Synthesis of two dopamine D4 receptor ligands:11C labelled chromeno[3,4-c]pyridin-5-ones

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity

“…The pK a for sulfonamide 14 was 8.2, suggesting that a decrease of acidity could eventually improve permeability and cell-based activity. Next, we introduced electron-donating groups at the ortho-position of sulfonamide (15,16). In these cases, a significant improvement of cell permeability was observed along with a slight increase of pK a (8.3 and 8.4, respectively).…”

“…Syntheses of the C8-substituted tricyclic coumarin derivatives are described in Scheme 1. First, the Pechmann condensation 15 between β-ketoester (25) and resorcinol (26) gave the tricyclic scaffold with a hydroxyl group at the 8-position (27) as H 2 SO 4 salt. Owing to the high reactivity of resorcinol, this reaction proceeded quite efficiently, unlike the case using phenol.…”

“…After evaporating the solvent, the residue was purified by column chromatography [SiO 2 , MeOH/DCM = 5/95−15/85 (v/v)], subsequently triturated with EtOAc−n-hexane, and dried at 60 °C under reduced pressure to afford 14 (38 mg, 72% yield). 1 (15). In a manner similar to that employed for the synthesis of 14, the title compound 15 (37 mg, 77% yield) was obtained using 45b (41 mg, 0.092 mmol) and methanesulfonyl chloride (0.036 mL, 0.46 mmol).…”

“…In a manner similar to that employed for the synthesis of 18, the title compound 24 (8 mg, 41% yield) was obtained using 48d (17 mg, 0.035 mmol) and methanesulfonyl chloride (0.014 mL, 0.18 mmol). 1 15 In a manner similar to that employed for the synthesis of 34b, the title compound 27 (5.76 g, 45% yield) was obtained using ethyl 4-oxopiperidine-3-carboxylate hydrochloride (10 g, 48.2 mmol) and resorcinol (5.31 g, 48.2 mmol). 1 tert-Butyl 4-({8-[2-(Dimethylamino)ethoxy]-5-oxo-1,5-dihydro-2H-chromeno [3,4-c]pyridin-3(4H)-yl}carbonyl)benzoate (29a).…”

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity

“…The pK a for sulfonamide 14 was 8.2, suggesting that a decrease of acidity could eventually improve permeability and cell-based activity. Next, we introduced electron-donating groups at the ortho-position of sulfonamide (15,16). In these cases, a significant improvement of cell permeability was observed along with a slight increase of pK a (8.3 and 8.4, respectively).…”

“…Syntheses of the C8-substituted tricyclic coumarin derivatives are described in Scheme 1. First, the Pechmann condensation 15 between β-ketoester (25) and resorcinol (26) gave the tricyclic scaffold with a hydroxyl group at the 8-position (27) as H 2 SO 4 salt. Owing to the high reactivity of resorcinol, this reaction proceeded quite efficiently, unlike the case using phenol.…”

“…After evaporating the solvent, the residue was purified by column chromatography [SiO 2 , MeOH/DCM = 5/95−15/85 (v/v)], subsequently triturated with EtOAc−n-hexane, and dried at 60 °C under reduced pressure to afford 14 (38 mg, 72% yield). 1 (15). In a manner similar to that employed for the synthesis of 14, the title compound 15 (37 mg, 77% yield) was obtained using 45b (41 mg, 0.092 mmol) and methanesulfonyl chloride (0.036 mL, 0.46 mmol).…”

“…In a manner similar to that employed for the synthesis of 18, the title compound 24 (8 mg, 41% yield) was obtained using 48d (17 mg, 0.035 mmol) and methanesulfonyl chloride (0.014 mL, 0.18 mmol). 1 15 In a manner similar to that employed for the synthesis of 34b, the title compound 27 (5.76 g, 45% yield) was obtained using ethyl 4-oxopiperidine-3-carboxylate hydrochloride (10 g, 48.2 mmol) and resorcinol (5.31 g, 48.2 mmol). 1 tert-Butyl 4-({8-[2-(Dimethylamino)ethoxy]-5-oxo-1,5-dihydro-2H-chromeno [3,4-c]pyridin-3(4H)-yl}carbonyl)benzoate (29a).…”

Pd‐catalyzed CH Activation and Oxidative Annulation to Access N‐methoxy‐7H‐Chromenoquinolinones and N‐methoxyphenyl quinolinones

“…[6] Additionally, 11 C-labeled radioligands containing the chromeno [3,4-c]pyridin-5-one scaffold have been employed in vivo PET studies for investigating the dopamine D4 receptor subtype, illustrating the utility of chromeno-pyridines in neuroimaging and receptor analysis. [7] Furthermore, other derivatives within the chromenopyridine family, along with coumarin-pyridine hybrids, have shown diverse biological activities, as depicted in Figure 1. [3,[8][9][10][11][12] This growing body of evidence highlights the chromeno-pyridine framework as a versatile and valuable scaffold for drug discovery and development.…”

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity

“…The pK a for sulfonamide 14 was 8.2, suggesting that a decrease of acidity could eventually improve permeability and cell-based activity. Next, we introduced electron-donating groups at the ortho-position of sulfonamide (15,16). In these cases, a significant improvement of cell permeability was observed along with a slight increase of pK a (8.3 and 8.4, respectively).…”

