IL33947A - D-2-(6-substituted-2-naphthyl) propanals,their preparation and pharmaceutical compositions containing them - Google Patents

Description

This invention relates to d propan The d ropanals of this invention can be represented by the following general In the above is a methoxy or methylthio j The compounds of Formula III exhibit and these compounds are employed in the treatment and alleviation of i pain and pyrexia in compounds of Formula III are especially useful in the treatment of such as inflammatory conditions of the muscular skeletal joints and other these compounds are useful in treatment of conditions by such as bone conditions and In those cases in which above conditions include pnin and pyrexia with the instant compounds are usoful for the of ons the measure of lammatory activity according to the induced endema in et of The Society for Experimental Biology and Medicine 544 shows d have fcimes the activity of phenyl The preferred manner of is oral tration which provides the use of the convenient daily dosage regimen which can be adjusted accordingly to the degree of a daily dose of from to 60 of the active compound per kilogram of body weight of the mammal is Most respond to the treatment comprising a dosage level in the order of to 5 For such administration a pharmaceutically acceptable nontoxic composition can be formed by the incorporation of any of the normally employed Suitable pharmaceutical pients include silica magnesium sodium glyceryl sodium dried skim propylene ethanol and the These compositions take the forms of sustained release and the In these pounds can be administered in conjunction with other medicinal agents depending upon the specific condition being The compounds of Formula III are prepared by a procedure which can be represented as In the above is as previously The compounds of Formula III can be prepared from the corresponding d propionic acids represented by Formula I by the following The latter compounds are first converted to the corresponding acid chlorides by reaction with thionyl chloride in benzene under reflux followed by evaporation of the The residual acid chloride is then treated with 2 equivalents of lithium aluminum tritertiarybutoxyhydride in an ether solvent as ethane and the like at a temperature of from to for from 30 minutes to 12 hours to yield the compounds of Formula III which can be recovered by conventional For the reaction mixture can be mixed with extracted with The benzene phase can then be evaporated in vacuo to and the residue recrystallized from The preferred process for preparing the compounds of Formula III comprises oxidizing the optical isomer propanols of Formula II corresponding to the respective d pro with chromium the molar ratio of the complex to the of Formula II being within range of from to about The reaction is conducted an inert organic solvent such as a halogenated dichlorcmethane carbon hydrocarbons such as and the amines such as and ethers such as ether and the The reaction is carried out at a temperatu of from 0 to 60 the time required being dependent upon the reaction Times of from 1 to 48 hours are usually The compounds of Formula II are then isolated from the reaction mixture by conventional For the reaction mixture be chromatographed on silica eluting with dichloromethane to yield the compounds of Formula II which can be crystallized from Compounds of Formula I can be prepared by any of several One such method by which they can be prepared is described in United Stated Serial 19G7 rial This method involves the reaction of a naphthalene with acetyl chloride in nitrobenzene in the presence of at least 3 molar equivalents of aluminum chloride to afford the corresponding naphthalene The resulting derivative is heated with morpholine in the presence of sulfur at about the resulting product is refluxcd with concentrated acid to furnish cetic acid The addition of a group at the position is out by esterifying the cid derivative by conventional methods such as by treatment with a such as in ether or with an such as in the presence of boron fluoride to afford the corresponding The ester product is then treated with sodium hydride an ether solven j such as and then treated with a methyl such as methyl to afford the ponding acid alkyl which is hydrolyzed to yield the unresolved compounds of Formula The of Formula I can be obtained by selective biological degradation or by the preparation of diastereo isomer salts of the propionic acid derivatives with resolved optically active amine bases such as cinchonidine and then separating the thus formed diastereo isomers by fractional The separated diastereo isomer salts are then acid cleaved to yield the respective d propionic acid The compounds of Formula II together with methods for their preparation have been described in United States July For they can be prepared by reducing the compounds of Formula I with lithium hydride in an inert organic ether The compounds of Formula I are treated with at least molar