IL35404A - Ypsilon-lactams of 7-sydnoneacetamido cephalosporanic acid and process of preparation - Google Patents

Description

OF CEPHALOSPORANIC ACID AND PROCESS OF PREPARATION already derivatives cephalosporin of general formula which represents a substituted or represents a substituted or substituted radical or aryl These ounds are distinguished by their biotic p Israel According to Patent they were prepared by of the corresponding acid ester of The of cephalosporin of general formula 1 oh the other be prepared according to the described in which consists of acylating of the corresponding The present invention has as object new derivatives optically active or racemic of general in 3 represents a hydrogen the phenyl a radical substituted by the group or a phenyl radical substituted by the group in this latter their salts with a therapeutically compatible mineral organic compounds of general formula can likewise be prepared essentially according to the process described file he of cis sydnone acids of general formula in the case where 3 is a phenyl radical substituted by the their salts with a therapeutically compatible mineral or organic are endowed with interesting biological and therapeutic properties They possess specifically an important antibacterial Among these one can mention the of DL cis sydnone acid of DL cis sydnone acid the of DL cis sydnone acid the of DL cis the of DL cis sydnone Cephalosporin C to a class allied to that of It possesses the bacteriological properties although to a lesser degree Chauvette et Antibiotics The antibiotic properties of the synthetic derivatives of cephalosporin C vary very appreciably depending on the substituent on the amino Chauvette that generally the most active substituents of amino type nitrogen are arylmercaptoacetylated derivatives and alk lmercaptoacetylated Nevertheless the most active derivatives possess the disadvantage of being strongly deactivated by the presence of serum in tests in vitro which makes it possible to predict a feeble activity in tests on animals or One has therefore searched for acylating couples whose effect would at the same time increase the bacterial activity of synthetic cephalosporins and lessen the loss of activity in the presence of Among the different couples studied for this purpose one can point out acylation with derivatives of carboxylic Pala et therapeutique depends on results obtained with derivatives of penicillanic acid acylated with a carboxylic series such an acylation has involved an important decrease of activity respect described the use of such an in cephalosporin The results obtained on the bacteriological scale are hardly encouraging considering that the inhibiting concentrations with respect to when they are are higher than those of other known synthetic derivatives of cephalosporin such as for example In when the methylated at position is substituted by amino group such as aromatic amine or nitrogenous heterocyclic there results a very appreciable drop in One can thus the minimum inhibiting concentration respect to a strain of Staphylococcus aureus is for example for cephalosporanic acid 1 for acid 10 and for carboxylic acid Any substitution of this function therefore involves diminishing the antibiotical Belgian Patent 724072 describes cephalosporanic acid and its This patent depends on an appreciably improved activity with respect to Klebsellia Pneumoniae and Escherichia Coli while cephalothin is hardly active with respect to these On the other it follows from the information provided in this patent that aceta cephalosporanic acid is appreciably less active with respect to strains than c o had not yet solved in a satisfactory The compounds obtained manifest an antibiotic activity with respect to Staphylococcus aureus diminished with to penicillin and deactivation in the presence of serum involves an additional in The compounds of the present invention possess the advantage of manifesting a strong activity at the same time bacteriostatic and bactericidal with respect to or strains of staphylococci and above all of being practically not deactivated in the presence of serum or Thus the minimum inhibiting concentrations are generally remarkably in the presence or absence of This strong activity appears unexpected as a function of the results provided in Dutch Patent Application for derivatives at position The process for preparing the of racemics or opticall cis sydnone l acids of general formula and in the case where is a phenyl radical substituted by the their salts with a therapeutically compatible mineral or organic which is likewise object of the consists essentially in that one condenses the of optically active or cis acid with sydnone acid of general formula or one of its functional which represents a hydrogen the phenyl radical or a phenyl radical substituted by the to obtain the Y of the corresponding cis sydnone acid which one if in the case where is a phenyl radical substituted by the NO2 to a catalytic in an acid or neutral and obtains the Y of the corresponding cis sydnone acid if causes a therapeutically compatible mineral or organic acid to act on this latter to the desired In its currently preferred methods of the process of the invention can be further characterized by the following the functional derivative of sydnone acid is the anhydride formed in situ by sydnone acid in the presence of a or alkyl such as for example dicyclohexyl or a halide or an anhydride or even a mixed anhydride the catalyst used for the reduction of the nitro derivative into the amino derivative is a metal of the platinum such as for example and one operates in the presence of an acid such as chloric the catalyst is fixed on an inert support such as activated an alkaline metal an alkaline metal magnesia or