DE1670654A1 - Orally effective cephalosporin antibiotics - Google Patents

Description

Orally effective cephalospo @ inan @ tibiotics The compounds according to the invention belong to the @ephalo @ sporin compounds, since they come under the following general formula: in which R is an organic radical @ R @ hydrogen or an acetoxy group and M is a pharmaceutically acceptable cation. The compounds @contain a double bond in the @ 3 position, a dihydrothiazine ring with a 6-La'stam fused therewith. Some compounds of this class have suggested that they are useful antibiotics for combating diseases caused by various Gram-positive and Gram-negative microorganisms, and some cephalosporin compounds, for example sodium @ephalothin- [7- (2 ' -thienyl) -acetamidocephalosporanic acid @ -sodium salt], are used to a considerable extent as parenteral antibiotics, but there is still a need for other and better antibiotics distinguish as antibiotics The new compounds according to this invention are the free acids, internal salts and pharmaceutically acceptable salts of compounds of the formula wherein R is hydrogen or a lower alkyl radical having 1 to 2 Kolilenstoffetomen and R 'is hydrogen or an acetoxy group. They can be individual compounds or different mixtures of stereoisomeric forms of optically active isomers. These compounds are generally prepared in the form of the zwitterions or inner salts; they can also be in the form of salsen with a pharmaceutically acceptable base, for example in the form of alkali metal salts, for example as sodium or potassium salts and as ammonium and substituted ammonium and amine salts or as the anion in a pharmaceutically acceptable anionic salt with a strong acid (ie, an acid addition salt of a strong acid having a pK'a below 4), for example, as sals with hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or trifluoroacetic acid and the like. Preferably these compounds are prepared in the above-mentioned zwitterion or inner salt form and used as antibiotics.

Examples of compounds according to the invention are given below as free Amino acid compounds indicated, however, it should be noted that ste in the various Salt forms that have been gelant can be used-7- [4- (aminomethyl) phenylacetamide @] cephalosporanic acid 7- [4- (α-Aminoethyl) phenylacetamide @] cephalosporanic acid 7- [4- (α-Aminopropyl) phenylacetamido] cephalosporanic acid 7 - [@ - (α- @ minoäthyl) phenylacetamido] desacetoxy cephalosporanic acid, and [4- (α @ Am @ nopropyl) phenylacetamido] desacetoxy - @@ @a sä @ r.

The new cephalosporanic acid compounds of this invention are in that it is related to cephalosporin C in that it forms the 5, 6-dihydro-6H-1,5-thiazine ring with a ß = lantam ring associated with it in 5,6-position contain the one for cephalospori. In contrast to cephalosporin C, that in the 7-position is characteristic Contains 5-amino N'-adipamyl group, the compounds according to the invention are distinguished but by an acylamido group in the 7-position with an α-amino-lower alkyl substituent in the 4-position on the phenyl ring of a phenylacetic acid residue as acyl group auso The new Desscetoxycephalosporanäureverbindungen also contain in position a methyl group instead of an acetoxymethyl group, as in Cephalosporin C the case is. In contrast to Cephalosporin C, it's a relatively small one has an antibacterial effect, the compounds according to the invention are also highly effective antibacterial agents that promote the growth of numerous types of microorganisms in able to inhibit the most varied of environments.

Cephalosporin Cl is the most suitable starting material for production of the compounds of the invention can be obtained by growing a cephalosporin C-producing organism can be produced in a suitable nutrient medium, such as it is described in British Patent 810,196.

Cephalosporin C can also be obtained according to a US Pat. No. 3,082 153 are produced in the process described in the cephalosporin C-generating Molds of the species to the Cepha # osporium I.M.I. 4913 @ heard. In a medlum, the appropriate nutrients, including a source of organic Contains nitrogen, used in the presence of molecular oxygen and that dabel Cephalosporin C produced is separated.

Cephalosporin C @ ä # t easily into the corresponding basic connection 7-Aminocephalosperanoic acid (7-ACA), by cleaving the 5'-amino N1-ad @ pamyl chain between your amido carbonyl group and its atmospheric nitrogen expediently by reaction of cephalosporin C with nitrosyl chloride in formic acid and subsequent hydrolytic Convert cleavage according to the method of US Pat. No. 3,188,311-If the If osporic acid compounds are desired, cephalospcrin C can be converted into desacetoxysephaloaporanoic acid (7-ADCA) by conventional methods, for example by catalytic hydrogenation of Cephalosporin C and subsequent hydrolytic removal of the 5-aminodipoyl side chain are transferred as described, for example, in US Pat. No. 3,129,224 is. The 7-ADCA is then replaced by the 7-ACA for the production of the 3rindications Connections used.

