IL36248A - Therapeutically active dihydrobenzo-thiazine-s-dioxides and process for their preparation - Google Patents

Description

NOVEL THERAPEUTICALLY ACTIVE AND PROCESS FOR THEIR PREPARATION Novel therapeutically active and process for their preparation The present invention relates to certain novel derivatives of of the general formula wherein X designates a branched chain group of 1 to 3 carbon and designates a 2 2 wherein and vhich the same or each designates hydrogen or or having a straight or branched chain of up to and including carbon or a phenyl group R and 2 R together with the nitrogen atom to which they saturated nitrogen containing are attached or represents a group of the 3 wherein and R which are the same or each designates hydrogen or lower alkyl or a phenyl group or they form together an having 2 or carbon A preferred compound of special interest is 3 The compounds formula I are charac by their activity on the central nervous system and particularly by their sedative and hypnotic Compounds of the I are prepared according to the invention by one of the following of the formula is condensed with a compound of the formulas X CO wherein X and R have the above indicated meaning and designates halogen or an sulphonic This condensation is effected in the presence of an alkaline A compound of the wherein X has the meaning indicated above and represents a halogen preferably chlorine or a lower a is with a compound wherein R has the meaning indicated A compound of the is subjected to cyclisation with a compound of the where X and R have the meaning given in the presence of an alkaline For preparing compounds for formula I wherein R designates a groups N where R and form together an alkylidine group or there is reacted a hydrazide of the wherein X is as defined with an aldehyde or a ketone of the formula R wherein is an alkylidene group or The desired hydrazone is formed with elimination of a molecule of In order to 2 obtain N hydrazide corresponding to this compound the double bond is saturated by a catalytic hydrogena tion or by reduction by means sodium borohydride in a methanolic The 2 which is a starting material for the procedure in is a novel compound and it is obtained by different routes which are ted in the following reaction As indicated in the above reaction scheme one can start with the hydrochloride of nitrile which is diazotized in a hydrochloric solution and the resulting diazonium derivative is acid of SO2 treated with an acetic n the presence of as catalyst in order to obtain the chloride of which is transformed into by the action of Catalytic hydrogenation of this intermediate in the presence of palladized carbon in an acid medium results in which is a desired It is possible to transform sulfonyl chloride by hydrolysis with the aid of into potassium by catalytic reduction in the presence of palladized yields benzenesulfonic acid The latter is subjected to eyelization at an elevated temperature in the presence of with elimination of HgO and formation of said desired The latter may also be obtained from starting with aniline hydrochloride The by diazotiation in hydrochloric solution and treatment with an acetic acid solution of in the presence of as catalyst yields benzenesul onyl chloride by successive ment with ammonia and sodium hydroxide at elevated temperature is cyclized and yields the desired The intermediates H are novel In order to prepare the benzothiazine derivative utilized as starting material in procedure is treated with an alkyl in the presence of an alkaline agent in order to obtain a corresponding alkyl which is saponified to the acid treatment with The liberated is transformed into the chloride by treated at elevated temperature with The following examples 1 to 11 illustrate the preparation of the starting materials for the process according to the present Example Chloride 253 g of chloride by salification of tonitrile et Lindwail Journal American Chemical Society l950 are suspended in 1 liter of concentrated hydrochloric acid and diazotized at with 5 g 5 of sodium nitrate dissolved 225 of After the ice solution poured in a number of portions into a mixture of 1500 ml of acetic acid containing about 180 g of and the reaction mixture is vigorously while a quantity of 30 g is added in many portions in order to enhance and maintain thevigorous reaction is obtained a vigorous evolution of nitrogen and a strong formation of After stirring for a further dilution with water volume of the suspension about there is obtained a yellow solid which is washed with and dissolved in the cold in 3 liters of The solution is washed until neutral and dried over sodium sulphate while being treated simultaneously in the cold with decolo izing after filtration the solution is for the preparation of By evaporation there is obtained a residue which is taken up in a little of or ethyl alcohol resulting in the sulfonyl o 24 Example 2 onamide A solution of the is treated during half an hour starting with 253 g of hydrochloride with a moderate stream of gaseous ammonia maintaining o the temperature between with there is obtained a solid which is washed with a little The solid is dried by the brief application of a hot air stream in order to eliminate the It is suspended in water in order to eliminate the ammonium chloride and dried in a current of hot There is obtained 157 S of the By recrystallization from and decolorization with carbon there is obtained l4l g of the Calculated 4 Example 3 Potassium A quantity of g of crystalline chloride is dissolved in ml of methanol and the solution is treated g of potassium hydroxide dissolved in 65 of methanol and is left to stand at powdery potassium chloride is separated and after this there starts to form crystals which settle in the reaction These are filtered off and left to stand at There is obtained a quantity of g of the By evaporation of the mother liquid there is obtained a second crop which is srystallized from methanol yielding a further g of the mixture It