HU182498B - Process for producing 7-bracket-iminoacetamido-bracket closed-3-thiomethyl-ceph-3-eme-4-caraoxylic acid - Google Patents

Abstract

1. Cephalosporin derivatives of the general formula see diagramm : EP0000005,P15,F1 wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R1 represents lower alkyl or aminocarbonylmethyl and X represents a group of the formulae see diagramm : EP0000005,P15,F2 see diagramm : EP0000005,P15,F3 see diagramm : EP0000005,P15,F4 in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts.

Description

2 (57) Extracts

The present invention relates to novel 7- (iminoacetamido) -3-thiomethyl-cef-3 g -em-4-carboxylic acid derivatives of formula (I) wherein

R is furyl, thienyl, or phenyl,

R 1 is lower alkyl or aminocarbonylmethyl, and

X represents a group of formula (a), (b) or (c) (wherein one of R ₂ and R ₃ or R ₄ R ₅ is hydrogen and the other represents lower alkyl) - and salts thereof and for the preparation of hydrates of salts. These new compounds have antibiotic activity and can be used as medicaments.

In the preparation of compounds of formula (I)

(a) compounds of formula II wherein:

X is as defined above and the carboxy group represented may be optionally protected with - acids of formula (III): - wherein R and R ₄ are as defined above - or by reacting a reactive derivative thereof, and optionally cleaved from the protecting group, or

b) reacting a compound of formula IV wherein R and R _x are as defined above, Y is a leaving group, with thiols of formula V where X is as defined above in the presence of water.

If desired, the antibiotic compounds of formula (I) are converted into a salt or a salt hydrate.

-1C-

CONH-I OR, ( ^{| a} )

R-c-conh - i

I

N

R, O ^X (Ib)

R, ON = C-COOH (III)

HS-X (V) ^ch 2 ' ^y (IV)

The present invention relates to novel 7- (iminoacetamido) -3-thiomethyl-cef-3-em-4-carboxylic acid derivatives of formula (I): wherein R is furyl, thienyl, or phenyl;

R 1 is lower alkyl or aminocarbonylmethyl, and

X is an (a), (b) or (c) is a group of formula (wherein R ₂ and R _3, or R ₄ and R _h groups is hydrogen and the other is represented by a lower alkyl group) - addition salts of these compounds and for the preparation of hydrates of salts.

The preparation and biological activity of 3-thiomethyl-cef-3-4-carboxylic acid derivatives structurally related to the compounds of formula (I) but having a different substituent at position 7 are described in U.S. Patent Nos. 2,527,291 and 2,534,071. It is disclosed in the German Federal Procurement Document. The novel compounds of formula (I) have a more antimicrobial activity than the known derivatives.

Exemplary salts of the compounds of formula I include alkali metal salts (such as sodium and potassium salts), ammonium salts, alkaline earth metal salts (such as calcunium salts), organic bases such as amines such as N-ethylpiperidine, procaine, dibenzylamine or N. , N'-dibenzylethyl ethylenediamine), alkylamines or dialkylamines, as well as salts with amino acids such as arginine or lysine. The salts can be both mono- and di-salts. The compounds of formula I wherein X is a triazine group of formula (b) may also form salts in the acidic enol form of the triazine group.

Examples of addition salts of compounds of formula I with organic and inorganic acids are hydrogen halides (such as hydrochlorides, hydrobromides and hydroiodides), salts with other mineral acids (such as sulfates, nitrates, phosphates and the like), alkyl and the like. sulfonates (such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like) and salts with other organic acids (such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like).

Salts of compounds of formula I may form hydrates. Hydrate formation can also occur during the production process, but salts which are almost completely anhydrous in the original hygroscopic form may subsequently form hydrates.

The above-mentioned lower alkyl groups may be straight or branched chain containing up to 7 carbon atoms. Examples of such groups include methyl, ethyl, npropyl, isopropyl, n-pentyl and n-heptyl. The lower alkoxy groups have the same meaning as above. The term "halogen" refers to all four halogens (i.e., fluorine, chlorine, bromine and iodine); the halogen atom is preferably chlorine or bromine.

