Synthesis and Pharmacological Properties of Silicon-Containing 1,4-Dihydropyridine Derivatives: Calcium Channel Antagonists and α1 Adrenoceptor Antagonists of the Sila-niguldipine Type

Racemic 3-(4,4-diphenyl-4-silapiperidin-1-yl)propyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (rac-sila-niguldipine, rac-1b), a sila analogue of the calcium antagonist rac-niguldipine (rac-la), and the sila-niguldipine derivatives rac-2b-rac-4b were synthesized in multistep syntheses, starting from dichlorodiphenylsilane. The silicon compounds rac-1b-rac-4b contain a 4,4-diphenyl-4-silapiperidin-I-yl group instead of the 4,4-diphenylpiperidin-1-yl moiety in the parent carbon compound rac-la. rac-Silaniguldipine and the precursor 3-(4,4-diphenyl-4-silapiperidin-1-yl)propanol (11) were structurally characterized by single-crystal X-ray diffraction. The pharmacological profiles of rac-1b-rac-4b were compared with that of rac-la across a range of receptor binding assays (radioligand binding studies at α 1 A and α 2 adrenoceptors, the L-type Ca 2 + channel, and the serotonin 5-HT receptor). The silicon compounds rac-2b-rac-4b exhibit a profile similar to that of SNAP 5089 and therefore may be of potential benefit in the treatment of diseases such as benign prostatic hyperplasia (BPH).