3-(aminoalkyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c] pyridin-5-ones as potential anticholinergic bronchodilators.
A series of 3-(aminoalkyl)benzopyrano[3,4-c]pyridin-5-ones was prepared and tested as potential orally active anticholinergic bronchodilators. Inhibition of methacholine-induced collapse in guinea pigs and inhibition of pilocarpine-induced bronchoconstriction in dogs served as in vivo models. Simultaneous measurement of salivary inhibition in the dog model allowed determination of a pulmonary selectivity ratio. The benzopyrano[3,4-c]pyridin-5-one parent ring system was prepared by Pechman condensation of phenols with a piperidine beta-keto ester. Alkylation with aminoalkyl halides, or with 1-chloro-2-propanone followed by reductive amination, yielded the 3-substituted target compounds. Bronchodilator potency was related to the extent of steric crowding surrounding the side-chain terminal amine function. Addition of a methyl substituent on the carbon alpha to the terminal amine often increased potency or pulmonary selectivity. After secondary pharmacological evaluation, compound 7a, designated CI-923, was selected for clinical trial as a bronchodilator.
Connor
D T
DT
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Unangst
P C
PC
Schwender
C F
CF
Sorenson
R J
RJ
Carethers
M E
ME
Puchalski
C
C
Brown
R E
RE
Finkel
M P
MP
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D006168:Guinea Pigs; D016210:Methacholine Chloride; D008688:Methacholine Compounds / Q000037:antagonists & inhibitors; D010276:Parasympatholytics / Q000138:chemical synthesis*; D010862:Pilocarpine / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D001993:Bronchodilator Agents; D008688:Methacholine Compounds; D010276:Parasympatholytics; D011728:Pyridones; D010862:Pilocarpine; D016210:Methacholine Chloride