In the compounds of formula (I), R is preferably furyl, thienyl or phenyl, particularly preferably furyl, and R ₄ is preferably methyl. In the compounds of formula (I), X preferably represents a group of formula (c) or a group of formula (a) or (b) wherein one of the substituents R ₂ and R 1 and R ₄ and R ₅ is hydrogen and the other is methyl. represents a group. X is particularly preferably 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-aza-triazin-3-yl or 1,4,5,6-tetrahydro-4-methyl-5-6-dioxo. as triazin-3-yl.

Preferred compounds of formula (I) are (. 7R) -7- [2- (2-furyl) -2-methoxyiminoacetamido] -3 - [(1,2,5,6-tetrahydro-2-). methyl 5,6-dioxo-aza-triazin-3-yl-thio) methyl] -ceph-3-em-4-carboxylic acid; and salts thereof and hydrates of these salts.

The compounds of formula (I) and their salts, as well as the hydrates of the salts, may be in the form of the partial isomers of the formula (Ia) or the anti-isomers of the formula (Ib) and the mixture of sin / anti. Particularly preferred are the isomers of the compounds of the formula I as well as mixtures of the predominantly syn isomers.

The acyl derivatives of the formula (I) and their salts or hydrates of the salts according to the invention can be prepared by:

a) a (II) - wherein X is as defined above and the carboxyl group optionally protected with - (III) with an acid of formula - wherein R and R ₄ are as defined above - are reacted, or a reactive derivative thereof, and deprotecting, or

b) reacting a compound of formula IV wherein R and R ₄ are as defined above, leaving Y, with water, reacting a thiol of formula V wherein X is as defined above and optionally converting the resulting product into a salt, and converted to the salt hydrate.

The starting materials of formula (II) may optionally contain a protected carboxyl group. For example, the carboxyl group may be protected in the form of a readily cleavable ester (such as a silyl ester such as trimethylsilyl ester) or a salt with an inorganic or tertiary organic base (e.g. triethylamine).

Examples of reactive derivatives of acids of the formula III include halides (such as chlorides, bromides and fluorides), azides, anhydrides (preferably mixed anhydrides with strong acids), reactive esters (such as N-hydroxysuccinimide esters) and amides. (such as imidazolides).

For example, the compounds of formula (IV) wherein Y is a leaving group include a halogen atom (such as chlorine, bromine or iodine), an acyloxy group (such as a lower alkanoyl group (e.g. acetoxy) or a lower alkyl or arylsulfonyloxy group such as mesyloxy or tosyloxy group) or azido group.

The compounds of formula (II) may be reacted in a manner known per se with the acids of formula (II) or reactive derivatives thereof. For example, the free acids of formula (III) may be condensed in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, with an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide to give then the ester group is cleaved. Oxazolium salts such as N-ethyl-5-phenylisoxazolium-3'-sulfonate can also be used as condensing agents instead of carbodiimides.

Alternatively, salts of compounds of formula II (e.g., trialkylammonium salts) are reacted with reactive derivatives of acids of formula III. The reaction is carried out in an inert solvent, such as one of the solvents mentioned above.

In another embodiment, the halides (preferably the corresponding acid chlorides) of the compounds of formula (III) are reacted with the amines of formula (II). The reaction is preferably carried out in the presence of an acid acceptor such as an aqueous alkali solution (preferably sodium hydroxide solution), an alkali metal carbonate (e.g. potassium carbonate). Water is preferred as the solvent, but aprotic solvents such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide may also be used.

Preferably, the compounds of formula (II) are reacted with the compounds of formula (III) or reactive derivatives thereof at a temperature in the range of from about -40 ° C to about room temperature (for example, about 0 to about 10 ° C).

The reaction of the compounds of formula (IV) with the thiols of formula (V) is carried out in a manner known per se, for example at about 40-80 ° C (preferably about 60 ° C) in water or between about 6 and 7 (preferably about 6 5).

