Add time:07/12/2019         Source:sciencedirect.com

Four different syntheses of the potent and selective muscarinic antagonist cyclohexy1(4- fluorophenyl)(3-piperidinopropyl)silanol (p-Fluoro-hexahydro-sila-difenidol, p-F-HHSiD (2b); isolated as hydrochloride 2b-HCI) are descirbed (starting materials: (CH3O)3SiCH2CH2CH2CI and Si(OCH3)4). In addition, the synthesis of the corresponding carbon analogue p-fluoro-hexahydro-difenidol (p-F-HHD (2a); isolated as 2a · HCI) and the syntheses of three p-F-HHSiD derivatives (3-5), with a modified cyclic amino group, are reported (3: piperidino/pyrrolidino exchange, isolated as 3 · HCI; 4: piperidino/ hexamethylenimino exchange, isolated as 4 · HCI; 5: quaternization of 2b with methyl iodide). The chiral compounds 2a, 2b, 3, 4 and 5 were prepared as racemates. In functional pharmacological studies, 3-5 behaved as simple competitive antagonists at muscarinic M1 receptors in rabbit vas deferens, M2 receptors in guinea-pig atria, and M3 receptors in guinea-pigileal smooth muscle. The pyrrolidino (3) and hexamethylenimino (4) analogues of the parent drug p-F-HHSiD for M1 and M3 receptors (pA2 values: 7.0–7.4) but exhibited lower affinity for cardiac M2 receptors (pA2: 5.9 and 6.0). Their affinity profile (M1 ∼ M3 > M2) is different from that of P-F-HHSiD (2b (M3 > M1 > M2), but qualitatively very similar to that of p-F-HHD highest affinity for M1 receptors (pA2: 8.5) but lower affinity forM2 and M3 receptors by factors of 5.6 and 3.6 respectively.

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