The invention # an @ {2 [@ (α-Aminoalkyl @ heny @] a @ e @@@@@@} @epha @osporanic acid compounds are identified by either A @ y @erung d @ r art or 7 ADCA as f @ eis acid or as a suitable water-soluble salt, like n'e @n in the USA Patent 3,207,755 are described with an a @ ylating agent that from the selected 4 (α-Amiroalky @) phenylacetic acid derived, according to the usual A @ ylation @ experienced he @ posed. E @ two @@ ylation agent for this purpose is the ealtn spre @ he @ d @ 4α-Aminoalkylphenyla @ etylchlorid ode @ bromid, @ dem d-'e amino group in the usual way with a blocking group, for example a carbobenzoxy- carboallyloxy @ert -Bu @ oxycarbonyl, ß-oxoalky @ den, furfuryloxy @ arbony @ -Adama @ ty @ oxycarboxyl group or the like is protected, The acylation of 7 ACA @der 7-ADCA is carried out in water or a suitable organic solvent carried out, preferably below practically neutral pH conditions and preferably lee at or slightly below room temperature for example above the freezing point of the reaction mixture and up to about 200Ce According to a + y p @sch working method, 7-ACA or 7-ADCA is added together with a row Amount of sodium bicarbonate or another gee @ g @ et @ n alkali. so there # preferably the pH of the mixture is kept between 5 and 9 and the salt formation and dissolution is promoted, dissolved in aqueous 50 volume percent acetone @ so that the K @@ centretion the 7ACA or 7-ADCAewab-s'.? ht% is. Mankuhl "-the solution to about 0 to @ ° C and puts under frills and coolness. d Solution of the protected 4 Am @ nos ky] phenyla @ etyl @ hlerid @ or bromide as a @ yl @ ermittel @n about 20% excess echuß ru The pH of the mixture can, if it changes, by adding Sodium carbonate or by introducing carbon dioxide around the neutral point (pH 6 bis) must be adhered to. When the addition of the acylating agent is complete, the reaction mixture becomes stirred further and allowed to warm to room temperature. Then the reaction product diluted with hydrochloric acid or another suitable acid to about plf 2: umd'efreie72 '/ 4'- (blocked-aAminaJkyl) pheny3 acetamido} cephalosporanic acid or the corresponding @ To form the acet xycephalosporanic acid, which is then mixed with an organic solvent, for example ethyl acetate, ext @ ahiext is. The organic solution ttelextrakt, which contains the blocked amino acid derivative of 7 ACA or 7-ADCA is combined with a alkaline material, for example sodium hydroxide Ka @@ umhydroxyd ammonium hydroxide and a suitable amine or other base which, if required, is a sodium, Kslm ammonium @ or other cation, adjusted to about pH 5.5 and with Water extracted-Dj. An aqueous solution containing the amino intermediate product as anion: in the salt form, is separated off and evaporated to dryness Rilek stand is absorbed in the minimum amount of warm methanol: and the desired The product is cooled by cooling and / or adding isopropanol, if necessary as an anti-solvent @ ogesch @ eden. The crystalline product obtained in this way is disposed of @ ev @, m @@ A @ e @ on washed and dried @ Before or after crystallization the intermediate product obtained can be used in the usual manner to remove the protective group the aminoalkyl function are treated, advantageously by hydrogenation under mild Conditions : ! n presence of a pal diumkatalyaaore or by treatment under mild acidic conditions for a short time t (for example with formic acid at approx Room temperature for about 1 to 5 hours). This intermediate can also with trifluoroacetic acid to remove the protective group and the Trifluoroacetic acid as the desired 7- {2 '- [4 "- (aminoalkyl) phenyl] acetamide} cephalosporanic acid or @ desa @ etoxycephalosporanic acid. By treating this acidic sweet with a suitable anion exchanger in base or A @ etatform according to the usual Process one can remove the trifluoroacetic acid sulphate group and the e zwitterionenfo @ m of the product. To anion exchange resins suitable for this purpose include, for example, the weak A @@ ion exchangers, for example the resins known under the trade names "Amberlite IR-4B" and "De-acidite-E" in the Ace @ etform and the strong @nionenausteuscher, who for the Entundnier E--., j n ,, i @@@@@@@@ sung @ e @@ ends warden, @@ sp @@@@. @@@ ber @ @@ @@@ @@@@@ @@ or @@ e- @@@@ @@@ ge @@ gnet @@ @@@ @@@@ @@@@@@ @@@@@@@. @r Her @@@ @@@ @@@@ @n Verl @@ ngen, wend @@@@@@ ''.: 5! -.:; '' ie '"- t': phrL.'rHer'-R @@@ @@@@@ @@@@@@ lite LA-1 "nd" Amberlite LA-2 "are brought to the market and in the USA patent 2,870,207. The anion exchange resin "Amb @ rlite LA-1" is a Representative of a group of high molecular weight liquid secondary amines that are insoluble in water, however, it is readily soluble in hydrocarbons and other non-aqueous solvents For example, "Amberlite LA-1" resin has a configuration of two highly branched ones aliphatic chains attached to the nitrogen atom. This structure is for its excellent solubility in organic solvents and its extraordinary low solubility in aqueous solutions responsible. These solitude properties in connection with the ability of secondary amines to react with acid to form the Corresponding amine salts to react, make the resin suitable for the removal of acidic Components from an aqueous solution are suitable.