such as example sulphuric phosphoric nitric boric formic acetic benzoic salicylic sulphonic phenylacetic acid nalidixic acid or methane sulphonic new derivatives of the object of the are used in therapeutics in the treatment of infections of such as furunculosis burns or infected They can be used by rectal or external They can be in the form of injectable suspensions or solutions dispensed in phials or plain or coated creams or These forms of use are prepared according to the usual processes of The dosage of the compounds ranges between and 5 per in the depending on the route of administration sydnone acid of general used at the start of the process of the invention can be prepared by by means of a dehydrating agent such as acetic of an imino diacetic acid of general formula C0 H An analogous method has already been described for preparing sydnone acid by Stewart other imino acetic can themselves be prepared by various One method for example consists of treating a bensaldehyde of general in which represents here and in what follows a hydrogen atom or a nitro with ethyl glycocollate chloride and potassium cyanide to form an ethyl phenyl glycocollate hydrochloride of general which one with an acid agent such as chloric to obtain the corresponding diacid general One converts this into a nitroso derivative of by the action of sodium Another method consists of treating an phenyl acetic acid of general with an ethyl hydrochloride to obtain an acetic acid of general which one saponifies with an alkaline agent to obtain the corresponding diacid of general which is converted into a nitroso derivative of general by the action of an examples illustrate the do not limit it in any starting matter used can be indifferently the of racemic cis acid or one of its optically active whose preparation is described in Example I of PL cis acid Stage acetic acid One mixes 13 of acetic acid according to the process described in ethyl glycocollate caustic soda in fifteen then leaves under agitation for t irty at One cools to 0 adds 18 of acetic and washes with one adds Volumes of N hydrochloric suctio rinses the precipitate with N hydrochloric then with one brings the filtrate to by the addition of cools for fifteen and washes with one obtains of amino acetic acid in the form of colourless soluble in dilute aqueous acids insoluble in water and at Analysis Calculated Found Bands at a 8 The compound is in the of internal salt As far as is this compound is not described in the Stage acid One agitates for one hour at ambient temperature of acetic acid obtained in stage A 75 of 2 caustic One adds 1 of 10 hydrochloric acid and evaporates to dryness in one takes up the residue with of then 100 of cools for fifteen One the washes it with ethanol then with one collects of crude one dissolves 23 of crude product in 100 of ethanol admixed with 15 of pyridine under ice for fifteen then wit ether and obtains 10 of imino diacetic acid in the form of colourless solvated with of soluble in dilute aqueous acids and scarcely soluble in insoluble in Analysis Calculated Spectrum Presence of at associated The acid exists in the form of internal As far as is this compound is not described in the Stage C acid One mixes of diacetic acid and 22 of hydrochloric one takes the internal temperature to and adds a solution of of sodium nitrite in 6 of water and agitates for forty minutes at ambient one extracts with methyl salting out with sodium dries the organic phases on sodium washes the filtrate with methyl acetate and evaporates the filtrate to one dissolves the crude diacetic acid in 60 of acetic anhydride and agitates for three hours at ambient one adds 20 of and leaves in contact for thirty one evaporates to dryness in takes up the residue in of then one takes the filtrate to pH 1 by the of 10 hydrochloric ice for fifteen washes with water d obtains DL acid in the of a solid yellow soluble in weak bases and insoluble in and aqueous Its melting point is Calculated Spectrum Presence of at and Presence of and phenyl at 1598 and As far as is this compound is not described in the Stage D of acid One agitates for sixteen hours at ambient one mixes of DL sydnone 3 of dicyclohexylcarbodii ide 20 of 422 of of DL cis acid and of one and washes the precipitate with nitromethane then with one collects of crude one takes the crude with of dimethylformamide washes with dimethylformamide adds of water to the washes with water and obtains acid in t e form of yellow crystals soluble dime insoluble in water 9 ether and nitromethane Analysis S Pound Spectrum Presence of at Presence of at Presence of and at and Presence of aromatic at and As far as is this compound is not described in Example II of PL cis sydnone erae acid Preparation of One mixes 5 of active of an aqueous solution of palladium chloride and of One agitates in an atmosphere of hydrogen for thirty minutes at ambient one filters the charcoal one washes with water until the washing waters are One mixes of of DL cis sydnone e e acid in example 6 of of hydrochloric acid and the charcoal obtained one agitates in an atmosphere of hydrogen for forty minutes at one separates the washes the filter with water of ethanol one washes with et anol and obtains 235 of DL c s inophenyl sydnone ethyl acid in of colourless crystals soluble in dilute aqueous acids and scarcely soluble in insoluble in Analysis Calculated Found Presence of at 1777 As far as is this compound is not described in the Example III of cis acid Stage A hydrochloride One agitates for hours at ambient temperature a mixture of 13 of ethyl glycocollate of potassium 15 benzaldehyde 130 of ethyl acetate and 13 of one decants the organic dries it on magnesium washes the filter with ethyl acetate and evaporates the filtrate to dryness in vacuo one collects 