A series of 1, 4-dihydropyridine-5-cyclic phosphonate derivatives, designed as analogues of 1, 4- dihydropyridine-3, 5-dicarboxylate calcium antagonists, was synthesized and examined for antihypertensive activity. Several compounds were proved to have activities superior or comparable to that of nifedipine in lowering blood pressure in normotensive and spontaneously hypertensive rats (SHR). Among these compounds, methyl 2, 6-dimethyl-5- (2-oxo-1, 3, 2-dioxaphosphorinan-2-yl) -4- (2-nitrophenyl) -1, 4-dihydropyridine-3-carboxylate (31, DHP-218) was approximately 7 times more active than nifedipine in SHR and was selected for further development and clinical evaluation. The structure-activity relationships are discussed.
Tri(1-imidazolyl)phosphine (1) gave the cyclic phosphite quantitatively in the reactions with the diols possessing favorably placed hydroxyl groups in which the distance between the two oxygen atoms is 2.7–3.0 A. The both five- and six-membered cyclic phosphites were obtained quantitatively from the reactions of the diols possessing flexible chains with 1. The course of the selective formation of ribonucleoside
The present invention is directed to a compound of formula (I),
methods for preparing these compounds, compositions, intermediates and derivatives thereof, and methods for treating inflammatory and serine protease mediated disorders.