FLUORINE-CONTAINING DERIVATIVES OF THE MUSCARINIC ANTAGONISTS SILA-PRIDINOL AND SILA-DIFENIDOL - SYNTHESES AND ANTIMUSCARINIC PROPERTIES

The fluorine-containing sila-pridinol and sila-difenidol derivatives p -fluoro-sila-pridinol (5a), p,p'-difluoro-sila-pridinol (6a), p-fluoro -sila-difenidol (7a), p,p'-difluoro-sila-difenidol (8a), p-fluoro-sila -difenidol methiodide (9a) and p,p'-difluoro-sila-difenidol methiodide (10a) were synthesized, starting from the silanes Cl3SiCH=CH2 (5a and 6a) and (CH3O)(3)Si(CH2)(3)Cl(7a-10a) respectively. The chiral compou nds 5a, 7a and 9a were obtained as racemic mixtures: The muscarinic ph armacology of the silanols 5a-10a was studied and compared with that o f their carbon analogues, the carbinols 5b-10b (studies on silicon-car bon bioisosterism). The affinities and receptor selectivities (M1-M4 r eceptors) of the Si-C pairs 5a/5b-10a/10b were found to depend on the following structural parameters: length of the carbon chain El-(CH2)(n )-N(El = Si or C; n = 2, 3), N-methylation, fluorine substitution of t he phenyl rings and the nature of the central atom (silicon or carbon) . Most interestingly, replacement of the central carbinol carbon atom in p-fluoro-difenidol methiodide (9b) by a silicon atom (--> 9a) leads to an increase in affinity for muscarinic receptor subtypes by factor s of 32-81. Such a high increase in biological activity by sila-substi tution (C-Si exchange) has not yet been reported.