Synthesis and bronchodilator activity of endo-2-(2-cyclopentyl-2-hydroxy-2-phenyl)acetoxy-7-methyl-7- azabicyclo-[2.2.1]heptane methobromide, a potent and long-acting anticholinergic agent.
The synthesis of the alpha-cyclopentylmandelate ester of quaternized endo-7-methyl-7-azabicyclo[2.2.1]heptan-2-ol (4, RS-11635) is described. The key step of this synthesis consists of the intramolecular trans-diaxial epoxide opening of 4-(N-methylamino)-1,2-epoxycyclohexane (8) to form the endo-azabicyclic structure 9. Evaluation of anticholinergic bronchodilator activity by intravenous administration in methacholine-challenged guinea pigs indicated 4 to be approximately twice as potent as ipratropium bromide (ED50 of 1.1 versus 2 micrograms/kg) and to have a duration of action nearly five times as long (230 versus 50 min). Evaluation of anticholinergic bronchodilator activity by aerosol administration in methacholine-challenged dogs also indicated 4 to be approximately twice as potent as ipratropium bromide and to have a duration of action nearly three times as long.
Pfister
J R
JR
Wymann
W E
WE
Weissberg
R M
RM
Strosberg
A M
AM
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D001985:Bronchial Provocation Tests; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D006168:Guinea Pigs; D009241:Ipratropium / Q000494:pharmacology; D008688:Methacholine Compounds; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D001993:Bronchodilator Agents; D008688:Methacholine Compounds; D010276:Parasympatholytics; C045177:RS 11635; D009241:Ipratropium