NL8104133A - CEPHALOSPORINE DERIVATIVES. - Google Patents

Description

"........." ~ · ~ 'w "' —...................... * ........ . ............. 'ί * ιγ.0.50.409 *

Cephalosporin derivatives

The present invention relates to new cephalosporin derivatives of the general formula 1, wherein R represents the pivaloyloxy-methyl or acetoxymethyl group, as well as acid addition salts of these compounds and hydrates of the compounds of the formula 5, respectively. from Iran acid addition salts.

The compounds of the formula I form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as other salts of inorganic acids, such as sulfates, nitrates, phosphates and the like, alkyl and monoarylsulfonates, such as ethanesulfonates, toluene sulfonates, benzene sulfonates and the like and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, asorbates and the like.

The compounds of the formula I as well as their acid addition salts can be hydrated. The hydration may take place in the course of the preparation process or may occur gradually as a result of hygroscopic properties of an initial anhydrous pressure.

The products according to the invention may be in the syn-isomeric form of the formula 7 or in the anti-isomeric form of the formula 8, respectively.

when mixtures of both these forms are present. Preference is given to the syn-isomeric form, respectively. mixtures in which the syn isomeric form is predominantly present.

Preferred products are methylene (6R, 7 ^) - 7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methozyimino] -acetamido] -3 - [[[ 2-methyl-5 - [[(pivaloyloxy) -methoxy] carbonyl] -2H-1,2,4-triazol-5-yl] thio] methyl] -8-oxo-5-thia-1-aza- bicyolo [4 * 2.0] oct-2-en-2-earboxylate pivalate, its acid addition salts and the corresponding hydrates.

The aforementioned cephalosporin derivatives can be prepared according to the invention by using the corresponding dicarboxylic acid, ie the (6r, 7S) -7- [2- (2-amino-4-thiazolyl) -2- [methoxyimino] acetamido ] -3 - [[3-carboxy-1-methyl-1H-1,2,4-triazol-5-yl) thio] methyl] -8-oz: o-5-thia-1-azabicyclo [4.2.0 ] oct-2-en-2-carboxylic acid (compound 2) or a salt of this compound subject to a suitable esterification and, if desired, the product obtained in an acid addition salt or hydrate, respectively. a hydrate of this acid addition salt 8104133 V v

4 2 A

revenue.

The dicarboxylic acid (Compound 2) used in the foregoing process can be prepared starting from 7-aminocephalosporanic acid as follows.

The 7-aminocephalosporanic acid is reacted in aqueous solution with 4J5-dih, ydro-1-methyl-5-thioxo-1H-1,2,4-triazole-3-carbonzunx (compound 3), for example at a temperature between about 40 and 80 ° C, expediently at about 60 ° C. The solution is preferably buffered at a pH of about 6 to 7, preferably 6.5,.

let thus obtained (6R, 7R) -7-amino-3 - / [(3-carboxy-1-methyl-1,2,4-triazol-5-yl) thio] methyl / -8-oxo-5-thia -1-azabicyclo [4.2.0] - oct-2-en-2-carboxylic acid (compound 4) is then added with a carboxylic acid of the general formula 5, wherein R represents a cleavable group, or with a reactive functional derivative of this acid converted to give a compound of the general formula 6 wherein 1 has the foregoing meaning.

-j

Possible protecting groups of R are, for example, protective groups which can be split off by acid hydrolysis, such as, for example, tert-butoxycarbonyl or trityl, or protective groups which can be split off by basic hydrolysis, such as, for example, trifluoroacetyl.

Protective groups for R are preferably chloro, bromo and iodoacetyl, in particular chloroacetyl. The latter protecting groups can be cleaved off by treatment with thiourea.

As reactive, functional derivatives of carboxylic acids of the formula V are, for example, halides, i.e. chlorides, bromides and fluorides; azides; anhydrides, especially mixed anhydrides with stronger acids; reactive esters, for example N-hydroxy-30 succinic imide star, and amides, for example imidazolides.

