History of anti-anxiety (anxiolytic) drugs is more than 6000 years. Quite possible, that alcohol and opiates were used as first anxiolytics because their medical application for such aims was determined in Minoan and Mycenaean cultures of XV and XIV-XIII cc B.C. as well as in Ancient Egypt. Teofast, the doctor who was a probationer in Ancient Hellas, prescribed opium to mentally diseased patients as soporific and sedative (“About treatment of insane people”).
At the beginning of XIX century bromides were used in the role of anti-anxiety medications and at the beginning of XX century – their place was occupied by barbituric acid – barbiturates. Anxiolytics arsenal was replenished with nonbarbituric sedative preparations (reserpine) in the middle of the century. However the use of mentioned above medicaments was accompanied with difficulties connected to absence of selective anti-anxiety action in concerned preparations.
The situation has significantly changed after synthesis of the first tranquilizers (meprobamate). As far as meprobamate at that times was considered to be quite a perspective anxiolytic with more selective anti -anxiety action if compare to barbiturates, Swiss pharmaceutical company “F. Hoffmann La Roche” in the beginning of 50s years has made a decision to start investigations to find a new substance of the same type. As L. H. Sternbach, a head of the scientific program, recollected, knowledge about biochemical processes in the brain, at that time was quite limited, that is the reason why the work was intended to be carried out in purely empiric way.
There was undertaken a search of materials which would allow to synthesize the largest quantity of new representatives of a certain chemical class for relatively a short period of time. In the judgment of the researchers the role of such chemical compounds was played by group of heterocyclics which have been studying since the beginning of 30s years. A number of substances of the type was synthesized. They were successfully crystallized and they easily created water-soluble salts but unfortunately, they did not possess necessary biological characteristics. However, in the course of investigations there was specified the chemical structure of the substances which were identified in future as quinasolin 3-oxides. As L. H. Sternbach recollects, soon after that, the work as for new quinasolins synthesis was stopped as “other problems, which seemed to be more important, required the use of all laboratory resources”.
In April 1957, during a careful tidying up of the laboratory rooms, doctor Earl Reeder, one of the colleagues of L. H. Sternbach, by pure accident paid attention to some hundreds of milligrammes of other substances: glacial compound of quinasolin 3-oxide with methylamine and its hydrochloride. Pharmacological checkouts have found out marked characteristics in one of them. These characteristics were typical for tranquilizers and sedatives, but, in contrast to chlorpromazine, reserpine and phenobarbital, they had more selective anti-anxiety action. Specification of the chemical structure of compound of quinasolin 3 –oxide with methylamine has shown that the present compound was not quinasolin- N –oxide any more and contained 7-members diazepin ring. The discovered facts gave the opportunity to apply in May 1958 for 2-amino-1,4 - benzodiazepine- 4-oxides with different vicarials in initial chemical structure. The novelty of synthesized substances allowed getting a patent without any difficulties by July 1959.
Barbituric acid was synthesized by professor of organic chemistry of Berlin industrial academy Adolph Byer in 1863 and was named in honour of Barbara – a friend of the scientist. Later in 1904 Emil Fischer and Josef Mering discovered salts of barbituric acid – correspondingly barbital and phenobarbital. Further barbital got the name “veranal” in honour of the city Verona (north Italy), where Romeo and Juliet tragedy happened - that was the name of a sleeping drink which the monk gave to Juliet. (Votchal B.E. “Essays of clinical pharmacology”).
All first synthesized benzodiazepine derivatives possessed similar biological characteristics and none of them differed too much from initial substance and surpassed in effectiveness. Just the first derivative of benzodiazepine–chlordiazepoxide was chosen as a subject of more detailed clinicopharmacological study.
During long-term studies of toxicity the brilliant results were gotten and clinical trials data looked hopeful. The interest of clinicians to new preparations was increasing very quickly – the number of patients who took benzodiazepine derivatives in the frames of different studies has grown to 16000 very soon. Apply for NDA was accepted without any complications and due to a positive relation of FDA it was approved in a record short period of time. Already in 1960 (in 2.5 years after start of pharmacological studies) the first from 1, 4 – benzodiazepines of central action – chlordiazepoxide with a trade name “Librium” (Libre – free, French; Liber – freedom, Lat.) went on the drugstores.
At the same time there were carried out experimental investigations on wild animals in San Diego Zoo and in laboratories of the company “Roche”. Doctor Leonard Hines was their initiator. On the basis of new data additional methods of synthesis of benzodiazepine derivatives were created. The process of alkylation appeared to be the most important from all. There was gotten a number of benzodiazepine derivatives, which were subjected to intensive pharmacological study. The appearance of new substances has contemporized with termination of Librium clinical trials. Their great results inspired the researchers for search of more effective preparation which could be widely adopted in the clinical practice. Comparison of Librium with other benzodiazepine derivatives already available at that time has not discovered significant differences in the spectrum of clinical activity. From all tested substances there was singled out the most active one – 1- methyl derivative of chlordiazepoxide.
Deep studies of pharmacological properties and toxicity as well as wide clinical trials of the new substance ended with purely good results. A decision was made as for preparation for new drug introduction which got a generic name Diazepam. In 1963 application of Diazepam with a trade name Valium took place. If compare with Librium, Valium found out really wider spectrum of clinical activity, first of all more pronounced neuromuscular action. Toxicity of new medicament appeared to be extremely low.
Already in the course of the first studies there was established an important role of chemical elements’ substitution in the structure of chlordiazepoxide. As a result the substance with maximally active combination of elements was synthesized. As it was expected, the received matter appeared to be one of the most pharmacologically active medications. The new preparation with a generic name Flunitrazepam and a trade name Rogipnol was introduced in Switzerland and other countries in 1975 as a powerful hypnotic preparation, therapeutic active dose of which was 1-2 mg.
An intensive search of new benzodiazepine derivatives continued and in some years the number of 1,4–benzo-getero–diazepines was more than 300. Total sum of received, identified and studied ones was about 4000 of interim and by-products.
With benzodiazepine derivatives’ appearance a new period in anxiety disorders treatment began. Nowadays benzodiazepine derivatives is the largest group of anxiolytic preparations, it counts more than 100 active substances, registered in different countries as medicaments. Problems connected to their use were widely discussed during a number of recently carried out symposiums, including the American psychiatric association conference (May 1997, San Diego, California, USA) , international conference “Anxiety-phobic and obsessive-compulsive disorders (clinic, therapy, neurophysiology, epidemiology)” (November 1997, Moscow).