The asylum of the 7-ACA or 7-ADCA can also be done with an appropriate 2- [4 '- (α-Aminoalkyl) phenyl] acetic acid in combination with a carbodiimide be performed. In such cases the acylation takes place at ordinary temperatures ratures. Any carbodiimides which act as the active group are suitable for this purpose have the -N = C = N = structure. Examples include N, N'-diethylcarbodiimide, N, N'Di-npropylcarbodiimide, N, N'-Diisopropylcarbodiimide, N, N'-Dicyclohexylcarbodiimide, N, N'diallylcarbodiimide, N, N'-bis (p-dimethylaminophenyl ) carbodiimide, N-ethyl-N '(4 "-ethyl-2" - @ xazinyl) -carboatimide and the like. Other suitable Carbodiimides are described in U.S. Patent 3,252,973.

Alternatively, the acylation of 7-ACA or 7-ADCA can be activated with one Derivative of the selected 2 = [4 '- (α-Aminoalkyliphenyl] acetic acid 3 expedient the corresponding acid anhydride or a mixed anhydride or an activated one Esters, for example the p-nitrophenyl or cyanomethyl ester, are carried out Some of these 4 = α-aminoslkyl) contain phenylacetic acid compounds as such or in a form suitable for the acylation of 7-ACA or 7-ADCA, for example in Formds Acyl halide, mixed anhydride or haloformate asymmetric carbon atoms and therefore can exist in optically active isomeric forms. These stereoisomers Compounds can be in the form of separate isomers or as different steroid isomers Mixtures of the optical isomers for the preparation of the compounds according to the invention An example of mixed compounds used in this invention is a stereoisomeric mixture of 7 = {2 '= [4 @ @ d @ and 1-α-aminoethyl) phenyl] acetamido} cephalospo @ anic acid, for example by reacting 7-ACA with mixtures of 2- [4 '- (d- and 1-α-aminoethyl) phenyl] acetic acid or their reactive derivatives or by mixing the individual d @ and 1 isomers of the 7- {2 '- [4' '- (α-Aminoäthyl] acetamid @} @ epha losporansäurs @ compounds, the As described in the following Be @ sp @ elen 1 to 4 are obtained will If the individual optical cephalosporiniosmer is desired the selected starting material can be 2V4 '- (α-aminoalkyl) phenyl] acetic acid be separated in the usual way, for Beiapie'Le by adding the free acid C @ nchonine, strychnine, brucine or the like converts, then the resulting salts to separate the diastereomeric salts, fractionally crystallized and then the separated isomeric salts are separately acidified to give the desired optically active d or l to release acid. Any of the d- and 1- 2- [4? - (α-aminoalkyl) phenyl] acetic acids thus obtained can a @ ls those with a carbodiimide for the acylation of 7-ACA or 7-ADCA ethgeeetzt or into the corresponding acid halide, mixed anhydride, using customary methods or H; Jogenformiat ala.

Acylating agents are transferred, whereby it is ensured that because # extreme conditions that could lead to racemization are avoided.

The following examples illustrate the invention and how to limit it.