The reaction of the 7-amino compound of the formula IV with the carboxylic acid of the formula 5 or a reactive functional derivative thereof can be carried out in a manner known per se. For example, an acid halide, preferably the chloride of a carboxylic acid of the formula 5, can be reacted with the amine of the formula 4. The reaction preferably takes place in the presence of an acid-binding agent, for example in the presence of an aqueous alkali, preferably caustic soda, or in the presence of an alkali metal carbonate, such as potassium carbonate, or in the presence of an alkylamine with a small number of carbon atoms, such as triethylamine. Water is preferably used as the solvent, optionally mixed with an inert organized solvent, such as tetrahydrofuran or dioxane. An aprotic organic solvent such as, for example, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide can also be used. The conversion can conveniently take place at temperatures between about -40 ° C and room temperature, for example at about 0-10 ° C.

The amino group protecting S is then cleaved off in the obtained compound of the formula 6, wherein. the desired dicarboxylic acid (compound 2) is obtained. Protective groups which can be split off by acid hydrolysis are preferably removed with the aid of an alkane carboxylic acid with a small number of carbon atoms, which may optionally be halogenated. In particular, 15-formic acid or trifluoroacetic acid is used. As a rule, the temperature is room temperature, although also slightly increased or. slightly reduced temperature can be used, for example in the range of about 0 ° C to + 40 ° C. Alkaline-cleavable protecting groups are generally hydrolyzed with dilute aqueous caustic at 0 ° C to 20 ° C. The protective chloroacetyl, bromoacetyl and iodoetyl groups can be cleaved off at about 0-30 ° C by means of thiourea in an acid, neutral or alkaline medium.

Cleavage by hydrogenolysis (for example cleavage of benzyl) is unsuitable here, because in the hydrogenolysis the oxime function wanted to be reduced to the amino group.

The resulting dicarboxylic acid of formula 2 can then be converted into a salt, for example into an acid addition salt as described above for the end products of formula 1, or also into salts with bases, for example alkali metal salts, such as the sodium and potassium salt; the ammonium salt; alkaline earth metal salts, such as the calcium salt; salts with organic bases, such as salts with amines, for example salts with H-ethylpiperidine, procaine, dibenzylamine, N-dibenzylethylenediamine, alkylamines or dialkylamines, as well as salts with amino acids, such as salts with arginine or lysine. The salts can be mono salts or also di-salts. The salts are prepared in a manner known per se, for example, by reacting the dicarboxylic acid of the formula II with an equivalent amount of the desired acid or. base, expediently in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone and others. When a second 8104133 t * 4 equivalent to "base" is used, the salt formation also takes place on the second carboxyl function. The temperature of the salt formation is not critical. It is generally at room temperature, but may also be slightly above or below it. , approximately in the range of 0 ° C to + 50 ° C.

The 4> 5-dihydro-1-methyl-5-thioxo-1H-1,2,4-triazole-3-carboxylic acid is in tautomeric equilibrium with the corresponding thiol within the meaning of the formulas according to the figure of the formula sheet.

The preparation of this compound is described in Example I.

The esterification according to the invention of the dicarboxylic acid of the formula II takes place by reaction with an agent releasing the pivaloyloxymethyl or acesboxymethyl group, preferably by reaction with the corresponding halide, in particular with the iodide. The reaction can be accelerated with the aid of a base, for example an alkali metal hydroxide or carbonate, or with an organic amine, such as triethylamine. Preferably an excess of the suitable halide is used. The esterification reaction is preferably conducted in an inert organic solvent, optionally mixed with water, such as dimethyl acetamide, hexamethylphosphoric triamide, dimethyl sulfoxide or, preferably, dimethyl formamide.

The temperature is preferably in the range of about 0-40 ° 0.

The preparation of the acid addition salts and hydrates of the compounds of the formula I, respectively. the hydrates of these salts can take place in a manner which is self-contained, for example the acid addition salts, for example by reacting the compound of the formula I with an equivalent amount of the desired acid, advantageously in a solvent such as water or in an organic solvent, such as ethanol, methanol, acetones and the like. The temperature of the salt formation is not critical. It is generally at room temperature, but may also be slightly above or below it, approximately in the range of 0 ° C to + 50 ° C.

The hydrates are usually prepared automatically during the preparation process or as a result of the hygroscopic properties of a first anhydrous product. For a targeted preparation of a hydrate, a completely or partially anhydrous product can be exposed to a humid atmosphere, for example at about + 10 ° G to + 40 ° C.

