SI8510744A8 - Cephalosporines derivates and process for preparing them - Google Patents

Description

PROCEDURE FOR THE PREPARATION OF CEFALOSPORINE DERIVATIVES

1. The technical field of the invention

This invention falls within the field of the chemistry of cephalosporin used for the treatment and prophylaxis of infectious diseases, designated by the international patent classification C 07D 501/36, A 61K 31/545.

2. Technical problem

The technical problem to be solved by the present invention is to obtain new cephalosporin derivatives, which are more active than previously known derivatives and which can remain in the bloodstream for a long period of time, thus providing longer application intervals, an obvious preference for both patients and treatment staff.

3. State of the art

Cephalosporins having a 2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido group in position 7 are known e.g. of DOS 25 56 736 and DOS 27 15 385. The cephalosporins of the present invention have such a substituent in position 7, but additionally have a specific substituent in position 3, which has not been disclosed or described so far in the above publications, viz. 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-ylthiomethyl group (or its tautomeric form 1,2,5,6-tetrahydro-2-methyl-5,6 dioxo-as -triazine-3-ylthiomethyl). Qualified selection here with respect to disclosure of the aforementioned disclosures provides unexpectedly novel cephalosporins with superior pharmacological properties such as increased antimicrobial activity and longer half-lives, i.e. the new cephalosporins provided by the present invention are retained in the bloodstream for an extended period of time.

4. Description of the solution to a technical problem with implementation examples

According to the above, the present invention relates to a process for the preparation of eephalosporin derivatives of the general formula

in which X denotes a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or its corresponding tautomeric form, namely 2,5-dihydro-6hydroxy-2-methyl A -5-oxo-as-triazin-3-yl group, and R <0> denotes hydrogen or a cleavable protecting group, as well as salts and hydrates of a compound of formula I in which R <0> denotes hydrogen, or hydrates of said salts of these compounds.

Examples of salts of the compounds of formula I are alkali metal salts such as sodium salt or potassium salt, ammonium salt, followed by alkaline earth metal salts such as calcium salt, organic base salts such as amine salts (e.g. N-ethyl salts -piperidine, procaine, dibenzyl-amine, N, N'-dibenzylethylethylenediamine, alkylamines or dialkylamines), and salts with amino acids (eg salts with arginine or lysine). These salts may be mono-salts or di-salts. The second salt formation can be carried out in compounds with a hydroxyl 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-sa-triazin-3-yl group.

The compounds of formula I also form acid addition salts with organic or inorganic acids. Examples of such salts are hydrochlorides and generally hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides), salts of other mineral acids such as sulfates, nitrates, phosphates, etc., alkyl sulfonates and monoarylsulfonates such as ethanesulfonates, toluenesulfonates, benzenesulfonates, etc. other salts with other organic acids such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula I and their salts may be hydrated. Hydration can be accomplished during the preparation process, or it may be gradual as a result of the hygroscopic properties of the product, which was initially anhydrous.

The cephalosporin derivatives of the present invention may exist in the syn-isomeric form

or in an anti-isomic form

or as mixtures of these two forms. The siri-isomeric form has advantages as well as mixtures in which the syn-isomeric form is predominant.

Suitable cephalosporin derivatives of the present invention are:

(6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2-methyl-5 -oxo-as-triazin-3-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and its salts as well as the corresponding hydrates.

According to the process of this invention, the above cephalosporin derivatives are obtained by reacting a compound of the general formula

III

in which X has the above meaning and the carboxy group and / or amino group may be present in protected form with an acid of the general formula

CH ₃ ON = C — COOH

RHH

IV in which R denotes a cleavable protecting group, or with a reactive functional derivative of this acid, and optionally by cleaving a protecting group R and a protecting group of the carboxy group which may be present, and optionally, for the preparation of salts or hydrates of the compounds with of formula I in which R ° denotes hydrogen, or hydrates of said salts, by converting compounds of formula I in which R ° denotes hydrogen, in salt or hydrate or in hydrate of said salt.