After the reaction of the compounds of formula (Π) and (III), the resulting products are deprotected. The silyl protecting group of the silyl ester compounds (silyl esters) can be removed very easily by aqueous treatment. The protected carboxyl groups in the form of a salt (e.g., triethylammonium salt) may be liberated by acid treatment. The acid may be, for example, hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.

The starting 7-amino compounds of formula (II) may be prepared by reaction of the corresponding compounds of formula (VI) wherein Y is a leaving group and thiols of formula (V). The reaction is carried out under the conditions described for the reaction of compounds of formula (IV) and (V).

When the compounds of formula (I) are obtained in the form of a syn / anti isomer mixture, the corresponding isomers are separated by known techniques, such as recrystallization or chromatography using a suitable solvent or solvent mixture.

The compounds of formula (I), as well as the salts and hydrates of these salts, possess antibiotic activity, in particular bactericidal activity. These compounds have a broad spectrum of activity with a wide variety of Gram-positive Gram-negative microorganisms (including 8-lactamase-forming Staphylococcus species and various β-lactamase-forming Gram-negative 4 bacteria such as Haemophilus influenzae, Escherichia coli, Proteus and Klebsiella species).

Accordingly, the compounds of the formula I and their salts and hydrates of the salts can be used for the prevention and treatment of infectious diseases. These compounds may generally be administered in a daily dose of about 1 to about 4 grams when used in the treatment of adults. Preferably, the compounds are administered parenterally.

The following compounds were tested for the antimicrobial activity of the compounds of formula (I):

Compound A: (7R) -7- (2- (2-Furyl) -2-methoxyiminoacetamido) -3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxoacetamide). Triazin-3-yl (thio) -methyl] -epheph-3-em -4-carboxylic acid, Compound B: (7R) -7- (2- (2-Furyl) -2-methoxyiminoacetamido) -3- [(1-Amino-1,2-dihydro-2-oxo-4-pyrimidinyl] -thio) methyl] -ceph-3-em-4-carboxylic acid, Compound C: (7R) -7- (2 phenyl-2-methoxyiminoacetamido) -3 - [(/ l, 2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl / thio) methyl] - 3-cephem-4-Carboxylic acid, Compound D: (7R) -7- (2- (2-furyl) -2-methoxyiminoacetamido) -3 - [(1,4,5,6-tetrahydro-) 4-Methyl-5,6-dioxo-aza-triazin-3-yl-thio) -methyl] -ceph-3-em 4-carboxylic acid, Compound E: (7R) -7- (2-Methoxyimino-2) - (2-thienyl / acetamido) -3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-aza-triazin-3-yl-thio) methyl] -ceph-3 -em4-carboxylic acid Compound F: (7R) -7- (2- (2-Furyl) -2-methoxyiminoacetamido) -3 - [(1-ethyl-1,4,5,6-tetrahydro-5) , 6-dioxo-as-triazin-3-yl-thio) methyl] -ceph-3-em-4-carboxylic acid, and Compound G: (7R) -7- (2- (Carbamoylmethoxyimino) -2- 2-furyl / acetamido) -3 - '[(/ l, 4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl / thio) methyl] CSF-3-em-4-carboxylic acid.

The results of the in vitro activity assays are summarized in Table I below.

The in vivo activity of the compounds was tested in mice. Groups of 10 to 10 mice were challenged intraperitoneally with an aqueous suspension of Proteus mirabilis and, after 1 hour, the test compound was injected subcutaneously. The number of surviving animals was determined on day 4. Dose values (CD-mg / kg) providing 50% survival of the experiment were determined by interpolation from data from experiments at different doses. The results are reported in Table 2.

Toxicity data for the compounds were determined in mice over a 24 hour study period. The results are shown in Table 3.