An optionally obtained syn / anti-mixture of a compound 40 of the formula 1 can be cleaved in the corresponding syn- and anti-forms in the usual manner, for example by recrystallization or by chromatographic methods using a suitable solvent resp. mixture of solvents. Preferably, however, the compound of the formula 1 is obtained in the syn-isomeric form by using a starting compound of the formula 5 in the syn-form.

The compounds of the formula I as well as the corresponding acid addition salts resp. the hydrates of these products are anti-biotic, especially bactericidal. They have a broad spectrum of activity against Gram-positive bacteria, for example streptococci, and against Gram-negative bacteria, such as, for example, Neisseria meningitidis, as well as against various β-lactamase-forming Gram-negative pathogens, such as Escherichia coli and Serratia marcescens.

The compounds of the formula I as well as the corresponding acid addition salts resp. the hydrates of these products can be used for the treatment and prophylaxis of infectious diseases.

For adults, a daily dose of from about 0.1 g to about 4 St, especially about 0.25 to about 2 g, is suitable. Enteral or parenteral administration is possible, a particular preference in the utility of the products of the invention for enteral, for example, oral administration.

The oral anti-microbial activity of the products of the invention can be demonstrated by in vivo tests in the mouse. In the following, the curative dose (CBj-q, mg / kg) means that dose in which 30% of the mice tested survive.

Taste connections:

Product A: Metbylene (6r, 7R) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -50-methoxyimino] -acetamidb] -3 - [[[2-methyl-5 - [[(pivaloyloxy) -methoxy] carbonyl] -2H-1,2,4-triazol-3-yl] thio] methyl] -8-oxo-5-thia-1-azabicyclo [4 * 2.0] oct-2 -a-2-carboxylate pivalate

Gefalexin (already known, recognized orally active cephalosporin) 35 Result (CD ^ Q, mg / kg) 8 104 134 6

Pathogen Product A Cefalexin p .o · s .c. p »0 · S .0.

Escherichia coli 0.047 0.002 3> 2 2.1

Serratia marcescens 0.68 0.05> 50> 50

Neisseria meningitidis 0.14 1.2

Streptococcus pyogenes 0.95 0.044 1 »8 1.2

Product A is significantly more effective than cephalexin after both peroral and subcutaneous administration.

The blood levels obtained after oral administration are shown in the rat in the following equation.

5 oral dose of antibiotic concentration in the blood in jig / τηΐ after minutes mg / kg 15 30 45 60 90 150

Product A 50 6 12 12 10 8 5 10 Cefalexin 50 8121418 * 5 The product A is at least as toxic as cefalexin (ID, -0. Po in the mouse after 24 hours:> 4000 mg / kg for Product A, 1600- 4500 mg / kg for cefalexin).

The products according to the invention can be used as a medicament, for example in the form of pharmaceutical preparations, which mix these or their salts with a pharmaceutically, organic or inorganic inert carrier material suitable for the enteral or parenteral, preferably enteral, use, such as, for example, water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyethylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, for example, as tablets, dragees, suppositories, capsules; or in liquid form, for example when solutions, suspensions or emulsions are present. They are optionally sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, salts for changing the osmotic pressure, anesthetics or buffers. They can also contain other therapeutically valuable substances.

Example I

Preparation of methylene (6l, 7l) -7- [1- 2- (2-amino-4-thiazolyl) -2 - [(z) -methoxyimino] -acetamido] -3 - [[[2-methyl-5- [ [(pivaloyloxy - 8104133) 7 methoxy] carbonyl] -2H-1,2,4-triazol-3-yl] -thioethyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-en-2-carboxylate pivalate: 3.9 s of the disodium salt of the (6r, 7R) -7- [2- (2-amino-4-thiazolyl) -2- [(Z) -methoxyimino] acetamido ] -3- [[3-carboxy-1-methyl-5H-1,2,4-triazol-5-yl) thio] methyl] -8-oxo-5-thia-1-azahicyclo [4 · 2.0 oct-2-en-2-carboxylic acid are dissolved in a mixture of 100 ml of dimethylformamide and 25 ml of water. To this solution are added 3.13 µg of methyl pivalate at 0-5 ° C under gassing with nitrogen. The reaction mixture is stirred at 0-5 ° C for 30 minutes, then poured into 500 ml of water and extracted three times with 200 ml of ethyl acetate each time. The aqueous phase is removed. The combined ethyl acetate phases are washed successively with water, dilute aqueous sodium hydrogen carbonate solution and further with water, dried over sodium sulfate and highly concentrated under reduced pressure at 40 ° C. After the addition of low-boiling petroleum ether, the precipitated crude product is filtered off with suction, washed with low-boiling petroleum ether and dried under high vacuum at 40 ° C. A beige-colored, amorphous impure product is obtained. - For purification, this product is subjected to a column 20 with 100 g of silica gel (0.2-0.5 mm) and ethyl acetate as an eluent, chromatographically. The pure beige amorphous title substance with Rf = 0.31 is obtained by thin layer chromatography on finished silica gel 601 -254 plates with ethyl acetate as the running liquid. The specific rotation is 25 ° = -121.6 ° (c = 0.4924 in acetone); the core resonance spectrum and the microanalysis correspond to the indicated structure.

