Cyclohexyl(4-fluorophenyl)(3-piperidinopropyl)silanol (p-fluoro-hexahydro-sila-difenidol, p-F-HHSiD) and derivatives: synthesis and antimuscarinic properties

Article abstract of DOI:10.1016/0022-328X(91)80194-O

Four different syntheses of the potent and selective muscarinic antagonist cyclohexyl(4-fluorophenyl)(3-piperidinopropyl)silanol (p-fluoro-hexahydro-sila-difenidol, p-F-HHSiD (2b); isolated as hydrochloride 2b * HCl) are described (starting materials: (CH3O)3SiCH2CH2CH2Cl and Si(OCH3)4).In addition, the synthesis of the corresponding carbon analogue p-fluoro-hexahydro-difenidol (p-F-HHD (2a); isolated as 2a * HCl) 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 * HCl; 4; piperidino/hexamethylenimino exchange, isolated as 4 * HCl; 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-pig ileal smooth muscle.The pyrrolidino (3) and hexamethylenimino (4) analogues of the parent drug p-F-HHSiD (2b) displayed the highest affinity 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 ca.M3 above M2) is different from that of p-F-HHSiD (2b) (M3 above M1 above M2), but qualitatively very similar to that of p-F-HHD (2a).The methiodide 5 exhibited the highest affinity for M1 receptors (pA₂ : 8.5) but lower affinity for M2 and M3 receptors by factors of 5.6 and 3.6, respectively.