The compounds of the formula I, their salts or the hydrates of the salts can be converted into pharmaceutical compositions, preferably in powder formulations. The pharmaceutical compositions may, if desired, contain other pharmaceutically acceptable substances in addition to the above active ingredients. The active compounds are preferably used for the preparation of parenteral pharmaceutical compositions

Table 1

Minimum inhibitory concentration ug'ml Tested microorganism strain _π ,, '""

Haemophilus influenza Strain 1 1.2 2.5 2.5 2.5 2.5 2.5 5.0 Strain 2 0.16 0.63 0.16 0.31 0.16 0.31 0.63 Strain 3 0.16 0.63 0.16 0.31 0.16 1.2 0.31 Strain 4 0.16 0.31 0.16 0.31 0.16 0.16 0.63 Strain 5 0.08 0.31 0.08 0.16 0.08 0.08 0.31 Strain 6 3 0.16 0.31 0.08 0.16 0.08 0.08 0.63 Strain 7 0.08 0.31 0.08 0.16 0.08 0.16 0.63 Klebsiella pneumoniae 10 20 20 5 40 40 2.5 Eaeherichia coli Strain 1 0.63 2.5 1.2 0.16 2.5 1.2 0.31 Strain 2 40 20 10 5 20 80 5 Proteus mirabilis Strain 1 2.5 10 10 10 10 20 5 Strain 2 5 40 20 20 20 40 10 Proteus vulgaris 5 40 10 1.2 10 20 1.2 Proteus rettger 0.63 2.5 0.63 0.63 2.5 10 0.63 Staphylococcus aureus ATCC 6538 2.5 0.16 2.5 0.63 2.5 5 1.2 penicillin-resistant strain 5 1.2 2.5 0.63 2.5 5 1.2

Table 2

Test compound "THE" "B. "C" "D" "E" "E" ,, G " ^cd 50 mg / kg 0.09 3.0 0.60 0.70 1.15 0.85 0.80 Table 3 Test compound "THE" ,, B " "C" "D" "E" "F" "G"

LD ₅₀ mg / kg iv 500-1000 1000-2000 1000-2000 500-1000 2000-4000 1000-2000> 4000

s. c. > 4000

po>5000>4000> 5000 pharmaceutically acceptable organic or inorganic inert carriers such as water or gum arabic. The pharmaceutical compositions are preferably marketed in the form of liquid compositions such as solutions, suspensions or emulsions. These compositions may be sterilized, if desired, and / or compositions, other auxiliaries such as preservatives, stabilizers, wetting agents, or emulsifiers, salts for modifying the osmotic pressure may be added to cut ⁷ pufferenyagokat.

The process of the invention is described in detail in the following examples without limiting the scope of the invention.

Example 1 (7R) -7- (2- (2-Furyl) -2-methoxyimino-acetamido) 3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo) Preparation of the sodium salt of -triazin-3-yl (thio) methyl] -ceph-3-em-4-carboxylic acid

Dissolve 5.06 g of 2-methoxyimino-2-furylacetic acid (80:20 syn / anti isomer mixture) in 150 ml of benzene and add to the solution under a nitrogen atmosphere,

At 5-10 ° C, 4.2 ml triethylamine, 2.6 ml oxalyl chloride and 6 drops of dimethylformamide are added. The mixture was stirred for 1 hour at 5-10 ° C and then for 1.5 hours at 25 ° C under nitrogen, then concentrated in vacuo at 40 ° C. The residue is suspended in 150 ml of acetone and the suspension is (7R) -7-amino-3-deacetoxy-3 - (/ l, 2.5) at 0 ° C.

A solution of 6-tetrahydro-2-methyl-5,6-dioxo-aza-triazin-3-yl-thio) 35 cephalosporanic acid in 150 ml of water was adjusted to pH 7.5 with 2N aqueous sodium hydroxide solution. . The reaction mixture is stirred for 2.5 hours under nitrogen atmosphere at -10 ° C while maintaining the pH of the mixture at 7.5 to 8.0 by the addition of 2N aqueous sodium hydroxide solution. Ethyl acetate (500 mL) was then added and the mixture was acidified to pH 1.5 with 2N aqueous hydrochloric acid. The organic layer was separated and the aqueous layer was extracted once with ethyl acetate. The organic layer was combined, washed twice with saturated brine, dried over sodium sulfate and evaporated to a final volume of about 100 mL. The insoluble material was filtered off from the residue and the resulting orange-red filtrate was diluted with ether (1000 mL). The (7R) 7- (2- (2-furyl) -2-methoxyiminoacetamido) -3 - [(1, 2,