The compound used as starting material in the foregoing process can be prepared as follows: a) Preparation of 4,5-dihydro-1-methyl-5-thioxo-1 H-1,2,4-tiiazole-30 3-carboxylic acid methyl ester: 12.9 8 of 1-methozyoxalyl-2-methyl-thiosemicarbazide are added to a solution of 1.6 g of sodium in 200 ml of methanol.

The mixture is refluxed for 4 hours. The precipitated substance is separated after 30 minutes. The mother liquor is evaporated under reduced pressure at 40 ° C. The evaporation residue is dissolved in 100 ml of water and acidified with concentrated hydrochloric acid. The crystalline product thus separated gives, after recrystallization from water, the pure, colorless 4> 5-dihydro-1-methyl-5-thioxo-1H-1,2,4-thiazole-3-carboxylic acid methyl ester with a mp 40-188-190 ° C (decompn.).

8104 133 8 b) Preparation of 4 • 5 ”dihydro-1-methyl-5-thioxo-1H-1,2,4-triazole-3-carboxylic acids 3.46 g 4> 5-dihydro-1-methyl-5- thioxo-1H-1,2,4-triazole-3-carboxylic acid methyl ester are dissolved in 50 ml of 1U sodium hydroxide solution.

Stirring for 5 minutes at 25 ° C, the reaction solution is made acidic with 25 ml of 2N hydrochloric acid and concentrated under reduced pressure at 40 ° C, the desired acid crystallizing. Bit is aspirated, washed with ice water and dried at 45 ° C under highly reduced pressure. Colorless 4'-5-dihydro-1-methyl-10'5 '' χοχο-1'-1,2,4 '' triazole-3-carboxylic acid with a melting point of 177-178 ° C (decomposition) is obtained.

c) Preparation of (6R, 7R) "7-amino-3 - [[(3" Carboxy-1-methyl-1,2,4-triazol-5-yl) thio] methyl] -8-oxo-5- thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid: 34 g of 7-aminocephalosporanic acid are added together with 25> 5 g of 4> 5-cli-hydro-1-methyl-5-thioxo 1H-1,2,4-triazole-3-carboxylic acid suspended in 500 ml of water. The pH is adjusted to 6.5 with 3M sodium hydroxide. The mixture is stirred under a nitrogen atmosphere at 55 ° C for 4 hours, keeping the pH constant at 6.5 with 3N sodium hydroxide solution using an autotitrification device. The dark solution is cooled to 25 ° C and brought to a pH of 3.5 with concentrated hydrochloric acid. After 15 minutes, the precipitated material is filtered off with suction, suspended in 500 ml of water and dissolved with 3 H sodium hydroxide solution at a pH of 7. The orange-red solution is mixed with. Adjusted hydrochloric acid to a pH of 3. The precipitated material is filtered off with suction and washed successively with 250 ml of water, 500 ml of acetone, 500 ml of low-boiling petroleum ether and dried overnight under reduced pressure at 40-45 ° C. (6R, 7R) - 7-amino-3 - [[(3-carboxy-1-methyl-1,2,4-triazo-5-yl) thio] methyl] -8-30 oxo-5- is obtained thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid as beige colored powder.

