Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D004837:Epinephrine / Q000037:antagonists & inhibitors; D007217:Indoramin / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D010080:Oxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D010080:Oxazoles; D013141:Spiro Compounds; D007217:Indoramin; D010656:Phenylephrine; D009638:Norepinephrine; D004837:Epinephrine; D010646:Phentolamine