24 of crude chloride which one purifies by on silica elution with a mixture and precipitation in ether with gaseous hydrochloric acid one obtains IS of eth l henyl hot in 4 washes with ethanol then with one obtains of pure hydrochloride in the of yellow soluble in insoluble in Analysis Calculated Found Spectrum Presence of ester at Presence of aromatic and As far as is this compound is not described in the Stage B L One heats at reflux for sixteen hours a mixture of of ethyl of water and of 10 hydrochloric after cooling the one adds of acetone and ice for thirty one washes the filter acetone and evaporates the filtrate to dryness in vacuo one takes up the residue with ice for one washes with acetone and obtains of diacetic acid in the form of colourless soluble in water and insoluble in acetone and For one dissolves of the chloride in 8 of washes with brings the filtrate to by addition of ice for fifteen washes with ethanol then with ether and obtains 1 of free acid in the of internal of Calculated Spectrum Presence of at Presence of iT0 and associated As far as is is not described in the literatur Stage C DL e acid One mixes 29 of i ino diacetic acid hydrochloride and 60 of adds a solution of of sodium nitrite in of water and agitates for thirty minutes at ambient one extracts with methyl acetate salting out wit dries the organic phases on sodium washes the filter with methyl acetate and evaporates to dryness in vacuo One thus obtains the crude diacetic acid with a quantitative One dissolves residue in 120 of acetic anhydride and agitates for three hours at ambient One then adds 40 of leaves in contact for thirty minutes and evaporates to dryness in vacuo one extracts the residue with 100 of an aqueous solution of sodium suction washes the filter with the sodium bicarbonate then with one brings the filtrate to 1 by the addition of 10 hydrochloric suction washes with water then with ether and obtains of DL sydnone acid in the form of yellow crystals soluble in weak bases and or amide insoluble in ether and aqueous Calculated C d Spectrum Presence of and As far as is this compound is not described in the literature Stage D sydnone One agitates for sixteen hours at ambient a mixture of of sydnone acetic 1 of dicyclohexyl carbodii ide 20 of nitromethane 422 of of cis a ino acid and of one washes the filter with nitromethane then with ether and collects crude One purifies it by suspension in of one and washes the filter with dimethylformamide then adds 20 of wate to the One the filtrate for fifteen washes water then with ether and obtains of of DL cis sydnone e acid in the form of colourless soluble in dimethylformamid insoluble in Calculated C Found Spectrum IV of cis sydnone ce e ac d One 200 of active 2 of solution of chloride and 2 of one agitates in an atmosphere of hydrogen at until reduction of the one ilters the charcoal one washes with water until the washing waters are One puts the charcoal thus obtained in suspension in 4 of with 383 of of DL cis sydnone cep acid and of hydrochloric one agitates in an atmosphere of hydrogen for thirty at one the washes the filter with water and evaporates the filtrate to dryness in One takes up the residue with of adds 6 of ice for fifteen She precipitate is and washed with one obtains of of DL cis aminophenyl sydnone e e acid in the form of colourless soluble in aqueous acids and scarcely soluble in insoluble in sis Calculated Pound As as is this is not described in the Example V of PL cis dnone acid One agitates for one night at about a mixture of 575 of acid in of dicyclohexylcarbodiimide 211 of of DL cis 5 of nitromethane and one drop cf one rinses the filter pastes concentrates to small volume in the solution of dimethylformamide takes up rinses with methanol then with ether and one collects of crude product one takes up in of dimethylformamide one adds 2 of washes with methanol then with ether and one obtains 160 of of L cis e e acid in the form of colourless soluble in dimethylformamide insoluble in methanol and with a melting point higher than Analysis Calculated rum Presence of at 17SS Presence of sydnone at Presence of amide at 1697 cm in the νΊ of PL cis sydnone ic operating as in example starting sydnone acid according to the described by and the of DL one obtains the of DL cis sydnone acid a yield of The compound is in the form of colourless soluble in di insoluble in ether and with a melting point higher than Analysis 0 Calculated Found Spectrum Presence of at 1779 Presence of amide at Presence of sydnone at 1736 As far as is this compound is not described in the insufficientOCRQuality

Claims (1)

1. The of cis sydnone in optically active or racemic of general in represents a hydrogen the phenyl a phenyl radical substituted by the group or a phenyl radical substituted by the group in the latter their salts with a therapeutically compatible mineral or organic aci of DL cis sydnone The of DL cis l sydnone of DL cis ophenyl sydnone 3 The of DL cis sydnone The of DL cis carboxylic The of LL cis sydnone acid o A process for preparing the compounds according to claim characterized in that one condenses the of optically active or race ic cis methyl acid with in which represents a hydrogen the radical or a phenyl radical substituted by the or with a functional derivative of this to obtain the of the corresponding sydncne acid which one if in the case where is a phenyl radical substituted by the to a catalytic in an acid or neutral and obtains the of the corresponding en sydnone acid causes a therapeutically compatible mineral or organic acid to act on this latter to form the desired Pharmaceutical compositions containing as active principl at least one compound according to claim 1 and a ceutical Box 33116 Attorneys for Applicant insufficientOCRQuality