Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium-antagonistic and antihypertensive activities: novel calcium-antagonist 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dim ethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol (NZ-105) and its crystal structure.
The effect of the 3-carboxylic-ester variation in 2,2-dimethyltrimethylene 3-alkoxycarbonyl-4-aryl-1,4-dihydro-2,6-dimethyl-5-pyridinephosphonat es (1) was investigated with relation to the calcium-antagonistic and antihypertensive activities: the analogs containing the alkyl groups of not more than 12 carbons and an amino functionality in the carboxylic-ester moiety were synthesized to be examined for biological activities. Among them, 2-[benzyl(phenyl)amino]-ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridine-carboxylate hydrochloride ethanol (NZ-105) showed particularly beneficial activities and was selected for further pharmacological studies and clinical development. Some aspects of the structure-activity relationships and solid-state structure of NZ-105 by X-ray crystallographic analysis were described.
Sakoda
R
R
Central Research Institute, Nissan Chemical Ind. Co., Ltd., Chiba, Japan.
Kamikawaji
Y
Y
Seto
K
K
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D003460:Crystallization; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D009596:Nitrophenols; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D014961:X-Ray Diffraction
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; C066425:efonidipine