d) Preparation of (6R, 7R) -3- [[(3-carboxy-1-methyl-1 Ξ-1,2,4-triazol-5-yl) thio] methyl] -7- [2- [2 - (2-chloroacetamido) -4-thiazolyl] -2- [(z) -methoxyimino] acetamido] -8-oxo-5-thia-1-azabicyclo [4.2.0] -35 oct-2-en-2- carboxylic acid:

75 g of phosphorus dichloride are added to 600 ml of dichloromethane dried over calcium chloride. The suspension is cooled to -10 ° G with stirring and 138 ml of H, H-dimethylacetamide are added dropwise over about 5 minutes, the temperature rising to -5 ° C. The suspension is cooled to -15 ° C 8104133 and stirred for 15 minutes. After cooling to -20 ° C, 100 g of 2- (2-chloroacetamido-4-thiazolyl) -2- (Z) -methoxyimino-acetic acid are added and stirred at -15 ° C for 45 minutes, with a yellow-orange solution arises. this solution is cooled to -30 ° C, ice is added and ice is stirred for 10 minutes at -5 ° C. The formed acid chloride containing dichloromethane phase is separated and first stored at about -15 ° C. This acid chloride solution is added to a solution cooled to 0-5 ° C, which is added by adding 111.5 g (6E, 7R) -7-amino-3 - [[(3-carboxy-1-methyl-1) 2,4-10 triazol-5-yl) thio-methyl] -8-oxo-5-thia-1-azabioyclo [4 · 2.0-yt-2-en-carboxylic acid on 3N sodium hydroxide solution to pH 8.2 in 500 ml of water was prepared, added dropwise over 50 minutes with vigorous stirring, keeping the pH value at 8.0-8.2 with 3M caustic soda using an autotiter. The mixture is stirred at 25 ° 0 for 2 hours. about 900 ml of dichloromethane and 6 l of n-butanol are added. The pH is brought to 2 with 3N hydrochloric acid with vigorous stirring. The organic phase is separated, washed three times with 3 l of water each time, stirred with 60 g of decolorizing carbon for 15 minutes and filtered. The light yellow filtrate is highly concentrated under reduced pressure at 60 ° C, whereby the reaction product precipitates. The latter is filtered off with suction and washed successively with n-butanol, ether and low-boiling petroleum ether and dried at 40 ° C overnight under reduced pressure. Impure beige (6th, 7E) -3 - [[(3-carboxy-1-methyl-1,2-1,2,4-25-triazol-5-yl) thio] methyl] -7- [2- ( 2-chloroacetamido) -4-thiazolyl] -2 - [(Z) -methozyiminojacetamido] -8-oxo-5-thia-1-azabioyclo [4 * 2.0] -2-an-2-carboxylic acid.

e) Preparation of the disodium salt of the (6E, 7R) -7- [2- (2-amino-4-thiazolyl) - 2- [(z) -methoxyimino] acetamido] -3- [[(3-carbosy -1 -30 methyl-1H-1,2,4-triazol-5-yl) thio] -methyl] -8-oxo-5-thia-1-azabioyclo [4 2.0] oct-2-en-2- carboxylic acid: 53 g (6E, 7E) -3 - [[(3-carboxy-1-methyl-1H-1,2,4-triazol-5-yl) -thioethyl] -7- [2- [2- (2-chloroacetamido) -4-thiazolyl) -2 - [(Z) -methoryiminoacetamido] -8-oxo-5-thia-1-azabioyclo [4.2.0-oct-2-en-35 2-carboxylic acid in 1 l of water suspended with 34 g of thiourea. The pH is adjusted to 7 by the dropwise addition of 1H sodium hydroxide solution to a dark brown solution. It is stirred overnight under a nitrogen fumigation at a pH of 7, keeping the pH constant with 1N sodium hydroxide using an autotit-40 tamper. The pH of the reaction solution is 810 * 133 • i · · 10 is brought back to 3 »5 with 1M hydrochloric acid with stirring. The precipitated substance (fraction i) is filtered off, washed with 250 ml of water and dried under reduced pressure at 40 ° C. Fraction I is colored brown and heavily contaminated; it is removed. The orange mother liquor is brought to pH 2.65 with 1H hydrochloric acid while stirring. The precipitated material is suctioned off and washed with 250 ml of water. The beige-colored suction product is azeotropically distilled under reduced pressure with ethanol, filtered off with suction, washed with ethanol and low-boiling petroleum ether and dried under reduced pressure at 40 ° C. There is thus obtained a beige-brown Cll fraction II, which is suspended by purification and conversion into the sodium salt in 2 l of methanol, 50 ml of a 2N solution of the sodium salt of 2-ethyl caproic acid in ethyl acetate are added and then stirred with 200 ml of water for 30 minutes. Slightly dissolved brown material is filtered off and removed.