If desired, the carboxy group present in the starting material of formula III can be protected e.g. by esterification to form an ester (which can be cleaved) such as silylester (e.g. trimethylsilyl ester). The carboxy group can also be protected in the form of an ester that can be easily hydrolyzed.

As readily hydrolysable esters we understand compounds in which the carboxy group is present in the form of an easily hydrolysable ester group.

Examples of such esters, which may be of the ordinary type, are lower alkanoyloxyalkyl esters (e.g., acetoxymethyl, pivaloyloxymethyl-, 1-acetoxyethyl- and 1-pivaloyloxyethyl-ester), lower alkoxycarbonylalkoxyalkyl esters (e.g. methoxycarbonyloxymethyl, 1-ethoxyloxymethyl, 1-ethoxyethoxy, 1-ethoxyethoxy) -isopropoxycarbonyloxyethyl ester), lactonyl esters (eg phthalidyl and thiophthalidyl ester), lower alkoxymethyl esters (eg methoxymethyl ester) and lower alkanoylaminomethyl esters (eg acetamidomethyl ester). Further, the carboxy group may be protected by the formation of salts with an inorganic or tertiary organic base such as triethylamine. The amino group in the compounds of formula III may be protected, e.g. with a silyl protecting group such as a trimethyl silyl group. Possible protecting groups denoted by R in the starting materials of formula IV are e.g. protecting groups which can be cleaved by acid hydrolysis (eg tert-butoxycarbonyl or trityl groups) or basic hydrolysis (eg trifluoroacetyl group). Suitable protecting groups designated by R are the chloroacetyl, bromoacetyl and iodoacetyl groups, in particular the chloroacetyl group. The aforementioned protecting groups may be cleaved by thiourea treatment in the compounds of formula I obtained by the process of the present invention.

Examples of reactive functional acid derivatives of formula IV are halides (i.e., chlorides, bromides and fluorides), azides, anhydrides, especially mixed strong acid anhydrides, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (e.g. imidazolides).

The reaction of the 7-amino-compounds of formula III with an acid of formula IV or a functional reactive derivative thereof can be carried out in a manner known per se. So e.g. the free acid of formula IV may be reacted with the aforementioned ester of a compound of formula III in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then ester group, followed by ester . Oxazolium salts (eg N-ethyl5-phenyl-isoxazolium 3′-sulfonate) may be used instead of carbodiimide. According to another embodiment of the present invention, an acid salt of formula III (e.g. a trialkylammonium salt such as triethylammonium salt) is reacted with a reactive functional acid acid of formula IV as mentioned above in an inert solvent (e.g. in one of the solvents mentioned above).

After further carrying out the process of this invention, an acid halide, preferably chloride, of an acid of formula IV is reacted with an amine of formula III. The reaction is conveniently carried out in the presence of an acid-binding agent, e.g. in the presence of an aqueous solution of alkali, in particular sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate, or in the presence of a lower alkylamine such as triethylamine. Water is used primarily as a solvent, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxane. The reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide. When using a silylated compound of formula III, the reaction is carried out in anhydrous medium.

The reaction of a 7-amino-compound of Formula III with an acid of Formula IV or its reactive functional derivative is conveniently carried out at a temperature between -40 ° C and room temperature, e.g. at a temperature of about 0 to 10 ° C.

Reaction of compounds of formula III with acids of formula IV or with reactive functional derivatives of these acids yields cephalosporins of general formula

in which X denotes a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo -as-triazin-3-yl group, R represents a cleavable protecting group, and the carboxy group may be present in protected form.

Said compounds of formula II can be converted to compounds of formula II, wherein R <0> denotes hydrogen, by cleavage of a protecting group protecting the amino group (herein denoted by R). The acid-hydrolysis cleavable protecting groups are removed primarily by lower alkanecarboxylic acid, which may optionally be halogenated. We mainly use formic acid or trifluoroacetic acid. Generally, acid hydrolysis is carried out at room temperature, although it can be performed at slightly elevated or slightly reduced temperatures, e.g. at a temperature in the range of 0 to + 40 ° C. The alkali-cleavable protecting groups are generally hydrolyzed with a dilute alkali metal hydroxide solution at a temperature of 0 to + 30 ° C. The chloracetyl, bromoacetyl and iodoacetyl groups may be cleaved by means of a thiourea in acidic, neutral or alkaline medium at a temperature of from about 0 to + 30 ° C. In this case, the use of hydrogenolytic cleavage (eg, cleavage of the benzyl group) is not appropriate, since during the hydrogenolysis the oxime group is reduced to the amino group.