5,6-Tetrahydro-2-methyl-5,6-dioxo-triazin-3-ylthio) methyl] -ceph-3-em-4-carboxylic acid is filtered off with suction and washed with ether and low-boiling petroleum ether . The cream product was dissolved in ethyl acetate (250 mL). The insoluble material is filtered off and 10 ml of 2N ethyl acetate / 2-ethyl-caproic acid sodium salt solution are added to the orange-red filtrate. The precipitated (7R) -7- (2- (2-furyl) -2-methoxyimino 60 acetamido) -3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo The sodium salt of triazin-3-yl (thio) methyl] -ceph-3-em-4-carboxylic acid is filtered off with suction, washed with ethyl acetate and low boiling petroleum ether and dried under vacuum at 25 ° C for 2 days. The resulting cream powdered product (7.8 g) contained the color and anti5 isomers in a ratio of 80:20 [α] D = -108.6 ° (c = 0.5, in water); R f = 0.10 (silica gel: F _SM plate: 4: 1: 1 butanol: glacial acetic acid: water and ultraviolet).

Example 2 (7R) -7- (2- (2-Furyl) -2-methoxyiminoacetamido) 3 - [(1-amino-1,2-dihydro-2-oxo-4-pyrrolidinyl) thio] Preparation of the sodium salt of methyl] ceph-3-em-4-carboxylic acid

In the same manner as in Example 1, however, 3.4 g of 2-methoxyimino-2-furylacetic acid and 7.11 g of (7R) -7-amino-3-deacetoxy-3 - (1-allino-1) were used. Starting from 2-dihydro-2-oxo-4-pyrimidinyl (thio) -cephaloaphoric acid. The product containing the slides and anti-isomers in a ratio of 70:30 (1.6 g) was obtained as a cream powder. Rf = 0.40 (silica gel F ₂₃₁ sheets of 4: 1: 1 butanol: glacial acetic acid: water mixture running with ultraviolet ^Elohi; VVA).

Example 3 (7R) -7- (2-Phenyl-2-methoxyiminoacetamido) -3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-triazin-3-yl) (thio) -methyl] -epheph-3-4-em-carboxylic acid sodium salt

However, 1.8 g of 2-methoxyiminophenylacetic acid (90:10 syn / anti isomer mixture) and 3.73 g of (7R) -7-amino-3-deacetoxy-3- ([1,2,5,6-Tetrahydro-2-methyl-5,6-dioxo-aza-triazin-3-yl] thio) -ephephalosporanic acid. The product containing the color and the anti-isomer in a ratio of 90:10 was obtained as a cream powder (2.2) g. [a] ² ° = -135 ° (c = 0.5, water), Rf = 0.17 (silica gel F ₂₃₄ sheets of 4: 1: 1 butanol: glacial acetic acid: water mixture running and for visualization of ultraviolet light) .

Example 4 (7R) -7- (2- (2-Furyl) -2-methoxyiminoacetamido) 3 - [(1, 4,5,6-tetrahydro-4-motyl-5,6-dioxo) Preparation of the sodium salt of -triazin-3-yl (thio) -methyl] -epheph-3-em-4-carboxylic acid

In the same manner as in Example 1, however, 3.4 g of 2-methoxyiminofurylacetic acid (80:20 syn / anti isomer mixture) and 7.46 g of (7R) -7-amino-3-deacetoxy-3- (1, 4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-aza-triazin-3-yl-thio) -ephephalosporanic acid. The product containing the color and anti-isomers in a ratio of 80:20 was obtained as a cream powder (2.8 g). [α] ²⁰ D = -44 ° (c = 0.5 in water); Rf = 0.34 (silica gel: F ₂₅₄ : 4: 1: 1 butanol: glacial acetic acid: water: ultraviolet light).

