Stereochemical influences upon antihistamine activity. Further studies of isomeric 4-amino-1, 2-diarylbutenes

Abstract

The acid‐catalysed dehydration of some 4‐amino‐1, 2‐diarylbutan‐2‐ols yields all four possible 4‐amino‐1, 2‐diarylbutenes. The structure and configuration of pure isomers have been established from spectroscopic data, and the ability of these compounds to anatagonize histamine‐induced contractions of the guinea‐pig ileum is reported. The most potent derivatives are all cis(H/Ar)‐4‐amino‐1, 2‐diarylbut‐2‐enes. These results together with other data are discussed in terms of the possible structural and conformational requirements of histamine antagonists.

Crystallographic and conformational studies on histamine H1 receptor antagonists. I. Structure of carbinoxamine maleate

“…The present findings that the five-membered aminoethyl ether chain assumes a conformation such as to reproduce the 6-6.20/~ distance observed for the derivatives of the fourmembered propylamino and propenylamino chains and that its conformation is weakly affected by the crystal forces confirm the results of James & Williams (1974b) and support the idea that a distance of 6-6.30 ,/k between the protonated N and the centroid of an unsaturated ring is relevant to the antihistaminic activity. Also, this hypothesis is confirmed, from a completely different point of view, by the structure-activity studies on substituted propenylamines (Casy & Ison, 1970;Ison Franks & Soh, 1973). 1-Aryl-l-benzylprop-l-en-3-amines have been synthetized and biologically tested for the cis and trans (H/phenyl) isomers and the first has been found to be two hundred times more active than the second.…”

The Crystal and Molecular Structure of the Antihistaminic Drug Triprolidine Hydrochloride Monohydrate [trans-1-(p-Tolyl)-1-(2-pyridyl)-3-(1-pyrrolidino)-prop-1-ene]

“…4. These planes are parallel and are separated by 3.466 (3) A, the displacement of their centroids is 4.004 (3) A and the closest approach of non-hydrogen atoms is the 3.533(3) A between C(3') and its in- molecule. Because the antihistamine receptor site is presumed to bind the antagonist via the pyridyl ring and the tertiary nitrogen atom this observation is probably important.…”

“…By suitable pharmacological screening of the geotnetric isomers of these unsaturated drugs some progress has been made towards defining the active conformations of their saturated analogs (1)(2)(3).…”

Structural Studies of Histamine H1 Effector Molecules: The Crystal Structure of the Antihistamine Drug (+)-Chlorpheniramine Maleate; [(+)-S-1-(p-Chlorophenyl)-1-(2-pyridyl)-3-N,N-dimethylpropylamine maleate]

“…Numerous studies using various methods ranging from pharmacological screening (1,2) through proton magnetic resonance (p.m.r.) (1,3,4) to quantum mechanics (5,6) have been made in the past in an attempt to define both the pharmacodynamic moieties of histamine antagonists and their stereochemical relationships.…”