Optionally, after the cleavage of an amino protecting group (denoted by R hereinafter), a carboxy protecting group may also be cleaved present. If the protecting group is a silyl-ester group, this group can be separated in particular by treatment with water. The lower alkanoyloxy alkyl-, alkoxycarbonyloxyalkyl-, lactonyl-, alkoxymethyl- and alkanoylaminomethyl-esters are cleaved mainly by the enzymatic route by suitable esterase at a temperature of about 20 to 40 ° C. If the carboxy group is protected by the formation of salts (eg triethylamine), the cleavage of the protecting group formed by the formation of salts can be carried out by acid treatment. For example, we can use e.g. hydrochloric, sulfuric, phosphoric or citric acid.

The protecting group protecting the carboxy group may be cleaved in the same manner as previously described for the cleavage of the protecting group marked R.

The preparation of salts and hydrates of compounds of formula I in which R ° denotes hydrogen or of the hydrates of said salts of compounds of formula I can be carried out in a manner known per se; e.g. by reacting an acid of formula I in which R ° denotes hydrogen, with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (eg ethanol, methanol, acetone, etc.). If a second base equivalent is used, salt formation is also carried out on the tautomeric enol form, which may also be present (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group) with X in Formula I) to form a di-sol. The temperature at which salt formation takes place is not critical. Salt formation usually takes place at room temperature, but can also take place at a temperature slightly higher or lower than room temperature, e.g. at a temperature in the range of 0 to +5 () ° C.

s

The preparation of the hydrate is usually carried out automatically during the preparation process, or as a result of the hygroscopic properties of the product, which was initially anhydrous. For the controlled preparation of the hydrate, fully or partially anhydrous carboxylic acid of formula I or its ester, ether or salt may be exposed to a moist atmosphere, e.g. at a temperature of about +10 to + 40 ° C.

The 7-amino compounds of formula III above can be obtained by reacting compounds of general formula

VII

COOH in which Y denotes a cleavable atom or group of atoms and the carboxy group may be present in a protected form, with a thiol of the general formula

HS-X VI in which X has the above meaning, in the presence of water.

Examples of cleavable atoms and cleavable groups denoted by Y in the compound of formula VII are halogen atoms (e.g., chlorine, bromine or iodine atom), acyloxy groups (e.g., lower alkanoyloxy groups, such as an acetoxy group), lower alkylsulfonyloxy or arylsulfonyloxy groups (e.g., mesyloxy or tosyloxy groups) and an azido group. A compound of the Vlia formula may be protected on a carboxy group in the same manner as previously described with respect to the starting materials of the formula III.

The reaction of the compounds of formula VII with the thiol of formula VI may be carried out in a manner known per se, e.g. at a temperature between about 40 and 80 ° C, suitable at about 60 ° C, in a polar solvent, e.g. in an alcohol such as lower alkanol (eg ethanol, propanol, etc.), dimethylformamide or dimethylsulfoxide, in water or in a buffer solution having a pH of about 6 to 7, preferably 6.5.

The syn-anti-mixture of compounds of the formula I, which may be obtained, can be separated into the corresponding syn- and anti-forms in the usual way, e.g. by recrystallization or by chromatographic methods, using a suitable solvent or mixture of solvents.

The compounds of formula I as well as their corresponding salts and hydrates have antibiotic, in particular bactericidal activity. They have a wide range of activities against gram-positive and gram-negative microorganisms, including β-lactamase-forming Staphylococce and various β-Iactamase-forming gram-negative bacteria, such as e.g. Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens, and Proteus and Klebsiella species.