The orange-colored filtrate is evaporated under reduced pressure at 40 ° C about 1 L, then 1 L of ethanol is added and concentrated to a volume of about 500 ml under reduced pressure. The whole brown resin, which is a strong mixture, precipitated is decanted. 1 L of ethanol is added to the decanted yellow-orange solution and it is highly concentrated under reduced pressure at 40 ° C, with dust precipitating on parts. After the addition of 2.5 l of methanol, a yellow solution is formed, which is strongly concentrated under reduced pressure at 40 ° C. The disodium salt precipitated therein is filtered off with suction, washed with methanol and low-boiling petroleum ether and dried under high vacuum at 35 ° C. Pure, beige colored disodium salt of the (6R, 7H) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] acetamido] -3 - [[(3-carboxy- 1-methyl-1,2-1,2,4-tri-azol-5-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] diet-2-en-2 * 2 O-carboxylic acid with [α] D = -38.7 (c = 1 in water).

Example II

Preparation of methylene (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- [(z) -methoxyimino] -acetamido] -3 "[. [[2-methyl-5- [ [(acetoxy) metho2y] -35 carbonyl] -2H-1,2,4-triazol-3-yl] -thio] methyl] -8-oxo-5-thia-1-azabicyclo [4 * 2.0] oct-2 -a-2-carboxylate acetate: 5.98 g (6E, 7E) -7-amino-3 - [[(3-carboxy-1-methyl-1,2,4-triazol-5-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid disodium salt are dissolved in a mixture of 70 ml of dimethylform-40 amide and 25 ml of water. 6.12 g of acetic acid bromomethyl ester are added to the solution under gassing with nitrogen at 0-5 ° C and stirred at 0-5 ° C for 3 hours. The reaction mixture is poured onto 500 ml of water and extracted twice with ethyl acetate while adding little acetone. The combined organic phases are washed successively with a dilute aqueous solution of sodium hydrogen carbonate and water, dried over sodium sulfate, and highly concentrated under reduced pressure at 40 ° C. After addition of low-boiling petroleum ether, the amorphous precipitated material is filtered off with suction, washed with low-boiling petroleum ether and dried at 10 ° C under a high vacuum. A beige crude product is obtained which is subjected to a column with 80 g silica gel (0.2-0.5 mm diameter) and ethyl acetate as eluent for purification by chromatography.

The pure beige, amorphous title substance (from ethyl acetate / 25 ° 15 low-boiling petroleum ether) is obtained with [α] D = -107-16 ° (o = 1.0358 in acetone). The core resonance spectrum and the microanalysis correspond to the indicated structure.

Figure III

A gelatin capsule of the following composition was prepared in the usual manner: methylene (6E, 7E) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] -acetamido J-3 - [[[2-methyl-5-L [(pivaloyl-, oxy) methoxy] carbonyl] -2H-1,2,4-triazol-3-yl] thioethyl] -8-oxo-5-thia -1-azabicyolo [4.2.0] o ct-2-en-2-carboxylate pivalate 500 mg luviskol (water-soluble polyvinylpyrrolidone) 20 mg mannitol. 20 mg talc 15 mg.

magnesium stearate 2 mg 557 mg

Yoorbeeld IT

A tablet of the following composition was conventionally prepared: methylene (6E, • 7E) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] -acetamido J-3— [[[2-methyl-5- [[(pivaloyl-oxy) methoxy] carbonyl] -2H-1,2,4-triazol-3-yl] thio] methyl] -8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-en-2-carbonyl pivalate 250 mg lactose 70 mg corn starch .. 65 mg polyvinylpyrrolidone 10 mg magnesium stearate 5 m / y 400 mg 8104133 * 12

A granulate is prepared in the usual manner with the active substance, the lactose, the polyvinylpyrrolidone and 40 parts by weight of the corn starch. This is mixed with the remaining 25 parts by weight of corn starch and 5 parts by weight of magnesium stearate and pressed into 5 tablets.