is recrystallized and after drying under vacuum over obtained a product of Exam 4 benzenesulfonic acid A solution of g of potassium onate in 1800 ml methanol is treated with 100 ml of concentrated hydrochloric the reaction mixture is chilled on ice and after filtration of the potassium chloride the filtrate is treated with decolorizing filtered and subjected to tion at ambient temperature and pressure with of palladized carbon After filtration the catalyst is washed with hot the filtrate is evaporated and the residue is crystallized from aqueous yielding 18 g of the product C 19 93 5 51 6 75 Example 5 Chloride 5 g of aniline hydrochloride and Hafez Journal 287 are suspended in a mixture of 20 ml of water and 20 ml of glacial acetic acid and ml of concentrated hydrochloric The iced solution is afterwards with decolorizing filtered and there is added at once with stirring a mixture of 180 ml glacial acetic acid g of 11 g in 200 ml The reaction mixture is heated to in order to enhance the reaction which continues When the temperature reaches about after about 30 the reaction mixture is diluted e with 300 ml of water the phase is separated and the aqueous phase is extracted with The united extracts are washed with with an aqueous solution of sodium again with dried and evaporated under reduced The brown residual oil is yielding a fraction boiling at at H is a yellowish oily substance which upon refrigeration solidifies to a large The solid is put on a porous plate or on a filter paper treated with a little yielding 11 g of a solid nearly After crystallization from ligroin it melts at Poundj Example 6 A suspension of g of 2 benzenesulfonyl chloride in 3 ml of concentrated ammonia is heated on a water the suspended material melts and afterwards After addition of 2 ml of sodium hydroxide the reaction mixture is for again heated an chilled and acidified with hydrochloric a solid precipitates which after crystallization from water yields g of the A quantity of g of benzenesulfonic acid is treated with 70 ml of and the reaction mixture is boiled n After evaporation under reduced pressure the residue is treated with ice and NaOH The alkaline solution is treated at elevated temperature with decolorizing filtered and acidified with hydrochloric yielding g of the crystallized product after recrystallization from A quantity of 110 g mo of crystallized is dissolved in liters methanol and the solution is treated at elevated temperature with and to the filtrate chilled on ice there is 730 ml of 73 concentrated hydrochloric 15 palladlzed carbon and hydrogenation is effected at ambient temperature and The absorption takes place gradually is continued for about 8 After concentration to a volume under pressure and leaving to stand in the there is obtained a product which is washed with and dried under a current of hot There is obtained of the desired φ For t Calculated Example 3 et To a solution of g of sodium 100 ml of absolute alcohol there is added g of dissolved in 125 of absolute The reaction mixture is treated with g of ethyl bromoacetate and 1 Afterwards the solvent is evaporated and the residue is treated with sodium After extraction with ether and drying over anhydrous the solvent is evaporated the residue is yielding 6 g of the product in the form of a yellowish clear oily very at 1 mm S Founds Example 8 The crude ester obtained from g of obtained according to the preceding is dissolved in of g of potassium hydroxide dissolved in 5 of methanol is added and the reaction mixture is heated under reflux during After the evaporation of the solvent the residue is crystallized from absolute alcohol yielding g of a white product stituted by the potassium of acetic from which is obtained on acidification the free which after from has a S C Calculated 0 Calculated 11 Example 9 ia To the suspension of g of acetic in ml of anhydrous benzene there is added ml reaction mixture is 1 The solvent and the excess of are eliminated by evaporation under reduced pressure and the residue is crystallized from ized with yielding 9 g of a white crystalline product 24 3 88 07 Example 0 butyric acid ethyl ester To a solution obtained from 1 15 g metallic sodium g in 20 ml absolute alcohol there is added a hot solution of g of in 80 ml absolute the reaction mixture is stirred dui g 10 minutes and about 8 ml 055 of ethyl bromobutyrate are added and boiled under reflux during 4 The solvent is evaporated under reduced pressure the residue is treated with chloroform and sodium hydroxide the phase is separated and washed with sodium with water until and dried over anhydrous After evaporation of the solvent there is obtained an oily residue which yields by distillation g of a product at mm in the form of a limpid liquid of yellow Fori 0 S S Founds Example 11 Butyric A quantity of g of k ml of an aqueous N solution of are boiled under refulx during 4 treated with decolorizing filtered and introduced drop by drop into an excess of hydrochloric The desired acid precipitates and after leaving to stand overnight in the cold there is obtained by filtration on a funnel the desired crystalline substance which is washed with water and xecrystallized from aqueous There is obtained g of a white crystalline Calculated Founds The following examples illustrate the process according to the Example acetic acid benzothia is dissolved in ml methanol saturated anmonia the reaction mixture is left to stand at ambient temperature during 4 hours while being stirred from time to After dilution with 80 ml it is under for some decolorized with carbon and By chilling there is obtained g of a crystalline while The mother liquid is concentrated to 30 ml resulting in a further crop of g of the product having the above Calculated Founds Exam A quantity of g ml of is to of e thymester dioxide in 10 ml After standing in a closed receptacle at ambient temperature during 48 hours with stirring from time to time it is heated briefly to boiling and the solvent is evaporated under reduced The oily residue