The compounds of formula I and their corresponding salts and hydrates may be used for the treatment and prophylaxis of infectious diseases. The daily dose is about 0.1 g to about 2 g for adults. Particularly preferred is the parenteral administration of the compounds of this invention.

The following compounds were tested to demonstrate the antimicrobial activity of the compounds of this invention:

(as representative representatives):

Compound A: (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2 (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2-methyl) -5-Oxo-astriazin-3-yl) -thio] -methyl] -8-oxo-5-thia-lazabicyclo [4.2.0] oct-2-en-2-carboxylic acid.

Compound B:

(6R, 7R) -7- [2- [2- (2-chloroacetamido) 4-thiazolyl] -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6-hydroxy 2- Methyl-5-oxo-as-triazin-3-yl) -thioylmethyl] -8-oxo-5-thia-1azabicyclo [4.2.0] oct-2-ene-2carboxylic acid.

In vitro activity: minimum inhibitory concentration (Mg / ml)

A B Haemophilus influenzae strain 1 0.08 1.2 strain 2 0.005 0.3 strain 3 0.005 0.16 strain 4 0.005 0.16 strain 5 0.0025 0.08 strain 6 0.0025 0.16 strain 7 0.0025 0.16 Klebsiela pneumoniae 1.2 10 Escherichia coli strain 1 0.02 0.16 strain 2 0.6 5 Proteus mirabilis strain 1 > 0.01 0.08 strain 2 > 0.01 0.10 Proteus vulgaris > 0.01 0.16 Proteus rettjeri > 0.01 0.16 Staphylococcus strain ATCC 6533 2.5 2.5 aureus strain resistant to penicillin 2.5 5 Pseudomonas aeruginosa strain 1 0.3 1.2 strain 2 10 > 80 strain 3 2.5 40 strain 4 5 30 strain 5 5 80 strain 6 10 80 strain 7 5 80

Serratia marcescens

0.08 2.5

In vivo activity

We intraperitoneally infected groups of 5 mice with an aqueous suspension of Escherichia coli. The test substance was administered subcutaneously in sodium chloride saline three times, i.e. 1 hour, 2.5 hours and 4 hours after infection. On the fourth day, we determined the number of surviving animals. Different doses were administered and the dose at which 50% of the test animals (CD50, mg / kg) survived was determined by interpolation.

Test substance A B CD ₅₀ , mg / kg <0.005 0.16

Toxicity

Test substance A B LD50, mg / kg i.v. 250-500 250-500 s.c. > 4000 2000-4000 p.o. > 5000 > 5000

The cephalosporin derivatives of the present invention can be used as medicaments, e.g. in the form of pharmaceutical preparations containing them together with a compatible carrier material. This carrier material may be an organic or inorganic carrier material suitable for enteral or parenteral administration, such as e.g. water, gelatin, arabic gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum gel, etc. The pharmaceutical preparations may be formulated in solid form (eg as tablets, dragees, suppositories or capsules) or in liquid form (eg as solutions, suspensions or emulsions). These pharmaceutical preparations may be sterilized and / or may contain additives such as preservatives, stabilizers, moisturizers or emulsifiers, osmotic pressure variation salts, anesthetics or buffers. Pharmaceutical preparations may also contain other therapeutically valuable substances. The compounds of formula I are generally administered in the form of pharmaceutical preparations which are particularly suitable for parenteral administration and for this purpose produce such preparations preferably in the form of lyophilizates or dry powders, which are diluted with conventional diluents (agents such as water or isotonic solution sodium chloride).

