Synthesis and structural, conformational, and pharmacological study of some of esters derived from 3-phenethyl-3-azabicyclo[3.2.1]octan-8-beta-ol and the corresponding N-endo-methyl quaternary derivatives.
A series of 8-beta-acyloxy-3-phenethyl-3-azabicyclo[3.2.1]octane and its N-endo methiodides were synthesized and studied by 1H and 13C NMR spectroscopy, and the crystal structure of 8-beta-p-chlorobenzoyloxy-3-phenethyl-3-azabicyclo[3.2.1]octane methiodide (2c) was determined by X-ray diffraction. In CDCl3 solution, 1b-1e display the same preferred conformation. The cyclopentane and piperidine rings adopt an envelope conformation flattened at C-8 and a distorted chair conformation puckered at C-8 and flattened at N-3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. In all cases, methylation takes place from the endo position. The ability of the title compounds to antagonize the acetylcholine-induced contraction of guinea pig ileum is also reported. An initial structure-activity relationship is proposed.
Izquierdo
M L
ML
Departamento de Química Orgánica, Universidad de Alcalá de Henares, Madrid, Spain.
Arias
M S
MS
Galvez
E
E
Rico
B
B
Ardid
I
I
Sanz
J
J
Fonseca
I
I
Orjales
A
A
Innerarity
A
A
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010276:Parasympatholytics; C070886:3-phenethyl-3-azabicyclo(3.2.1)octan-8-ol