Example A mixture atte 475 mg (5 mmol) Methylehlorformist in 25 ml. Aeetonf das 2DropfenDimehylasylamiM @ athaltowirdia eineaaem 1d ii . r,: Stirring for 30 minutes dropwise with 1.4 g (5 mmol) of 4- [N- (tert-putoxycarbonyl) d-α-aminoethyl] phenylacetic acid in the 25 ml of acetone containing 500 mg of triethylamine, added to to form the mixed anhydride. Then slowly stir for 5 minutes a previously treated with activated charcoal and cooled mixture of 1.5 g (5.5 mmol) 7-ACA in 30 ml of water containing 550 mg (5.5 mmol) of triethylamine was added Mixture is stirred in the cold for another hour to be as complete as possible Conversion to the blocked amino-7-L2, - {2 '- [4 "- (N-tert-butoxycarbonyl-d-α-aminoethyl) phenyl] -acetamido} cephalosporanic acid to ensure.

To purify the acid obtained, the acetone is removed and washed the residue with water, the mixture is cooled and extracted into a non-aqueous solution Solvent by mixing the mixture in the presence of ethyl acetate with 1N hydrochloric acid acidified to pH 2.5. A deposition of 7-ACA is not found. The solvent system is separated and the product in the ethyl acetate layer is over magnesium sulfate dried. After removal of the ethyl acetate, 2.5 g (93% yield) of the desired N-blocked Cephalosports ns obtained as a @morphic residue which does not crystallize can be. redent 7-ACA is triturated with diisopropyl ether and dried in vacuo, whereby 2.0 g of 7- {2 '- [4 "- (N-tert-butoxycarbonyld - @ - aminoethyl) phenyl] acetamido} cephalosporanic acid can be obtained with the following analysis values: Anal. Ber.for Cl! .. Gef.

% C 56.28 55.94% 86 6.41% N 7.88 6.91 The pK'a of the compound is 4.95. The ultraviolet spectrum gives Am260 = 8050 in ethyl alcohol.

Example 2 1 g of the 7- {2 '- [4 "- (N-tert-butoxycarbonyl-d-α-aminoethyl) phenyl] acetamido} cephalosporanallic acid prepared as in Example 1 is gelat in 10 ml of cold trifluoroacetic acid and kept in the cold for 2 hours, to cleave the tert-butoxycarbonyl protective group and the trifluoroacetic acid salt of 7- {2 '- [4 "- (d-α-aminoethyl) phenyl] acetamido} caphalosporanic acid.

This salt is made from the solution by adding clay to anhydrous Xthyi # ther deposited in 3 portions of 30 ml each. The salt gets from the liquid separated, washed in a centrifuge with ethyl ether and in a vacuum desiccator dried. @ Mak receives 800 mg (78% yield) of the trifluoroacetic acid salt of 7- [d-4-α-Aminoäthylphenylacetamido] caphalosporanic acid with pK'a values of 4.7 and 9.2. The ultraviolet spectrum in ethanol gives Am260 = 7730.

500 mg (0.9 mmol) of the trifluoroessic acid salt of 7- {2 '- [4 "(d-α-aminoethyl) phenyl] acetamido} cephalosporanic acid are dissolved in 4 ml of water and one hour at room temperature in 20 ml of a liquid mixture of 25% anion exchange resin ("AmberliteLA-1") idercetatforminMethylisobutylksn.r'.ge stirs, the aqueous phase is separated, with methyl isobutyl ketone and then with Ethyl ether washed The zwitterion product (inner salt) 7- {2 '- [4' '- (d-α-aminoethyl) pheny @] @ acetamido} cephalosporanic acid precipitates out when the mixture is concentrated in vacuo and crystallizes however not. The weight of the product obtained is 265 mg (68% yield). The infrared and ultraviolet spectrum agree with the assumed structure The compound has pK'a values of 4.8 and 9.35 and a specific rotation value of + 103.6 °.