The following examples illustrate the process of the present invention:

Example 1

Preparation of (6R, 7R) -7- [2- [2- (2-Chloroacetamido) -thiazolyl] -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2 -methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

22.24 g of 2- (2-chloroacetamido-thiazol-4-yl) -2- (Z-methoxyimino) -acetic acid was suspended in 240 ml of methylene chloride. 13.39 ml of triethylamine were added to this suspension to give a light-brown solution. This solution was cooled to 0 to 5 ° C and treated with 16.72 g of phosphorus pentachloride. The mixture was stirred for 5 minutes at 0 to 5 ° C and then without stirring for 20 minutes. The resulting yellow solution was evaporated at 35 ° C in vacuo. Shake the evaporation residue twice with n-heptane and decant the latter. The resinous residue was treated with 240 ml of tetrahydrofuran and then the insoluble triethylamine hydrochloride was filtered off. The yellow filtrate contains acid chloride.

g (7R) -7-amino-3-desacetoxy-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-astriazin-3-yl) -thio] -cephalosporic acid was suspended in a mixture 300 ml of water and 150 ml of tetrahydrofuran. A solution of 2N sodium hydroxide was added dropwise to this suspension with a good nitrogen purge until a brownish solution having a pH of 8 was obtained. This solution was cooled to 0 to 5 ° C and treated for 15 minutes with an acid chloride solution in tetrahydrofuran. obtained as described in the previous paragraph. The mixture was then stirred at 25 ° C for 2.5 hours. The pH of this mixture was kept constant at 8 by the addition of 2N sodium hydroxide solution. Tetrahydrofuran was removed from the almost black-colored solution at 40 ° C in vacuo. Then add 100 ml of 2N sulfuric acid. The precipitated material is filtered off under suction in vacuo, washed with water and then vacuumed thoroughly. The wet brown filter material was dissolved in 1.5 l of acetone. The dark colored solution was filtered through Hyflo from a small amount of dark colored insoluble material, treated with activated charcoal, stirred for 30 minutes and filtered again through Hyflo. The orange-red filtrate was dried over sodium sulfate, concentrated in vacuo and evaporated with ethyl acetate. Black resin precipitates. This resin is filtered and discarded. The two-phase filtrate containing water was azeotropically distilled three times with benzene at 40 ° C in vacuo. The precipitated material is filtered off under vacuum in vacuo and dried at 40 ° C in vacuo. This substance was mixed twice with 1 L of acetone (each time) leaving a brown discolored resin discarded. The combined orange-colored acetone extracts were concentrated to about 150 ml at 40 ° C in vacuo and the brown resin was filtered off and discarded. The filtrate was treated with 1 L of ethyl acetate and concentrated at 40 ° C in vacuo. The precipitated material is filtered off under vacuum in vacuo, washed with ethyl acetate and then with ether [i.e. (6R, 7R) -7- [2- [2- (2-Chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy) -2-methyl-5-oxo-as-triazin-3-yl) -thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid, fraction I, as beige colored, amorphous acid.]. This fraction I can be used directly to prepare the desired cephalosporin derivative.

The ethyl acetate mother liquor was concentrated extensively in vacuo at 40 ° C, diluted with water and the precipitated material filtered off under vacuum in vacuo [i.e. (6R, 7R) -7- [2- [2- (2-Chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) -acetamido] -3 [[(2,5-dihydro-6-hydroxy- 2-Methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo-5-thia-lazabicyclo [4.2.0] oct-2-en-2-carboxylic acid, fraction II ; this beige colored, amorphous acid - representing fraction II - is slightly purer than fraction I, as determined by thin layer chromatography].

To prepare the disodium salt, dissolve 3.5 g of this acid (fraction II) in a mixture of 20 ml of acetone and 11 ml of water. This solution was treated with 7 ml of a 2N solution of the sodium salt of 2-ethylcaproic acid in ethyl acetate, crystallizing the disodium salt. Now a further 25 ml of acetone is added portionwise and the mixture is maintained in the freezer for 2 hours. The crystallizate was then filtered off under vacuum in vacuo, washed successively with 25 ml of ice-cold acetone / water (80: 20), pure acetone and petroleum ether at low boiling point and dried overnight at 40 ° C in high vacuum. Disodium salt of (6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] 2- (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6) is obtained -hydroxy-2-methyl-5-oxo-astriazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] -oct-2-en-2-carboxyl acids in the form of light yellow crystals;

[a] _D ²⁰ = -142.7 ⁰ (c = l in water). Nuclear magnetic resonance spectrum and microanalysis correspond to the structure ascribed.

