5‑amino‑quinoline‑8‑carboxamide derivatives as 5‑ht4 receptor agonists
A technology of formamide and amino, applied in the field of new quinoline compounds of formula and their pharmaceutically acceptable salts
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Embodiment 1
[0447] Example 1: 5-amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-carboxamide Preparation of hemifumarate
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[0449] Step (i): 5-Amino-6-chloro-N-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4-piperidinyl]methyl}quinoline-8-methanol Preparation of amides
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[0451] 5-Amino-6-chloro-N-[(4-piperidinyl)methyl]quinoline-8-carboxamide (5.60 g, 0.017 mol, obtained from Preparation 2) and tetrahydropyran-4-carbaldehyde (2.40 g, 0.021 mol) in dichloroethane (70 mL) was cooled to 10°C. Sodium triacetoxyborohydride (7.45 g, 0.035 mol) was added to the above reaction mass. It was further stirred overnight at RT while monitoring the progress of the reaction by TLC. After completion of the reaction (TLC), the reaction mass was concentrated and the slurry thus obtained was quenched in water (150 mL). The pH of the resulting material was adjusted to ~9.5 using aqueous ammonia and the product was extracted with DCM (3 x 100 mL). The c...
Embodiment 2
[0460] Example 2: 5-amino-6-chloro-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl] Preparation of Methyl}quinoline-8-carboxamide L(+)-tartrate
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[0462] Step (i): 5-amino-6-chloro-N-{[3-(tetrahydro-2H-pyran-4-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl Preparation of ]methyl}quinoline-8-carboxamide
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[0464] 5-Amino-6-chloro-N-{[3-azabicyclo[3.1.0]hex-6-yl]methyl}quinoline-8-carboxamide (0.30 g, 0.947 mmol, obtained from 4) and tetrahydropyran-4-carbaldehyde (0.14 g, 1.228 mmol) in dichloroethane (30 mL) were cooled to 10°C and treated with sodium triacetoxyborohydride (0.40 g, 1.886 mmol). The reaction mass was stirred overnight at RT while monitoring the progress of the reaction by TLC. After the reaction was complete (TLC), the reaction mass was poured into (40 mL). The pH of the resulting material was adjusted to ~9.5 with aqueous ammonia and the product was extracted with DCM (3 x 25 mL). The combined organic phases were washed wit...
Embodiment 3 to 19
[0473] The compounds of Examples 3 to 19 were prepared by following the experimental procedure described in Examples 1 to 2 given above with some non-critical changes.
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