j 8104133

Claims (14)

1. Cephalosporin derivatives of the general formula 1, wherein R represents the pivaloyloxymethyl or acetoxymethyl group, as well as acid addition salts of these compounds and hydrates of the compounds of formula 1 and 1, respectively. of their acid addition salts. Cephalosporin derivatives according to claim 1 in the syn isomeric form grate mixtures wherein the syn isomeric form predominates. 3. Methylene (6R, 7S) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxy-imino] -acetamido] -3- [[[2-methyl-5- [[(pivaloyloxy) methoxy] earbonyl] - 10 2H-1,2,4-triazol-3-yl] thio] methyl] -8-02: o-5-thia-1-aza'bicyclo- [4.2.0 oct-2-en-2-carboxylate pivalate as well as acid addition salts of this compound and hydrates of this compound, respectively. acid addition salts. 4. Methylene (6r, 7 * 0-7- [2- (2-amino-4-thiazolyl) -2- [(Z) -methyl-15-imino] -acetamido] -3 - [[[2-methyl- 5 - [[(acetoxy) methoxy] carbonyl] - 2H-1,2,4-triazol-3-yl] thio] methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 2-carboxylate acetate as well as acid addition salts of this compound and hydrates of this compound or acid addition salts. 5. Compounds according to any one of claims 1-4 as pharmaceutically active substances. Terbindings according to any one of claims 1-4 as pharmaceutical preparations for enteral, for example oral treatment and prophylaxis of infectious diseases. 7. Methylene (6R, 7H) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -2-methoxyimino] -acetamido] -3 - [[[2-methyl-5- [[(pivaloyloxy) methoxy] -carbonyl J-2H-1,2,4-triazol-3-yl] thio] methyl] -8-oxo-5-thia-1-azabicyclo [4 * 2.0] oct-2- a 2-carboxylate pivalate as well as acid addition wells of this compound and hydrates of this compound, respectively. acid addition salts for the enteral, for example, oral treatment and prophylaxis of infectious diseases. Rare-like preparations, characterized by a content of a compound according to any one of claims 1-4. 9. Pharmaceutical preparations for the enteral, for example, oral treatment and prophylaxis of infectious diseases, having a content of a compound according to any one of claims 1-4. 10. Pharmaceutical preparations according to claim 9> containing methylene (6R, 7R) 7- [2- (2-amino-4-thiazolyl) -2 ~ [(Z) -methoxyimino] -acetamido] -3 - [[[2 -methyl-5 - [[(pivaloyloxy) methoxy] carbonyl] -2H-40 1,2 ', 4-triazol-3-yl] thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2 .0] - 8104133 Si · Τ - * oct-2-an-2-carboxylate pivalate or an acid addition salt of this compound, a hydrate of this compound and an acid addition salt thereof. Process for the preparation of compounds according to any one of claims 1 to 4, characterized in that the corresponding dicarboxylic acid, ie the (6th, 7E) -7- [2- (2-amino-4-thiazolyl) ) -2- [methoxyiminoacetamido] -3- [[3-carboxy-1-methyl-1H-1,2,4-triazol-5-yl) thia] -methyl] -8-oxo-5-thia-1 -azabicyclo [4.2.0] - oct-2-an-2-carboxylic acid or a salt of this compound subject to a suitable esterification and, if desired, the obtained product in an acid addition salt or hydrate reap, a hydrate of this acid addition salt revenue. 12. Process according to section 11, characterized in that a pivaloyloxymethyl halide, in particular the iodide, is used as the preservative agent. Use of compounds according to any one of claims 1-4 in the treatment of reap, disease prophylaxis. Use of compounds according to any one of claims 1 to 4 in the enteral, e.g. oral treatment, respectively. prophylaxis of infectious diseases. Use of methylene (6E, 7E) - 7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] -acetamido] -3 - [[[2-methyl -5 - [[(pivalo-yloxy) methoxy] carbonyl] -2H-1,2,4-triazol-3-yl] -thio] methyl] -8-oxo-5-thia-1-azabicyclo [4 * 2.0 oct-2-en-2-carboxylate pivalate as well as acid addition salts of this compound and hydrates of this compound, respectively. acid addition salts according to claim 14,8104133