(HYDROXYMETHYL)DIPHENYL(PIPERIDINOALKYL)S ILANES OF THE TYPE (HOCH2)(C6H5)(2)SI(CH2)(N)NC5H10 (N=2, 3) AND THEIR METHIODIDES - SYNTHESIS, STRUCTURE AND ANTIMUSCARINIC PROPERTIES

Starting from (MeO)(3)SiCH2Cl (10) and Ph(2)(H)SiCH2OH (16), respectiv ely, the (hydroxymethyl)diphenyl(piperidinoalkyl)silanes (HOCH2)Ph(2)S i(CH2)(2)NC5H10 (6) and (HOCH2)Ph(2)Si(CH2)(3)NC5H10 (8) have been syn thesized [10 --> Ph(2)(MeO)SiCH2Cl (11) --> Ph(2)(CK2=CH)SiCH2Cl (12) --> Ph(2)(CH2=CH)SiCH2OAc (13) --> Ph(2)(CH2=CH)SiCH2OH (14) --> Ph(2) (CH2=CH)SiCH(2)OSiMe(3) (15) --> 6; 16 --> Ph(2)(H)SiCH(2)OSiMe(3) (17 ) --> 8; NC5H10 = piperidino]. N-Quaternization of 6 and 8 with Mel ga ve the corresponding methiodides 7 and 9, respectively. As shown by IR -spectroscopic studies, compounds 6 and 8 form intramolecular O-H...N hydrogen bonds in solution (CCl4). In the crystal, 6 (space group Pna2 (1); two crystallographically independent molecules) also forms intram olecular O-H...N hydrogen bonds whereas 8 (space group PT) forms inter molecular O-H...N hydrogen bonds leading to the formation of centrosym metric dimers (single-crystal X-ray diffraction studies). The (hydroxy methyl)silanes 6-9 and the related silanols (HO)Ph(2)Si(CH2)(2)NC5H10 (sila-pridinol; 1), sila-pridinol methiodide (2), (HO)Ph(2)Si(CH2)(3)N C5H10 (sila-difenidol; 3) and sila-difenidol methiodide (4) were inves tigated for their antimuscarinic properties. In functional pharmacolog ical experiments as well as in radioligand competition studies, all co mpounds behaved as simple competitive antagonists at muscarinic M(1)-, M(2)-, M(3)- and M(4)-receptors, In general, the silanols 1-4 display ed higher receptor affinities (up to 100-fold) than the corresponding (hydroxymethyl)silanes 6-9. In the (hydroxymethyl)silane series, compo und 7 was found to be the most potent muscarinic antagonist [pA(2)/pK( i) = 8,71/8,6 (M(1)), 8,23/7,8 (M(2)) 8,19/7,8 (M(3)); pK(i) = 8,2 (M( 4))]. In the silanol series, the related compound 2 showed the most in teresting antimuscarinic properties [pA(2)/pK(i) = 10,37/9,6 (M(1)), 8 ,97/8,8 (M(2)), 9,08/8,8 (M(3)); pK(i) = 9,4 (M(4))].