Numerous clinically used compounds having favorable tranquigiing and toxic properties possess the 1,4-benzodiazepine skeleton. This group of active substances is readilyaccessible, e.g. by ring enlargement of quinazoline derivatives, by ring contraction of benzoxadiazocines, and by synthesis from aminobenzophenones, constructing the sevenmembered ring in many cases in one step. The relationships between type and position of substituents and the pharmacological properties are illustrated using 1,3-dihydro-5-phenyl-1,4-benzodiazepin-2-ones as examples.
General IntroductionThis review is meant to give a short outline of the history of the discovery and further development of the chemistry of tranquilizers of the 1,4-benzodiazepine type. It will be limited with very few exceptions to published and also unpublished work carried out in our laboratories~"]. It will concern itself mainly with the most important synthetic routes leading to pharmacologically and clinically interesting types of 1,4-benzodiazepines, and will contain also a short discussion of the pharmacological properties of these compounds.In view of this, the main subject will be 5-phenyl-1,4-benzodiazepine derivatives which are the most extensively studied group. It should, however, be pointed out that most of the reactions have been used for the synthesis and transformations of 1,4-benzodiazepine derivatives bearing substituents other than phenyl on C-5.
. IntroductionIn the search for a new class of drugs possessing tranquilizing properties similar to those of meprobamate and chlorpromazine, it was decided in the middle 1950's to investigate new types of heterocycles which might ultimately lead to compounds showing the desired properties. As a rather neglected group of chemically interesting compounds, we selected the benzheptoxdiazines, as they were called in the German scientific literature.The first compounds of this t e were obtained in 1891 by van Auwers and von Meyenburgfi by dehydration of o-acylamino ketoximes (1) or aldoximes with a Beckmann mixture. At that time they were considered to be acylindazoles (2).These compounds were further studied in 18931'1 and reinvestigated in 1924c3] when it was agreed upon that they are best represented by structure ( 3 ) . In the mid thirties, a few further members of this class of compounds were prepared, specifically compound (4)F41 and dose analogs thereof. They were relatively easy to synthesize, crystallized very well, and were easy to purify. These were the reasons which made this group of heterocycles so attractive for [ ' I Dr. Leo H. Sternbach Chemical Research Department, Hoffmann-La Roche Inc., Nutley, New Jersey 071 10 (USA) [**I For a complete review see G. A. Archer and L. H. Sternbach, Chern. Rev. 68, 747 (1968). further exploration. Derivatives to which basic substituents could be attached, as illustrated by conversion of (5) into (6), appeared to be particularly interesting.Closer chemical study of these compounds led to the conclusion that the so called "benzheptoxdiazines" did not ...