This product 7- {2 '- [4 "- (d-α-aminoethyl) phenyl] -acetamido} -cephalosporanic acid exhibits minimal inhibitory concentrations (MIC) versus four. clinical isolates won penicillin resistance Staphylosoecus aureus ton 0.2 to 0.8µg / ml in the presence of menachlischsm Blood serum from 0.3 to 0.8 µg / ml in the absence of serum compared to a MIC from 1.4 to 9 µg / ml for penicillin G and from 0.9 to 2.2 µg / ml for sodium cephalothune a commercially available antibiotic based on measurements using the gradientan = plates = method on The product has a medium effective dose (EDo versus ß-hemolytic Streptococcus pyogenes, strain C203 when administered twice to mice of 7.5 mg / kg Against grief-negative organisms are after a standardized gradient plate method following minimum inhibitory concentrations found: Organism: MIC µg / ml N <9 Shigolla 8po 24 N-10 Eecherichia colitp N-26 Escherichia coli 6 X-26 Klebsiella pneumonise0 X-68 Aerobacter aerogenes 10 K-1 Klebsiella pneumoniae> 50 Shlgella sonnet20 Example 3 According to the procedure of Example 1 is 7- {2 '- [4 "- (N-tert-Potoxycarbonyl-1-α-aminoethyl) phenyl] acetamido} cephalosporanic acid by reaction of 2- [4 '- (N-tert-butoxycarbonyl-1-α-aminoethyl) phonyl] @cetyl chloride made with 7-ACA, after trituration of the compound in Diiso aainthyl) pheylaatamidccephalogpo ? aRSuralsPrcdu "e-! äg) lt @ H {, dasn .'- cMschmälst, but with about'10'Czey" sotstM <pUHraoJttHauptabsnpptiöna; Aet'sg NU in ethyl alcohol 7400 and in water 8200. The compound has a pK @ a of 4.9 on- The Inf @@ o @ spectrum s @@ immt m @@ t d @@ structure @ per @ in. The product @ wets @ f @ ende Ana ysenw @@ te on Anal.Ber. for C25H31N3O8S Found:% C 56.27 55.69% H5? E6.39,% H 5.86 6.39% N 7.88 7.64 'i' Example 4 1 g 7- {2 '- [4 "- (N- tert-butoxycarbonyl-1-α-aminoethyl) phenyl] acetamido} cephalosporanic acid (as prepared in Example 3) is dissolved in 10 ml of cold trifluoroacetic acid and Held in the cold for 2 hours in order to cleave the SshMEgMasseateM and the trifluoroacetic acid salt of 7- {2 '- [4 "- (1-α-aminoethyl) phenyl] -acetamido} cephalosporanic acid. The salt is made from the solution by adding anhydrous ethyl ether in three parts of 30 ml each. separated off beae en Ph, washed on a centrifuge and dried in a vacuum desiccator. The weight of the trifluoroacetic salt of 7- {2 '- [4 "- (1-α-aminoethyl) phenyl] acetamido} cephalosporanic acid 820 mg. The salt has pK'a values of 4.7 and 9.2. The ultraviolet @ spectrum results in Am260 mu = 6 700.

500 mg of the trifluoroacetic acid salt of 7- {2 '[4 "- (1-α-amino-Am260 mµ = 6,700.

Wbieer dissolved and one hour at room temperature with 20 ml of a liquid mixture of 25% anion exchanger "Amberlite lite LA-1" in the acetate form stirred in methyl isobutyl ketone.

The aqueous phase is separated and with methyl isobutyl ketone and then washed with water. By concentrating the aqueous mixture until it is almost is dry, 275 mg (70% yield) of a crystalline zwitterion product are obtained (inner avala) of 7- {2 '- [4 "- (1-α-aminoethyl) phenyl] acetamido} cephalosporanic acid. The ultraviolet spectrum shows Am260 = 7720. The compound has two pK'a values at 4.7 and 9.3. However, the infrared spectrum agrees with this product. Of the specific rotation value of the connection is + 97.8 °.

The product 7- {2 '- [4 "- (1-α-aminoethyl) phenyl] -acetamido} -cephalosporanic acid has a minimal value based on measurements using the gradient plate method Inhibitory Concentration (MIC) versus clinical isolates of penicillin-resistant Staphyllococcus aurez from 0.1 to 1 µg / ml in the presence of human blood serum and from 0.4 to 0.5 µg / ml in the absence of serum compared to an MIC of 1.4 to gAl for penioillin 2 G as a control and 0.9 to 2.2 µg / ml for sodium oephalothin, a commercially available antibiotic. The product has a medium effective Dose (ED50) of 5.14 mg / kg against ß-hemolytic Streptococcus pyogenes, strain C 203 when administered twice to mice. Compared to grief-negative Organiamen it has the following minimal inhibitory concentrations: Organi @ MIC mcg / ml N-10 10 N-2611 X-26 7 X-68 4 A50 Shigella sp. 16 Example 5 2.75 g (10.4 mmol) of 2- [4 '- (tert-butoxycarbonylaminomethyl) phenyl] acetic acid are dissolved in a mixture of 30 ml of dioxane and 15 ml of acetone. The mixture 1.05 g (10.4 mol) of triethylamine in 5 ml of peton are added. One cools them Mix in an ice-alcohol bsd and then add dropwise over 20 minutes Stir in a solution of 1.41 g of isobutylochloroformate in 5 ml of dioxane. The e mixture stir for an additional 10 minutes at about -50 for complete conversion to desired to ensure mixed anhydride. The chilled mixture is then used all at once with a freshly prepared solution of 2.83 g (10.4 mmol) 7-ACA and 1p05 g triethylamine mixed in 20 ml of cold water.

