IL31199A - Alpha-monoglyceride of 4-(2'-carboxyphenylamino)-8-trifluoromethylquinolines - Google Patents

Description

MONOGLYCERIDE CARBOXYPHENYLAMINO New quinoline derivatives and of Company The present invention has as object new derivatives as well as a process for preparing these The invention has more specifically as object quinoline derivatives of general formula in which the radical is at the and R and each represent hydrogen a radical of formula and being aralkyl or aryl as well as the therapeutically compatible mineral or organic salts of the compounds for The compounds object of the invention are Among the compounds of general formula I may be as particularly the following compounds and its and its The process of the invention is illustrated by the annexed diagram it is essentially characterized in that one causes a act on a to form the ketonide of with R which is possibly subjected to an acid hydrolysis to obtain the corresponding salt of 3 8 by the action of a basic provides the free then if this latter compound into the desired therapeutically compatible The group of the substituted is chosen from the lower and one uses specifically the The one condenses with the quinoline derivative is specifically The reaction of the with is advantageously effected in the presence a basic agent such as an The elimination of the alkanol formed can be obtained specifically by heating the medium above the alkanol boiling point or by under reduced The hydrolysis of the ketonide of in the presence of an acid agent such as hydrochloric sulphuric acid or and by preferably eliminating the free ketone from the reaction by The basic agent used to decompose the salt of with R is specifically caustic caustic sodium sodium trisodic phosphate or trisodic The action of the basic agent on the salt is effected or in a mixture of water and one or solvents such as dimethylformamide It is not necessary to isolate the The basic agent can be made to act directly in the reaction hydrolysis of the or else after having introduced into this a solvent or a mixture of suitable The therapeutically compatible acid chosen to salify the for which R is specifically hydrochloric acetic citric maleic nicotinic acid and malic The 8 can be prepared notably and an An example of such a leading to the obtaining of a compound not described in the is given below by way of It is worthy of note that this compound possesses a notable action and an intense analgesic The compounds of formula for which R can likewise be prepared by a variant of the process of the invention illustrated by the annexed diagram and which is essentially characterized that condenses an anthranilate of in the presence of an with to obtain with R The acid a the condensation of and of the anthranilate of is specifically hydrochloric acid or sulphuric are obtained processes similar to those used by and and ROBERTS or similar to that of French Patent by condensing the suitably substituted derivatives of aniline with ethyl ethoxalylacetate ethyl ethoxymethylene or acrylic by cyclizing the product by releasing the possible additional carbox l b sa by then by The of dioxolan can be obtained according to method described French Patent following examples the invention Example It at the and To 80 of 2 dloxolane adds 100 of then distils off the toluene unde reduced ao as to eliminate the water the anhydrous thus one under inert of oily suspension of sodium then 6f One agitates for five at in vacuo between and 100 of One adds an aqueous solution of sodium extracts the aqueous phase methylene washes the methylene chloride extracts with dries concentrates to dryness by distillation under reduced washes the residue with petroleum ether dries crystallizes it in isopropyl ether and obtains o The product appears in the form of colourless soluble in acetone and methylene little soluble in isopropyl ether insoluble in 61 9 As far is this compound is not described in the The starting product ethylqui is obtained according to the process described Stage ethyl malonate A mixture of of and 5 ethoxymethylene ethyl malonate carried to under inert One maintains it for one hour at this while eliminating distillation the ethanol One finishes the elimination of ethanol by distillation under reduced cools and collects 115 of anilinomethylene ethyl used as it is for the following A sample of this product is crystallized in petroleum ether As far as is this compound is not described in the methylene ethyl obtained in Stage and of phenyl oxide is heated under At about the ethanol formed begins to At the end of about 30 the interior temperature reaches and the reaction mixture is carried to One maintains reflux for one adds 2 of allows to isolates by iltering the crystals thus washes dries them and obtains of used as is for the following A sample of this product is crystallized in As far as is this compound is not described in the Into a mixture of of water and 100 of aqueous solution of caustic one under inert of crude obtained in Stage One carries the reaction mixture to