ABSTRACT
Structure-activity considerations of N alpha-guanylhistamine, the first compound found with detectable H2-antagonist activity, led to the synthesis of a series of conformationally rigid guanylhistamine analogues, namely, (imidazolylphenyl)guanidines, imidazolylbenzamidines, and (imidazolylphenyl)formamidines. It was found that in the guanidine and benzamidine classes, the meta-substituted derivatives (3, 4, 7, and 8) possessed H2-antagonist activity, whereas in the class of formamidines, only the para-substituted derivative 10 was found active. A subsequent increase in the size of the substituent at the formamidino group of 10 led to compounds (15-20) of high H2-antagonist affinity, which was related to the gastric antisecretory effect. Members of this structurally novel class of H2 antagonists were 20- to 50-fold more potent than cimetidine both "in vitro" and "in vivo". Structure-activity relationships are discussed in terms of ionization properties, partitioning behavior, conformational aspects of the selected compound 17, and of possible modes of interaction with the histamine H2 receptor. It was found that the formamidine moiety was an important structural feature and that H2-antagonist activity requires correct steric and electronic properties. Compound 17 (DA 4577), owing to its pharmacological profile and demonstrated safety in animals, was selected to be clinically investigated.
Subject(s)
Amidines/analysis , Histamine H2 Antagonists/analysis , Imidazoles/analysis , Amidines/pharmacology , Animals , Cimetidine/analysis , Dogs , Gastric Acid/metabolism , Histamine/analysis , Histamine H2 Antagonists/pharmacology , Imidazoles/pharmacology , Male , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
Six 1,2-diphenyl-3,5-pyrazolidinediones substituted in the 4-position with small-ring cycloalkyl groups were prepared and tested for analgetic-antiinflammatory activity. Three of the synthesized compounds exerted an analgetic-antiinflammatory activity quantitatively superior to that of phenylbutazone used as a reference standard. In particular, one of the compounds (VI) proved twice as potent as phenylbutazone while possessing the same ulcerogenic effect.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Pyrazoles/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Pyrazoles/pharmacology , Rats , Stomach Ulcer/chemically inducedABSTRACT
In continuation of reasarch on polycyclic terpenoid amines and their derivatives, the synthesis of a new tricyclic amine: 7-methylamine-1,7-dimethyltricyclic[2,2,1,0(2,6)]heptane is described.
Subject(s)
Polycyclic Compounds/chemical synthesis , Terpenes/chemical synthesis , Amines/chemical synthesis , Crystallization , Indicators and ReagentsABSTRACT
During the study of the transpositions undergone by the amide of canphen-4-carboxylic acid on treatment with concentrated hydrochloric acid, the formation of the amide of 2-chlorobornan-4-carboxylic acid alone, arising in two polymorphous forms, has been confirmed. Its reduction produced 2-chloro-4-aminomethylbornane; the detachment of hydrochloric acid at the amide of canphen-1-carboxylic acid.
