desired enaminones (14a-e) in moderate yields [18,22]. Bromination of all enaminones was achieved via electrophilic substitution using Br 2 and base at 0 • C to produce bromoenaminones 15a-e [18,22].…”

“…Next, dione 13 was condensed with various amines in the presence of AcOH as catalyst at 65 • C to generate the desired enaminones (14a-e) in moderate yields [18,22]. Bromination of all enaminones was achieved via electrophilic substitution using Br 2 and base at 0 • C to produce bromoenaminones 15a-e [18,22]. Selected compounds were subjected to N-acylation via deprotonation of the secondary enaminone in tetrahydrofurane (THF) at -78 • C by sodium bis(trimethylsilyl)amide (NaHDMS), followed by subsequent trapping by the relevant acid chloride.…”