reflux and maintains it there for two hours and The solution obtained is poured over a mixture of ice and 100 of solution of hydrochloric One isolates by the precipitate thus washes it with introduces it into a solution of 20 of sodium bicarbonate in 2 litres of with acetic acid so as to bring the pH to about One isolates the precipitate formed washes dries it and obtains of used as it is for the following A sample of this product is crystallized in the hot and in with treatment with One thus pure 51 As far as is this compound is not in the Stage lquinoline Into 110 of one under inert crude obtained in Stage One carries the mixture rapidly to reflux and reflux for an hour and fifteen One cools the reaction mixture to about adds thereto 20 of isopropyl cools it to and allows to One isolates by the precipitate washes dries it and obtains of A sample of this product is crystallized in with treatment with One thus obtains pure As far as is this compound is not described in the Stage luoromethyl quinoline Into of phosphorus one by small of crude obtained in Stage leaves for 15 minutes ambient then carries to reflu and maintains the reflux for one One eliminates the excess phosphorus oxychloride by under reduced To the resin one adds then 80 of aqueous solution of ammonia at One extracts the aqueous phase with washes the ethereal extracts with a dilute aqueous of ammonia then with After treatment with charcoal and concentration to obtains of methylquinoline which one uses as it is for the preparation of A sample of crude is crystallized in petroleum ether 2 Founds 52 2 As far as is this compound is not described in the Stage methyl quinoline with trifluoromethyl at the one introduces of crude fluoromethylquinoline obtained in then methyl anthranilate One reaction mixture to reflux and it there for fifty One allows the crystallization to isolates by the precipitate introduces it into 300 of saturated aqueous solution of sodium adds methylene eliminates by filtration insoluble separates by decantation the organic washes it with water and concentrates it to The residue is crystallized in methanol and one obtains Absorption at 3297 d 3264 corresponding the groupin Absorption at 1691 corresponding to the carbonyl Absorption at cm and cm corresponding to the C As far as is this compound is not described in the Example with at the and R H introduces of acetonide in example brings the temperature of the reaction mixture maintains for cools to allows to isolates the crude by washes it and introduces it into a mixture of 60 of 40 of water and 10 of triethylamine There is dissolution the One isolates the crystallate by washes it and obtains 16 of crude The crude base is crystallized in methanol with treatment with charcoal and one obtains of compound appears in the form of a solid soluble in the and very little soluble in methylene and insoluble in Analysis C Example at and R the variant of the One heating at a mixture of 48 of anthranilate in French Patent One leaves the filtrate at a temperature of for three the it then introduces it into a mixture of of amide 160 of water and One isolates the crystallate by washes dries it and obtains of methylquinoline identical to the product Example As has been indicated the products according to the invention are endowed with interesting pharmacological They possess specifically a notable inflammatory action and an intense analgesic They can be used treatment of all the muscular articular or rheumatic dental migraines and as supplementary treatment of febrile and infectious These products are used by rectal or by local route in topical application on the skin and the can be presented in the form of injectable solutions or dispensed in in dose as coated suppositories and The useful dosage ranges between milligrammes and one gramme day in the adult depending on the derivative used and route following pharmacological annex shows advantage of the with the corresponding Table I Pharmacological Annex COMPARATIVE TESTS following comparative tests were conducted to determine the and analgesic activities of trifluoromothylqainoline and glafenine or DATA Activity on Inflamed Paw Induced by used ia that of Branooni et Pharmacodynamic It consists in injecting to of about 150 which been fed only giuoose for hours of naphthoylheparaiaino in 00 of saline the plantar aponeurosis of a hind Tho test produots are administered orally an aqueous suspension ono hour before tho The degree of inflammation is The of the paw is expressed in arbitrary It ia immediately before and two hours after tho injection of The dose determined and the results are reported in Table TABLE i 0 In of RU is about g Activity on Ultraviolet pigs from to had thoir shaved 24 hours before tho Tho animals received orally various dosages tho and our later throe of 8 of the shaved of each animal wore exposed to ultraviolet radiation for two Two hours tho of erythema was on a of 0 to Tho roculta reported i The the degree of erythema by compared to tho was 10 and about 100 for glafenine as can the in