The mixture is left to stand at 0 ° C. overnight. The mixture will concentrated in vacuo to remove some of the dioxane and acetone, then with Diluted 30 ml of water and washed with 150 ml of ethyl acetate. Then the mixture covered with 200 ml of ethyl acetate and adjusted to pH 2.8 with 1N hydrochloric acid while stirring set. The layers are separated, the e washed twice with 100 ml of water each time, layers Oa6 ') ethyl acetate containing the blocked amino product.

About 150 ml of water and adjust the pH of the mixture with in potassium hydroxy to 6.5 to the potassium salt of 7- {2 '- [4 "- (N-tert.-Butoxycarbonylamin@methyl) phenyl] acetamido} cephalosporanic acid to create. This salt in the aqueous phase is washed with 100 ml of ethyl acetate and after separating the aqueous phase from the ethyl acetate, the aqueous phase becomes Is evaporated in vacuo, leaving the salt as semi-crystalline Ru. remains behind. This The residue is obtained by dissolving it in 15 ende parmes warm methanol, filtering the obtained solution and ant. iagt3e Z ° ats t. aae. a ii. tion of the salt purified. The salt crystals in the liquid mince are cooled to 0 ° C, filtered off and then dried in vacuo. 1.0 g of the 7 {2 '- [4' '- (N-tert-butoxycarbonylaminoethyl) phenyl] acetamido} cephalosporanic acid aluminum salt is obtained. The infrared spectrum agrees with the specified product. The ultraviolet spectrum gives Am260 - 8140. The pK's value is 4.8.

0.75g of this salt are dissolved in 15 ml of water and then with a:. m., t Tuesday; :; stirred at 40 ° C. for about 395 hours. Then you narrow it in the vacuum su of a rubber-like body that crystallizes. The thus obtained 7- {2'-f4 "- (aminomethyl) phenyl7-aoetamidot-oephalo-. Sporenot is in hot or Only slightly soluble in cold water, but insoluble in ethyl acetate and acetic acid soluble in formic acid. The salt is suspended in 10 ml of water and made with 1 N hydrochloric acid to pH 1, whereby most of the pesticide dissolves. Man the solution is filtered and the pH is adjusted by adding 5N sodium hydroxide on 4t2 a. A small amount of flaky precipitate forms which The filtrate, which is the inner sale of 7- {2 '- [4 "- (aminomethyl) phenyl] acetamido} cephalosporanic acid, is filtered off contains, makes about 20 ml and is concentrated to dryness in a vacuum, whereby Krietalliaation he follows. The crystalline acid is washed three times with 2 ml of cold water each time and filtered each time. The crystalline product 7- {2 '- [4 "- (aminomethyl) phenyl] acetamido} cephalosporanic acid has pK'a values of 4, 7 and 9, 4 in a mixture of 2/3 dimethylformamide in Water on. The infrared spectrum agrees with the specified structure. That Ultraviolet spectrum gives Am260 = 6930.

<The product 7- {2 '- [4 "- (aminomethyl) phenyl] acenyl] acetamido} oephalosporanic acid exhibits a minimum inhibitory concentration (MIC) against but 4 clinical isolates of penicillin-resistant staphyloaccus aureua of 0.4 µg / ml in the presence of monosan blood serum and from 0.8 to 1 µg / ml in the absence of serum according to the gradient plate method. The product has a medium effective Doses (ED50) of 6.75 mg / kg versus ß-hemolytic Streptococcus pyogenes strain C 203 when administered twice to mauve.

