Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities

“…1,27 To a round bottom flask already containing the dried, desiccated 3-bromo- N -propanamide (1.0 eq) was added NaO t Bu (1.05 eq). The reaction vessel was placed under vacuum and anhyd.…”

“…1,27 To the round bottom flask already containing the dried, desiccated phenylazetidin-2-ones (1.0 eq) was added anhyd. DCE under vacuum.…”

Discovery of (R)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonist with Analgesic Efficacy

“…For indazoles 33−34, hydroxytetralins (35−36), and unsubstituted isoquinolines (4, 37−40), a variety of amino arenes were coupled with chromanyl amine salts 9 using N,N-disuccinimidyl carbonate (DSC) to provide the desired urea products. 36 …”

“…After 20 min, (R)-7-fluoro-2,2-dimethylchroman-4-aminium (R)-2-hydroxy-2-phenylacetate 29 (1.0 g, 2.88 mmol) was added, followed by acetonitrile (10 mL) and i-Pr 2 NEt (1.508 mL, 8.64 mmol). After 5 h at ambient temperature, the reaction mixture was diluted with EtOAc (300 mL), washed with 1N NaOH 1-((R)-7-Fluoro-2,2-dimethylchroman-4-yl)-3-((S)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ure (36). A mixture of DSC (465 mg, 1.81 mmol) and acetonitrile (5 mL) was stirred at ambient temperature, and a solution of (S)-8-amino-1,2,3,4-tetrahydronaphthalen-2-ol 3 (282 mg, 1.73 mmol) in acetonitrile (5 mL) and pyridine (0.146 mL, 1.81 mmol) were added.…”

N-Aryl-N′-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: Screening, synthesis of simplified derivatives, and structure–activity relationship analysis

“…Concerning more specifically N-aryl-N 0 -(chroman-4-yl)ureas or thioureas, two recent works described compounds like 18 and 19 ( Fig. 2) as potent TRPV1 receptor antagonists [35,36]. For the moment, it is not known if such compounds also exert antiproliferative activity on glioma cells and/or if the antagonism of TRPV1 receptors could explain the antiproliferative activity of our tightly related chromans.…”