Patent GB-858558-A (GB)
Title: Diazepine derivatives
IPC: A61K31/00
Filed: 1958-01-21
Abstract: The invention comprises (1) a process for producing compounds of the general formula:  <FORM:0858558/IV(b)/1> (wherein R and R5 each represent hydrogen or carbamoyl, X represents hydrogen, halogen or alkyl and R1, R2, R3 and R4 each represent hydrogen or alkyl) by p reacting o-phenylene-diamine or an appropriately nuclear-substituted o-phenylenediamine with a b -diketone R1,CO,C (R2R3),CO,R4 or an acid R1 CH=CH,COOH or a malonic ester or mono-or di-substituted malonic ester or diethyl mesoxalate, to produce, respectively, an unsaturated, monoketo, diketo or triketo heterocyclic intermediate, if desired reacting this intermediate with one or two molar equivalents of nitro urea to add one or two carbamoyl groups, and reducing the intermediate or its mono- or di-carbamoyl derivative to produce the required saturated derivative of diazepine, the carbamoylation being effected either before or after the reduction; and (2) as new compounds, the compounds of the above general formula except unsubstituted tetrahydrobenzodiazepine, and non-toxic water-soluble salts thereof.  The reduction stage in the above process is advantageously effected with lithium aluminium hydride. In Examples (1) o-phenylenediamine and crotonic acid give 2-oxo-4-methyl-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydro diazepine and this is reduced to 2-methyl-1 : 5-benzo-2 : 3 : 4-5-tetrahydrodiazepine; (2) acetylacetone and o-phenylenediamine give an unsaturated intermediate which is hydrogenated in presence of platinum oxide to give 2 : 4-dimethyl-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine; (3) the product of (1) is carbamoylated to give the 1-carbamoyl-4-methyl compound; (4) the product of (1) is dicarbamoylated to give the 1 : 5-dicarbamoyl-2-methyl-compound; (5) the intermediate of (1) is carbamoylated to give 1-carbamoyl-2-methyl-4-oxo-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine and this is reduced to 1-carbamoyl-2-methyl-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine, which is also prepared by reacting the product of (1) with benzyl chloride to give 1-benzyl-4-methyl-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine, carbamoylating this to 5-benzyl-1-carbamoyl-2-methyl-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine and debenzylating this by hydrogenolysis; (6) the product of (2) is monocarbamoylated; (7) 1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine (prepared by reacting o-phenylenediamine with p-toluenesulphonyl chloride to give N : N1-bis-p-toluenesulphonyl-o-pheny-lenediamine, reacting this with trimethylenedibromide in presence of sodium and butanol to give 1 : 5-di-p-toluenesulphonyl-1 : 5-benzo-tetra-hydrodiazepine and heating this with sulphuric acid) is monocarbamoylated; (8) crotonic acid and p-chloro-o-phenylenediamine give 2-methyl-4-oxo-7-chloro-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine, this is monocarbamoylated to give 1-carbamoyl-2-methyl-4-oxo-7-chloro-1 : 5 - benzo-2 : 3 : 4 : 5-tetrahydrodiazepine and this is reduced to 1-carbamoyl-2-methyl-7-chloro-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine; and (9) 3 : 4-diamino-toluene and acetyl acetone give an unsaturated intermediate which on reduction yields 2 : 4 : 8-trimethyl-1 : 5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine and this on carbamoylation gives the 1-carbamoyl compound. Hydrochlorides of some of the products are described, and sulphates are also referred to.ALSO:Pharmaceutical compositions, stated to be suitable for use as sedatives, comprise a compound of the formula: <FORM:0858558/VI/1> (wherein R and R5 each represents hydrogen or carbamoyl, X represents hydrogen, halogen or alkyl and R1, R2, R3 and R4 each represents hydrogen or alkyl) or a non-toxic, water-soluble salt thereof in admixture with a pharmaceutical carrier, desirably in dosage unit i.e. coherent units containing a desired dose, form. They may take the form of tablets, powders, capsules or suspensions. Examples describe tablets containing 2-methyl -1:5-benzo-2:3:4:5-tetrahydrodiazepine dihydrochloride or 1-carbamoyl-4-methyl-1:5-benzo-2:3:4:5-tetrahydrodiazepine, and capsules containing 1:5-benzo-2 : 3 : 4 : 5-tetrahydrodiazepine dihydrochloride or 1-carbamoyl-2methyl-1:5-benzo-2:3:4:5-tetrahydrobenzodiazepine.