It is suspended in ether and there is a solid which is separated by filtration of a There is obtained g of a product of by crystallization from alcohol and decoloriza Port Calculated 95 35 Example To a solution of sodium methylate obtained from 7 g of metallic sodium in 200 ml of methanol there is added at ambient temperature g of and the reaction mixture is boiled with stirring during After chilling to ambient temperature there is g of and the reaction mixture is brought again to the boil with agitation during 3 The methanol is distilled off and the residue is taken up into 200 ml of methylene the organic solution is four times with 100 ml each time of NaOH and twice with dried over sodium sulphate and The residue is crystallized from and there is obtained 44 g of the product 55 11 36 Founds 77 Example dioxide A quantity of 2 ml of is added to g butyric suspended in 35 of anhydrous re hours and decolorized with and taken again in benzene in order to eliminate the excess of SOClg and nally the residue dissolved in ml of anhydrous This solution is introduced gradually drop by drop with stirring into 50 ml of benzene and a current of gaseous ammonia is bubbled the passage of ammonia is continued for a further hour and the reaction mixture is left to stand for a few hours resulting in a precipitate which is filtered off on a and There is obtained g of a white crystalline product by crystallization from aqueous ethanol Founds Example 16 dioxide To g of acetic acid ethyl ester lved in 40 ml of methanol there is added g of hydrazine hydrate and the reaction mixture is for ation r ef 4 After filtration and refrigeration there is obtained g of the crystalline product 04 Example To ml of in 30 ml of anhydrous benzene there is added gradually drop by drop at ambient temperature S of chloride dissolved in 90 ml anhydrous After stirring for 8 at ambient temperature the solvent is evaporated reduced pressure the residue is treated with chloroform an aqueous solution of organic phase is washed with and dried over anhydrous decolorized with carbon and the solvent is The oily residue solidifies upon treatment with The solid is obtained by filtration on a funnel and crystallized from aqueous ethanol resulting in g of a white crystalline Fori le 18 0 acethydrazi To g of dissolved in ml of methanol there is ml to stand overnight in a closed There is obtained an abundant precipitate which is separated by filtration on a funnel and crystallized from absolute alcohol resulting in g of white crystalline l 7 Example 19 To g of suspended in ml of anhydrous methanol there is added portionwise with chilling and stirring of The resulting solution is stirred at ambient temperature during an and after this The solvent is evaporated and the residue is treated with aqueous NaOH and the oily base is extracted with the extract is dried over anhydrous and treated with decolorizing and with hydrochloric The hydrochloride of the After to stand overnight in the cold the precipitate is filtered on a dried and crystallized mixture There is obtained g of the desired product in the form of white Example 20 thia 1 To a solution of g of in 120 of absolute ethanol there is added g g of metallic sodium dissolved in 40 ml absolute salt g of in 20 ml absolute alcohol and a small quantity of potassium After boiling under reflux during 7 hours evaporation of the solvent at reduced pressure on a water bath there obtained an oily residue which is treated with 250 ml of chloroform and of the extracted organic phase is separated and washed again with 50 ml of of NaOH and afterwards with water dried over anhydrous After decoloration with and evaporation of the solvent there is obtained an oily residue which er By from a water alcohol mixture there is obtained g of a white crystalline 5 Founds In the following Table I there are given melting points and other analytical of analogous products prepared according the preceding 19 I A ethyl alcohol TT insufficientOCRQuality

Claims (1)

1. WHAT IS CLAIMED of of the general wherein X group of 1 to 3 carbon and group of the wherein and R be identical different each designates hydrogen or an or alkynyl group having a straight or branched chain of not more than carbon or a phenyl group or 1 2 and R form together with the nitrogen atom to which they are a or R designates a group of the formula wherein J and R which are identical or each designates hydrogen or a lower group or a phenyl group or form together an group containing 2 or 3 carbon Process for the preparation of compounds according to Claim 1 characterized in that of the formulas is condensed compound of CO R X and have the meaning given in Claim 1 and Q designates halogen or a sulphonic acid Process for the preparation of compounds according to Claim characterized in that a compound of the formulas wherein X has the meaning given in and designates an halogen atom or a lower alkoxy group la condensed with a compound of the formula wherein R has the meaning given Process for the preparation of compounds according to Claim in that a compound of the is subjected to cyclisation by reacting it with a compound of the formula X CO R wherein X and R are as defined in Claim f Process for the preparation of compounds according Claim 1 wherein R designates a group of the wherein and form together an alliylidene group of 2 or 3 carbon characterized in that a of the formulas wherein is as defined in Claim 1 is rested with an aldehyde or a ketone of the formula wherein is an of 2 or 3 carbon according to Claim 6 charac in that one molecule of hydrogen is added to the compound obtained so as to form a compound of the is an group of 2 or 3 carbon atoms and X is as defined in Claim Derivatives of dioxide of the general formula as defined in Claim as hereinbefore described and with reference to any of the Process for the preparation of compounds as claimed in Claim substantially as hereinbefore described and with reference to any of the Pharmaceutical containing an active insufficientOCRQuality