IL38004A - 1,3-dihydro-1-(3-(benzoyl)propyl)-5-phenyl-1,4-benzodiazepin-2-one derivatives - Google Patents

Description

derivatives ROBINS 2 The present invention relates novel and is more particularl conoerned pharmaceutical compositions containing and methods of making and using the Israel Patent Specification inter benzodiazepine compounds substituted in the with a phenyl or monohalophenyl group and in the Imposition with a group where is a lower alkylene group and ma inter be a phenyl These known compounds have anticonvulsant novel phen have the structural formula 0 wherein R is hydrogen or and pharmaceutically acceptable acid addition The novel concept of the present inventio resides in the introduction of the radical into the one position of the nucleus to give the novel compounds of formula which 3 possess more anticonvulsant properties than the aforeeaid known compounds Example 3 The new compounds are particularly effective in blacking convulsive seizures induced in laboratory animals by electroshock and The compounds also possess minor and sedative The novel compounds of the present invention are ormulated for use by incorporating them into standard ceutical dosage forms tablets and containing to 500 the exact dosage varying with the weight and age of the subject being and the severity of the Amon the pharmaceutical which can be used are magnesium carbonate and The novel compounds of formula I form pharmaceutically acceptable salts with inorganic acids and strong organic acids and such salts are within the purview of the present The salts are formed using acids such as hydrobromic and sulfuric acids with strong organic a cids such as maleic and benzoic acids The salts are prepared by methods known to the The preparation of the novel may be accomplished by mixing and reacting the appropriately substituted with halides The reaction sequence is illustrated by the wherein has the values given and X is preferably The reaction of the ac hydrogen present on the amide nitrogen of the is carried out in an inert solvent by reaction with an alkali metal hydride or an alkali metal amide and the alkali metal salt of thus formed is reacted with the halide which is preferably used in the form of its as for increased yields and minimal formation of undesirable A general procedure for the preparation of the onea is as A stirred solution of a selected in a suitable organic solvent for dimethylformamide is treated with an equivalent amount of an alkali metal hydride in mineral oil or an alkali metal amide and the stirred mixture is heated at a temperature of from about to about until the evolution of gaseous An equivalent amount of is then added and the reaction mixture is four hours at the temperature range given The reaction mixture is poured into water and the product is extracted from the aqueous solution using a suitable organic solvent such as fluoro The henyl is stirred in dilute mineral acid at room temperature for a period of time sufficient fluoro to regenerate the free The product is isolated and is purified in an appropriate manner such as crystal lization from a suitable distillation or The used as starting materials are known to the art and are readily prepared by methods disclosed in Patent Example 1 propyl A suspension of of sodium hydride in mineral oil in 200 of was treated with 10 of and the temperature was raised to After gas evolution ceased the stirred mixture was treated with of and heated at for 24 The mixture was poured into extracted with the extracts were dried over magnesium sulfate and concentrated to an The oil was dissolved in a mixture of hydrochloric acid and benzene and stirred over night at room The layers were made the benzene layer was separated and concentrated to an oil after drying over magnesium The oil was chromatographed on a column of magnesium silicate using to From the column of a glassy solid was A sample was molecularly distilled for Calculated for Found Example 2 propyl A stirred mixture of of sodium hydride in mineral 011 mineral oil was removed with petroleum and of 7 in 200 dimethylformamide was heated at until the evolution gas To the stirred mixture was then added of and the heating continued at with four 200 amounts of The benzene extracts were mixed with 200 of hydrochloric acid and the heterogeneous mixture stirred overnight at The heterogeneous mixture was made basic using dilute sodium hydroxide the layers were separated and the benzene layer after drying over magnesium sulfate was concentrated to an The oil was chromatographed on a magnesium silicate column using the The product was recrystallized repeatedly from iso propanol to give pure material which melted at calculated for Found Example 3 The pharmaceutical activity of the oompounda of Example 1 and was with that of known from Israel Patent 21557 and also with that of a synthetic oompound in which a fluorine eubatituent was duoed into the of the radioa 8 The compounds tested were the from Israel Patent j compound of Example i Ί Example j ANTICONVULSANT MUSCLE RELAXANT ACTIVITY SEDATIVE ACTIVITY AND ACUTE ORAL TOXICITY Anticonvulsant Anticonvulsant activity of compounds was determined by the methods of Toman et and Swinyard 1952 The values were calculated by probit analysis with confidence limits determined by the method 6f Litchfield and When so all results were statistically significant when compared with The compounds were injected intraperitoneally to groups of five female mice using geometrically spaced Behavioral effects were noted thirty minutes after 12 13 insufficientOCRQuality

Claims (1)

1. CLAIMS having the structural formula wherein is hydrogen or and their pharmaceutically acceptable acid addition and pharmaceutically aooeptable aoid addition and pharmaceutically acceptable acid addition k pharmaceutical composition containing as active ingredient a oompound acoording to any one of Claims 1 to ProcesB of preparing a acoording to any one Claims 1 to wherein a substituted of insufficientOCRQuality