It shows against gram-negative organisms on the basis of measurements the following minimal inhibitory concentrations according to the gradient plate method Organism MIC mg / ml N-9 36 N-1010 N-26 8 X-26 5 X-68 4 K-1 5 Shigella sonnei 12 Example 6 From a mixture that 5 g (0.0186 mol) of 2- [4 '- (tert-butoxyoarbonylaminomethyl) phenyl] acetic acid, 1.9 g of triethylamine and 2.52 g of isobutyl chloroformate in 100 ml of tetrahydrofuran is of the amine-blocked 2- [4 '- (tert-butoxycarbonylaminomethyl) phenyl] acetylisobutyl mixed anhydride manufactured. The mixture containing the mixed anhydride is stirred with stirring and Cooling is replaced with a solution obtained by stirring 4.0 g of 7-aminobisacetoxycephalosporanic acid in 60 ml of tetrahydrofuran and 60 ml of water with the addition of triethylamine up to one pH 8 was prepared.

The reaction mixture obtained is allowed to react completely Intermediate, 7- {2 '- [4 "- (N-tert-butoxycarbonylaminomethyl) phenyl] acetamido} desacetoxycaphalosporanic acid then isolated according to the procedure described in Example 1. It will be 2.06 g of this Product received. The ultraviolet spectrum gives Am260 = 4770, the compound has pK'a values of 5.55 and 7.1. By reprecipitating the compound from diethyl ether and petroleum ether becomes 1.6 g of a purer product with ultraviolet absorptions of Am220 = 12,800, Am260 = 5,700 and pK'a values of 5.5 and 7.2.

1.6 g of 7- {2 '- [4 "- (N-tert, -Butoxycarbonylaminomethyl) phenyl] -acetamido} -desacetoxycephalosporanic acid are treated as in Example 4 with 6 ml of trifluoroacetic acid in order to protect the group from the aminomethyl group and remove the trifluoroacetic acid salt of 7-2'-f4 '' - (Aminomethyl) phenylJ-acetamidG-deacetoxycephalosporanic acid. that from the Solution is deposited by adding ethyl ether. There will be 1.2 g of this salt obtain. The ultraviolet spectrum gives Am260 = 6500.

The product has pK's values of 5.55 and 9.1.

, 1 g of the trifluoroacetic acid salt is added to a mixture of 2 1 laasor and 2 ml of methyl isobutyl ketone given, in the Sala nichet loalich vint. 3 ml of water are added and the suspension obtained is treated with the anion exchange resin "LA-1" from Rohm and Haas in the acetate form. The mixture is stirred for about an hour, to ensure full implementation see below. Then the precipitated solid becomes filtered off, adt Waaaart Hrthylieobutylketon and acetonitrile washed and dried, whereby 390 mg of the desired 7- {2 '- [4 "- (aminomethyl) phenyl] acetamido} -3-methyl-3-cephen-4-carboxylic acid can be obtained in the form of the inner salt. The infrared spectrum agrees with this Structure corresponds @ The ultraviolet spectrum gives Am216 = 13070. Am260 = 7130. The Moore Stein test gives a great tip. The product has pK'a values of 5.35 and 9.2.

This 7- {2 '- [4 "- (aminomethyl) phenyl] acetamido} -3-methyl-3-cephem-4-carboxylic acid compound When tested on Mäuaan all oral antibiotic proves to be effective if it given twice to a group of mice as described above. The ED50 value is 31.2 mg / kg body weight compared to an LD50 value of 3250 mg / kg. For agar dilution tests this compound exhibits MIC values of 48 hours against various bacteria less than 6.25 micrograms / ml versus Streoptococus faecalis uhd of less than 6.25 microg @ amm / ml against Escherichia coli # 2. the Connection points.

Mit-verte against 4 different clinical isolates of penicillin @ esistentem Staphylococcus aureus from 5 to 8 micrograms / ml (µg / ml) in the absence of human Blood serum and from 5 to 11 micrograms / ml in the presence of human blood serum on.

Claims (25)