Table Analgesic Tho test used was based on the observation made by et whereby the intraperitoneal injection of acotio acid to mice causes characteristic repeated stretching and which persist for more than six prevent or suppress this can be considered as an external of diffuse abdoninal An aqueous acetic containing 10 arabia was used and the doeo which gave rise to the syndrome under these conditions was por of body 60 of Tho tost compounds wore admlnisterod orally half an hour boforo tho intraperitoneal of acotio tho mice having tho night boforo the In each individual five mice are used for level including tho oach the were observed and oounted for rainutes starting immediately after the injootion of aoetio The effect was expressed as the peroentago of protection respect to tho controls and the was calculated acoording to Litchfield and Wilooxon method results in Table j TABLE III j Table III shows that RU exhibits very good analgasio aotivity which is nearly 6 tircss greater than that of The of RU is as compared to for In another series of tho acetio acid was injected 1 7 and 24 hours after tho administration of tho RU It was thus possible to deterrnino the duration of tho analgesic The results are given in Table They show that tho analgesic aotivity of RU is considerable and highly 4 hours administration of and 10 and significant even 7 hours after if ono uses 20 νί mouse roars 0 1 2 75 62 4 57 6 1 So 7 64 3 59 6 2 73 59 4 6 29 5 4 71 71 6 44 43 5 7 5 4 4 24 5β 5 64 5 70 4 according to Dunn i Analgesic Activity on Inflamed The test used is the method of Randall and Selitto 409 and is based on the elevation by analgesio agents of the pain threshold in inflamed The mation was induced by injection under the plantar aponeurosis of the hind paw of rats of cc of a suspension of The pain was produced by gradually increasing mechanical pressure applied to the plantar surface of the The pain threshold is given by the minimum pressure which induces the characteristic withdrawal progressively after the injection of the s yeast and reaches a plateau of after 4 test compounds are administered this The is measured by the pressure expressed in grams For the it is 40 The doses administered and results obtained are shown in Table TABLE V The results show that RU is about twice as active as and that it reaches its maximum effect more Concentration in Rat Blood The test compounds were administered orally to rats weighing about 200 and the lasma levels of the corresponding acids were measured spectrophotometrically 4 hours The results are reported in Table TABLE Table VI shows that tho glafenine level about t that of Acute The at which of the animals of RU was on groups of 10 specific pathogen free male Swiss weighing about 20 to Tho were for 6 hours and were placed in a 3terilo atmosphere at Thecompound was administered orally at different dosos in a volume of 100 por 20 g o body The animals for eight days and the was about for RU and for CONCLUSIONS On the basis of these it can be that tho activity profile of RU is different from that of glafenino since is only half as active as glafenine in Test A while it is 10 times as in Test O tho basis of tho analgesio it can be concluded that RU i3 nearly six times as active as glafenino in Test C and about as active in Test The lower blood levels of RU despite a definitely stronger seem to indicate a difference in the mechanism of account tho difference in it can be established that RU has a much higher index than 1 2 CF7 is at the insufficientOCRQuality

Claims (1)

1. CLAIMS The derivatives of of formula in which the radical is at tho the and and each represent hydrogen a ketonide of Q being aralkyl or aryl as well as the therapeutically compatible mineral or organic of the compounds for which R 7 and and its A process for preparing the derivatives of dihydroxypropyloxycarbonyl of general in which the is at the osition or and each represent hydrogen a ketonide of formula C and being aralkyl or aryl as well as the therapeutically compatible mineral or organic salts of the on a 8 to form the ketonide of the corresponding dihyroxyp phenyl 8 line which one if to an acid hydrolysis to obtain the corresponding salt of line by action of a basic agent provides the free then if this last compound to the action of a therapeutically compatible mineral or organic to form the desired 1 A process according to claim characterized in that one causes a to act on a methylquinoline to form the of by acid hydrolysis and then by action of a basic provides the desired uoromethylquino A according to Claim characterized in startin from and one obtains carbonyl and its A variant the process according to claim 3 characterized in that one condenses a in the presence of an acid with to after treatment with a basic A process according to claim characterized in starting one obtains phenyl Therapeutic compositions containing at least one compound according to claim 1 a Therapeutic compositions containing at least one compound according to clai 2 and a insufficientOCRQuality