Example 2

Preparation of disodium salt of (6R, 7R) -7- [2- (2-chloroacetamido) -4-thiazolyl] 2- (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy- 2-Methyl-5-oxo-astriazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

15.3 g (6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8xo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid ( fraction I, see below) is suspended in 150 ml of water along with 5 g of thiourea. After vigorous nitrogen purging and vigorous stirring, the pH is adjusted to 6.8-7.0 with saturated sodium hydrogen carbonate solution to form an orange-colored solution. The pH of this solution was maintained constant at 6.8 for 6 hours by the addition of sodium hydrogen carbonate solution using an autotitrator. 2.5 g of thiourea (further plural) are then added and the solution is stirred for a further 3 hours while maintaining the pH value at 6.8 by addition of saturated sodium hydrogen carbonate solution. After that, keep the red solution overnight in the refrigerator, turning dark. Adjust the pH of this solution to 2.0 to 2.5 by adding 100% formic acid, eliminating the substance. The precipitate was filtered off under vacuum in vacuo and washed with 100 ml of 10% formic acid. The mother liquor is discarded. The brown colored filter material was suspended in 200 ml of water and the pH was adjusted to 7 with triethylamine to give a brown colored solution. This solution is mixed with 2 g of activated charcoal, the carbon is filtered off for 30 minutes and the brown filtrate is still adjusted to pH 3.5 by the addition of 100% formic acid with good stirring. The precipitated substance is filtered off under vacuum in a vacuum, washed with 50 ml of 10% formic acid and then discarded. The dark yellow colored filtrate was adjusted to pH 2 - 2.5 using 100% formic acid, precipitating the substance. The substance is filtered off under vacuum in vacuo, washed with ice water and dried. To convert the disodium salt, the resulting cephalosporanic acid was suspended in a mixture of 40 ml of acetone and 40 ml of water and treated with 20 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate. 50 ml of acetone were added to the resulting orange-colored solution, eliminating the brown colored resin, which was decided by filtration. The yellow filtrate was stirred for 30 minutes, crystallizing the disodium salt. The mixture was treated in portions with 50 ml of acetone and maintained overnight in the refrigerator. The crystallizate was filtered off under vacuum in vacuo, washed successively with a mixture of acetone / water (85: 15), pure acetone and light petroleum at low boiling point and dried overnight at 40 ° C in vacuo. The title compound is obtained in the form of beige crystals;

[α] _D ²⁰ = -144 ° (c = 0.5 in water). Nuclear magnetic resonance spectrum and microanalysis correspond to the structure ascribed.

The following example illustrates pharmaceutical preparations containing cephalosporin derivatives of the present invention.

Example A

Preparation of dry ampoules for intramuscular administration:

The lyophilisate from 1 g of disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamido] -3 - [[ (2,5-Dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-en-2-carboxylic acids. This lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution prior to administration.

For

F. Hoffmann-La Roche AG:

A MkAD-OORiUP VALUE

STATEMENT OF THE BEST WAY FOR ECONOMIC USE

IZUMA

The best way to economically use this invention is from the preparation of (6R, 7R) 7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamido] -3 - [[(2,5- dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid as a trihydrate of disodium salt, which has a strong antibacterial activity and remains in the bloodstream for a long period of time. The preferred method of this compound is apparent from Examples 1 and 2 above and comprises reacting an aqueous suspension of (7R) -7-amino-3-desacetoxy-3 [[(2,5-dihydro-6-hydroxy-2-methyl) -5-Oxo-as-triazin-3-yl) -thio] -cephalosporanic acid with a solution of 2- (2-chloroacetamidothiazol-4-yl) -2- (Z-methoxyimino) -acetyl chloride in an organic solvent, followed by reaction ( 6R, 7R) -7- [2- (2-Chloroacetamido) 4-thiazolyl] -2- (Z-methoxyimino) -acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2-methyl- 5-Oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo- [4.2.0] oct-2-ene-2 carboxylic acid (obtained in aqueous suspension) with thiourea , which gives the desired end product in the form of an acid that is conveniently converted to the disodium salt trihydrate by reacting the acid itself in an aqueous solvent such as an acetone / water mixture with at least two equivalents of 2-ethylcaproic acid in a solvent such as ethyl acetate at room temperature. Using the aqueous solvent after treatment, the resulting salt is automatically hydrated with 3.5 moles of hydrated water per mole of substance (trihydrate).