Example 5 (7R) -7- (2- (2-Thienyl) -2-methoxyiminoacetamido) 3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo) Preparation of the sodium salt of -triazin-3-yl (thio) -niyl] -cephe-3-sm-4-carboxylic acid

Example 1, except that 1.85 g of 2-methoxyimino-2-thienylacetic acid (about 70:30 syn / anti isomer mixture) and 3.71 g of (7R) -7-amino-3 starting from -deacetoxy-3 - ((1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-triazin-3-yl) thio) -phephalosporanic acid. The product containing the color and anti-isomers in a ratio of about 70:30 was obtained as 6 cream-colored powders (2.4 g). [α] D 20 = -128.2 ° (c = 0.5 in water); R _f = 0.21 on silica gel _{F S51} 4: 1: 1! butanol: glacial acetic acid: running on water and exposed to ultraviolet light).

Example 6 (7R) -7- (2- (2-Furyl) -2-methoxyiminoacetamido) 3 - [(2,5-dihydro-2-methyl-5-oxo-6-hydroxy-triazinyl) Preparation of (-thio) -methyl] -ceph-3-em-4-carboxylic acid disodium salt

In the same manner as in Example 1, however, 10.12 g of 2-methoxyimino-2-furylacetic acid (syn isomer) and 18.7 g of (7R) -7-amino-3-deacetoxy-3 (1, 2, Starting from 5,6-Tetrahydro-2-methyl-5,6-dioxo-aza-triazin-3-yl-thio) -ephalosporanic acid, the sodium salt of 2N ethyl acetate-2-ethyl caproic acid was prepared with 20 µl (2 molar equivalent) of salt. using a solution. The product (color isomer), 5.3 g, was obtained in the form of a substantially colorless powder, [α] ²⁰ D = -141.6 ° (c = 0.5 in water); R t = 0.14 (on silica gel F ₂₃₁ plate with 4: 1: 1 butanol: glacial acetic acid: water and developed under ultraviolet light). The product

Contains 3.5 moles of hydrated water.

Example 7 (7R) -7- (2- / 2-Furyl-2-methoxyimininoacetanido) 3 - [(1-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-aza) Preparation of sodium salt of triazin-3-yl) -thio) -methyl] -epheph-3-em-4-carboxylic acid

The procedure described in Example 1 was followed, except that 1.69 g of 2-methoxyimino-2-furylacetic acid (sine isomer and 3.85 g of (7R) -7-amino-3-deacetoxy-3 - (ethyl) -1 Starting from 4,5,6-tetrahydro-5,6-dioxo-triazin-3-yl / thio) -cephalosporanic acid, the product containing color and antiisomer in a ratio of about 70:30 was obtained as a cream powder (2.1 g [.alpha.] D @ ²⁰ = -47.2 DEG (c = 0.5 in water); Rf = 0.47 (on silica gel F ₂₅₄ plate with 4: 1: 1 butanol / glacial acetic acid: water) and in ultraviolet light).

Example 8 (7R) -7- (2- (Carbamoylmethoxyimino) -2- (2-furyl) acetamido-3 - [(1, 4,5,6-tetrahydro-4-methyl-5,6- Preparation of the sodium salt of dioxo-triazin-3-yl (thio) methyl] -ceph-3-em-4-carboxylic acid

9.76 g of (α- (carbamoylmethoxyimino) -furfuryl) cephalosporanic acid sodium salt (about 70:30 syn / anti isomer mixture) and 4.77 g of 1,4,5,6-tetrahydro-4-methyl- 5,6-Dioxo-3-mercapto-triazine is suspended in 200 ml of phosphate buffer solution, pH 6.4. The pH of the resulting suspension was 1 N aqueous sodium hydroxide in a nitrogen atmosphere.