of lithium aluminum preferably 1 to inert organic ethers include diethyl dipropyl dibutyl and the The reaction is carried out at a temperature between and the boiling point of the solvent preferably between and The compounds of Formula II are then by destroying the excess lithium if such as by adding excess ethyl The mixture is then diluted with filtered and extracted with an inert organic solvent immiscible with The organic phase can be evaporated to and the compounds of Formula II obtained by recrystall the can be reduced by treating them with diborane in tetrahydrofuran at a temperature between 0 and 65 PREPARATION 1 To a mixture of of of acetyl and 20 of there are added of aluminum The resulting mixture is stirred for 48 hours at then it is washed with water until free of chloride The mixture is dried sodium sulfate and evaporated under reduced The is refluxed in 2 of morpholine containing gram of sulfur for two the reaction mixture is then filtered and The resulting reaction derivative is extracted with diethyl the extracts are combined and The residue is Sn 10 of oc c acid for two cooled to with sodium The then extracted with other and the extracts are washed water to ty dried and to yield acetic acid was prepared from the corresponding naphthalene by this PREPARATION 2 To mixture of 22 of methyl acetate by treating of acetic acid with of diazomethanc in and of sodium hydride in 150 of 2 of iodide are The reaction is allowed to stand for several then is diluted with ethanol followed by water and extracted methylene The extracts are washed water to over sodium filtered and evaporated to yield methyl The resulting product is added to a mixture of 15 of 200 of methanol and 25 The reaction mixture is allowed to stand for 24 then the mixture is acidified 200 of two normal chloric The acidified mixture is extracted with methylene the extracts are washed dried over sodium sulfate and evaporated to yield ropionic Similarly acid waa prepared from yl PREPARATION 3 230 portion of propionic acid in methanol is dissolved in of warm The resulting solution is boiled until it becomes then sufficient methanol is added to make the solution clear This hot solution is added to a solution of 296 cinchonidine in of methanol heated to about 60 The solutions are combined while and the mixture is then allowed to reach room temperature over a 2 hour After the reaction mixture has reached room it is stirred for an additional 2 hours and j then The filtered solids are washed with portions of cold methanol and 100 Grams of the cinchonidine salt crystals are added to a stirred mixture of 600 of ethyl acetate and 450 0 of a 2 aqueous hydrochloric After the mixture has been stirred for 2 the ethyl acetate layer is removed and washed with water to dried over sodium sulfate and evaporated to yield d ropionic PREPARA 4 To a mixture of of lithium aluminum hydride and 100 of ethyl there is added a mixture of of d ropionic acid and 100 of ethyl 0 The mixture is stirred at for 30 and 10 1 of water is added to the The resulting mixture is evaporated under reduced pressure to yield 1 Repeating the above procedure with the d isomer of the compound of Preparation 2 yields the corresponding optical isomers of This invention is further illustrated by the following but EXAMPLE 1 solution of 23 of d pionic acid in 100 of benzene and 20 of thionyl chloride is heated under reflux for 2 eaction mixture is then evaporated in vacuo to yield the corresponding acid A solution of the residue in 300 of tetrahydrofuran is cooled to and treated with 47 of lithium aluminum molar A er stirring the reaction mixture at this temperature for 1 the mixture is allowed to warm up to room temperature and is poured into The mixture is then extracted with and the organic phase is in vacuo to yield d propanal which is recrystallized from Repeating this procedure with the d isomer of the compound of Preparation 2 yields the ing d 2 A solution of 580 of 1 in of is treated with g of chromium and stirred at room temperature for 5 The mixture is then poured onto a column of silica Elution with dichloromethane yields 260 of d which is recrystallized from dichlorom in Repeating the above procedure with the compound of Preparation 4 yields the corresponding d 119 EXAMPLE Ingredients per tablet ά th propanal 10 cornstarch 200 sucrose are thoroughly mixed and pressed into single scored EXAMPLE 4 Ingredients Quantity per d propanal cornstarch 100 393 stearate The above ingredients are mixed intimately and pressed into single scored 14 insufficientOCRQuality

Claims (1)

1. d ropanal compounds represented by the wherein is methoxy or d d A pharmaceutical composition for use in treatment of and fever which in dosage form a compound of formula I in Claim 1 in combination with a pharmaceutically acceptable A process for preparing a d of formula I in Claim oxidizing the corresponding d th or reducing the corresponding d process of Claim 5 for preparing d process of Claim 5 for preparing d insufficientOCRQuality