“…Syntheses of the C8-substituted tricyclic coumarin derivatives are described in Scheme 1. First, the Pechmann condensation 15 between β-ketoester (25) and resorcinol (26) gave the tricyclic scaffold with a hydroxyl group at the 8-position (27) as H 2 SO 4 salt. Owing to the high reactivity of resorcinol, this reaction proceeded quite efficiently, unlike the case using phenol.…”

“…After evaporating the solvent, the residue was purified by column chromatography [SiO 2 , MeOH/DCM = 5/95−15/85 (v/v)], subsequently triturated with EtOAc−n-hexane, and dried at 60 °C under reduced pressure to afford 14 (38 mg, 72% yield). 1 (15). In a manner similar to that employed for the synthesis of 14, the title compound 15 (37 mg, 77% yield) was obtained using 45b (41 mg, 0.092 mmol) and methanesulfonyl chloride (0.036 mL, 0.46 mmol).…”

“…In a manner similar to that employed for the synthesis of 18, the title compound 24 (8 mg, 41% yield) was obtained using 48d (17 mg, 0.035 mmol) and methanesulfonyl chloride (0.014 mL, 0.18 mmol). 1 15 In a manner similar to that employed for the synthesis of 34b, the title compound 27 (5.76 g, 45% yield) was obtained using ethyl 4-oxopiperidine-3-carboxylate hydrochloride (10 g, 48.2 mmol) and resorcinol (5.31 g, 48.2 mmol). 1 tert-Butyl 4-({8-[2-(Dimethylamino)ethoxy]-5-oxo-1,5-dihydro-2H-chromeno [3,4-c]pyridin-3(4H)-yl}carbonyl)benzoate (29a).…”

Pd‐catalyzed CH Activation and Oxidative Annulation to Access N‐methoxy‐7H‐Chromenoquinolinones and N‐methoxyphenyl quinolinones

“…[6] Additionally, 11 C-labeled radioligands containing the chromeno [3,4-c]pyridin-5-one scaffold have been employed in vivo PET studies for investigating the dopamine D4 receptor subtype, illustrating the utility of chromeno-pyridines in neuroimaging and receptor analysis. [7] Furthermore, other derivatives within the chromenopyridine family, along with coumarin-pyridine hybrids, have shown diverse biological activities, as depicted in Figure 1. [3,[8][9][10][11][12] This growing body of evidence highlights the chromeno-pyridine framework as a versatile and valuable scaffold for drug discovery and development.…”

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity

“…The pK a for sulfonamide 14 was 8.2, suggesting that a decrease of acidity could eventually improve permeability and cell-based activity. Next, we introduced electron-donating groups at the ortho-position of sulfonamide (15,16). In these cases, a significant improvement of cell permeability was observed along with a slight increase of pK a (8.3 and 8.4, respectively).…”

“…Syntheses of the C8-substituted tricyclic coumarin derivatives are described in Scheme 1. First, the Pechmann condensation 15 between β-ketoester (25) and resorcinol (26) gave the tricyclic scaffold with a hydroxyl group at the 8-position (27) as H 2 SO 4 salt. Owing to the high reactivity of resorcinol, this reaction proceeded quite efficiently, unlike the case using phenol.…”

“…After evaporating the solvent, the residue was purified by column chromatography [SiO 2 , MeOH/DCM = 5/95−15/85 (v/v)], subsequently triturated with EtOAc−n-hexane, and dried at 60 °C under reduced pressure to afford 14 (38 mg, 72% yield). 1 (15). In a manner similar to that employed for the synthesis of 14, the title compound 15 (37 mg, 77% yield) was obtained using 45b (41 mg, 0.092 mmol) and methanesulfonyl chloride (0.036 mL, 0.46 mmol).…”

“…In a manner similar to that employed for the synthesis of 18, the title compound 24 (8 mg, 41% yield) was obtained using 48d (17 mg, 0.035 mmol) and methanesulfonyl chloride (0.014 mL, 0.18 mmol). 1 15 In a manner similar to that employed for the synthesis of 34b, the title compound 27 (5.76 g, 45% yield) was obtained using ethyl 4-oxopiperidine-3-carboxylate hydrochloride (10 g, 48.2 mmol) and resorcinol (5.31 g, 48.2 mmol). 1 tert-Butyl 4-({8-[2-(Dimethylamino)ethoxy]-5-oxo-1,5-dihydro-2H-chromeno [3,4-c]pyridin-3(4H)-yl}carbonyl)benzoate (29a).…”

Pd‐catalyzed CH Activation and Oxidative Annulation to Access N‐methoxy‐7H‐Chromenoquinolinones and N‐methoxyphenyl quinolinones

“…[6] Additionally, 11 C-labeled radioligands containing the chromeno [3,4-c]pyridin-5-one scaffold have been employed in vivo PET studies for investigating the dopamine D4 receptor subtype, illustrating the utility of chromeno-pyridines in neuroimaging and receptor analysis. [7] Furthermore, other derivatives within the chromenopyridine family, along with coumarin-pyridine hybrids, have shown diverse biological activities, as depicted in Figure 1. [3,[8][9][10][11][12] This growing body of evidence highlights the chromeno-pyridine framework as a versatile and valuable scaffold for drug discovery and development.…”