Synthesis and Pharmacology of Combined Histamine H1‐/H2‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

Abstract

The classical histamine H₁‐receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b—d, 10) were connected with a 2‐guanidinothiazole containing structure (28) derived from the H₂‐receptor antagonist tiotidine in order to obtain combined H₁‐/H₂‐receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H₁‐ and H₂‐receptor antagonist activity at the isolated guinea‐pig ileum (H₁) and the isolated guinea‐pig right atrium (H₂), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H₁‐receptors. The tricyclic cyproheptadine and its 10,11‐dihydro derivative (30–32, 34), however, cause a decrease of H₂‐receptor antagonist potency compared to the diphenhydramines (29a—d, 33a—d). Using nitroethenediamine as the polar group is apparently more favourable to H₁‐ and H₂‐receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4‐fluoro‐ or 4‐methyl‐substituted diphenhydramine as H₁‐receptor antagonist moiety (29c, d) display the most potent H₁‐ and H₂‐receptor antagonist effects. The presented concept is a very promising way to combine H₁‐ and H₂‐receptor antagonist properties in one molecule.