For:

F. HOFFMANN-LA ROCHE AG

AVKEL1JA OkAD-GORtur

\ š

Claims (6)

PATENT APPLICATIONS A process for preparing a cephalosporin derivative of the general formula COOH in which X denotes a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or 2,5-dihydro-6-hydroxy-2-methyl-5- oxo-as-triazin-3-yl group and R ° denotes hydrogen or a cleavable protecting group selected from chloroacetyl, bromoacetyl, iodoacetyl, trifluoroacetyl, t-butoxycarbonyl, trityl and formyl groups, as well as pharmaceutically acceptable salts and hydrates of the compounds of formula I , in which R ° denotes hydrogen, or hydrates of said salts, characterized in that it comprises reacting compounds of the general formula COOH in which X has the meaning given above and the carboxy group and / or amino group may be protected by a trimethylsilyl group having an acid of the general formula CH ₃ ON = C — COOH RHN IV in which R denotes a cleavable protecting group as defined at R ° or with a reactive functional haiid, azide, anhydride, ester such as Nhydroxysuccinimide ester, or amide of this acid in an inert diluent at a temperature between about - 40 ° C and room temperature the temperature and optionally cleavage of the protecting group R and the protecting group protecting the carboxy group and possibly present, and optionally for the preparation of salts or hydrates of a compound of formula I in which R ° denotes hydrogen, or hydrates of said salts, conversion of compounds with formula 1, wherein R ° is hydrogen, a pharmaceutically acceptable salt or hydrate or hydrate of said salts. Σθ A process according to claim 1 for the preparation of compounds of the general formula ch ₃ on = c'n-J // \\ • CONH • S-X COOH II in which X and R have the meanings given in claim 1 and the carboxy group can be protected as in claim 1, characterized in that it comprises reacting a compound of the general formula h ₂ n · 3. A process according to claim 1 or 2, wherein said compounds are obtained in a sinisomeric form or a mixture in which the syn isomeric form predominates using * starting compounds of formula IV in the syn-isomeric form or in the form of a mixture in which the syn-isomeric form predominates. 4. Cephalosporin derivatives of the general formula wherein X is a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or 2,5-dihydro-6-hydroxy- 2-methyl-5-oxo-as-triazin-3-yl group and R ° denotes hydrogen or a cleavable protecting group selected from chloroacetyl, bromoacetyl, iodacetyl, trifluoroacetyl, t-butoxycarbonyl, trityl and formyl groups, and the carboxy group may be protected by a trimethylsilyl group, 11 as well as pharmaceutically acceptable salts and hydrates of compounds of formula I in which R ° denotes hydrogen, or hydrates of said salts. The compound of claim 4, wherein R ° is hydrogen and X is a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, respectively. (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo) as-triazin-3-yl) thio] ethyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid as well as pharmaceutically acceptable salts of this compound and hydrates of this compound and the hydrate salts of this compound. -5 — X III COOH in which X has the above meaning and the carboxy group and / or amino group may be protected as in claim 1 with an acid of the general formula CH ₃ ON = C — COOH RHN IV in which R has the above meaning. or with a reactive functional halide, azide, anhydride, ester such as N-hydroxysuccinimide ester, or an amide of this acid, in an inert solvent at a temperature between about -40 ° C and room temperature and optionally cleaving a protecting group protecting the carboxy group and which is possibly present. 6. (6R, 7R) -7- [2- [2- (2-Chloroacetamido) thiazolyl] -2- (methoxyimino) acetamido] -3 [[(2,5-dihydro-6-hydroxy-2-methyl- 5-Oxo-as-triazin-3-yl) thio] methyl] -8-oxo-5-thia-lazabicyclo [4.2.0] oct-2-en-2-carboxylic acid.