s P t e n n., a n aeha 1. Oral actives of structural formula wherein R 'denotes a hydrogen atom or an alkyl group having Ni or 2 carbon atoms and R' denotes a hydrogen atom or an acetoxy group, its internal salts, stereoisomeric mixtures or salts with a pharmaceutically acceptable acid or base. -7 =. ¢ m. ncetj.'pt. am. o = h. t = acid * 3, [4 "- (d-α-aminoethyl) phenyl] acetamido} -cephalosporanic acid. 4.7- {2 '- [4 "- (1-α-aminoethyl) phenyl] acetamido} -cephalosp @ ran acid. 5. A mixture of stereoisomers of 7- {2 '- [4 "- (d, l-α-aminoethyl) phenyl] acetamido} cephalosporanic acid. St 7- {2 '- [4 "- (aminomethyl) phenyl] acetamido} desacetoxycephalosporanic acid. 7. Pharmaceutical agent, characterized by a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 8. Process for the preparation of orally active cephaloaporin antibiotics of the general structural formal: wherein pure water atom or an alkyl group with 1 or 2 carbon atoms and R @ denotes a hydrogen atom or an acetoxy group or their inner salts, stersoisomeric mixtures or salts with a pharmaceutically acceptable acid or base, characterized. da # ds ma -aminocephalosporanic acid or 7-amino desacetoxycephalosporanic acid or their water-soluble solos with an acylating agent acylates at least one residue of the structure contains, wherein R is as defined above and the amino group has a conventional protecting group, and the protecting group is removed. 9, the method according to claim 8, characterized in that # one the Acylation in an aqueous medium or an organic solvent in a Temperature between the freezing point of the reaction mixture and room temperature performs 10. The method according to claim 8 or 9 @ characterized because # man the acylation is carried out at a practically neutral pH. 11. The method according to claim 8, 9 or 10, characterized in that that the acylation is carried out at a temperature in the range from about 0 to 5 ° C. ' 12. The method according to any one of address 8 to 11, characterized in that the man an N-blocked 2- [4 '- (α-aminoslkyl) phenyl] acetic acid chloride as acylating agent or bromide is used. 13. The method according to claim 12, characterized in that one ale Reaction medium used aqueous acetone. 14. The method according to any one of claims 8 to 11, characterized in that that all ethylating agents are a mixed anhydride from an N-blocked 2- [4 '- (α-aminoalkyl) phenyl] -easetic acid and a lower carboxylic acid is used. 15r method according to Anapruch 14, characterized in that ale Aqueous tetrahydrofuran is used as the reaction medium. 16. The method according to claim 14, characterized in that as Reaction medium used a mixture of acetone and dioxane. 17. The method according to claim 8, 9 or 10, characterized in that that the acylation at room temperature with a 2- [4 '- (α-aminoalkyl) phenyl] acetic acid in conjunction with a carbodiimide. 1 $., Method according to Anapruoh 8, 9 or 10, thereby marked, since the acylation with an activated jet, such as a p-nitrophenyl or Cyanomethyl ester flirted through. 19. The method according to any one of claims 8 to 18: characterized that one removes the protective group from the amino group of the N-blocked 2- [4 '- (α-aminoalkyl) phenyl] acic acid moiety dea products by hydrogenation under mild conditions in the presence of a palladium catalyst removed. 20. The method according to any one of claims 8 to 18, characterized in that that the protective group of the amino group of the N-block @ erten 2- [4 '- (α-aminoalkyl) phenyl] acetic acid an @ ells of the product removed by brief treatment under mildly acidic conditions. 21. The method according to claim 20, characterized in that the Product for about 1 to 5 hours at about room temperature when exposed to formic acid suspends. 22. The method according to any one of claims 8 to 18, characterized in de8 you get the Sahutsgruppe from the amino group of the N-blocked 2- [4 '- (α-aminoalkyl) phenyl] acetic acid moieties of Product by treatment with trifluoroacetic acid to give the corresponding Trifluoroacetic acid salt of the 7- {2 '- [4 "- (aminoalkyl) phenyl] acetamido} cephalosporanic acid thus obtained or -desacetoxycephalosporanic acid removed. 23. The method according to claim 22, characterized in that the Trifluoroacetic acid salt of 7- {2 '- [4 "- (aminoalkyl) phenyl] acetamido} cephalosporanic acid or -desacetoxycephalosporic acid by treatment with an "" anion exchange resin in base or acetate form converted into the zwitterion form of the product. 24. The method according to any one of claims 8 to 23, characterized by because optically active 2- [4 '- (α-aminoalkyl) phenylj-acetic acids are separated and the separate diaatereoteomeric acids or suitable derivatives for acylation used. 25. The method according to claim 24, characterized in that # one Separating mixture of optically active 2- [4 '- (α-aminoalkyl) phenyl] acetic acids, by reacting the fret acids with cinchonine, strychnine or brucine, the @produced Separates salts into the diastereoisomeric salts by fractional crystallization and then sue the separated diastereoisomeric salts by separate acidification releases desired optically active d- or 1-acid.