Adjust to 6.4. The resulting dark solution was stirred under nitrogen at 55-60 ° C for 6 hours while maintaining the pH of the mixture between 6.4 and 6.5 with 1 N aqueous sodium hydroxide solution from an automatic titrator. The reaction mixture was cooled to 0-5 ° C and acidified to pH 2 with 2N aqueous hydrochloric acid. The precipitated product (free acid) is filtered off, washed with ice water and dried in vacuo at 40 ° C overnight. The final product was obtained as a crude free acid (6.5 g). For purification, the product obtained is dissolved in 150 ml of methanol, the active sol is added to the solution and the suspension is refluxed for 2 minutes. The mixture was filtered through a pleated filter and the orange-red filtrate was concentrated in vacuo. The resulting resinous material was separated and removed. The concentrated methanolic solution was poured into ether. The precipitated free acid is filtered off with suction and washed with ether and low boiling petroleum ether. The purified free acid (4 g) was then dissolved in 100 mL of methanol and treated with 5 mL of 2N ethyl acetate.

2-Ethyl caproic acid, sodium salt solution was added. A small amount of insoluble material was filtered off and the orange-red filtrate was concentrated in vacuo at 40 ° C. Ethanol is added to the concentrate, the precipitated sodium salt is filtered off with suction, washed with ethanol and low-boiling petroleum ether, and finally dried under vacuum at 40 ° C overnight. The color and anti-isomers were azole (7R) -7- (2- (carbamoylmethoxyimino) -2,2-furyl) -acetamido) -3 - [(1, 4,5, The sodium salt of 6-tetrahydro-4-methyl-5,6-dioxo-aza-triazin-3-yl-thio-methyl] -ceph-3-em4-carboxylic acid is obtained in the form of a cream powder (3 g). [α] ^2θ = -30.1 ° (c = 1, water); R f = 0.29 (on silica gel F ₂₅₄ plate with 4: 1: 1 butanol: glacial acetic acid: water and exposed to ultraviolet light).

Starting from the process described above, starting from equivalent amounts of α- (methoxyiminofurfuryl) cephalosporin and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-3-mercapto-triazine, 7R) -7- (2/2-furanyl / -2-methoxyiminoacetamido) -3 - [(/ l 2,5,6tetrahidro-2-methyl-5,6-dioxo-as-triazin-3-yl (-thio) methyl] -epheph-3-em-4-carboxylic acid is obtained. This product is identical to the compound prepared in Example 1.

Example 9

Preparation of a powder for intramuscular administration of (7R) -7- (2- (2-furyl) -2-methoxyiminoacetamido) 3 - [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-) The sodium salt of as-triazin-3-yl (thio) methyl] -ceph-3-em-4-carboxylic acid is lyophilized in the usual manner and 1 g of the lyophilisate is filled into an ampoule. Prior to injection, the contents of the powder vial are mixed with 2.5 ml of 2% aqueous lidocaine hydrochloride solution.

Claims (11)

Patent claims A process for the preparation of 7- (iminoacetamido) -3-thiomethyl-cef-3-em-4-carboxylic acid derivatives of formula (I) wherein R is furyl, thienyl or phenyl, R 1 is lower alkyl or aminocarbonylmethyl, and X represents a group of formula (a), (b) or (c) (wherein one of R ₂ and R ₃ or R ₄ and R ₅ represents a hydrogen atom and the other represents a lower alkyl group) - and salts thereof. for the preparation of hydrates of the salts, characterized in that: a) reacting a compound of formula II wherein X is as defined above and the carboxyl group is optionally protected, with an acid of formula III wherein R and R are as defined above or a reactive functional derivative thereof , and deprotecting, or b) reacting a compound of formula IV wherein R and R 1 are the above leaving groups Y with cg 1 'thiol of formula IV where X is as above and optionally obtaining the product salt or hydrate thereof. (Priority: June 3, 1977) 2. A process according to claim 1 wherein the starting material is a compound of formula II and an acid or a reactive functional derivative of formula III wherein X, R, and R _x are as defined in claim 1. (Priority: June 3, 1977) A process according to claim 1 or a process according to claim 2, characterized in that in the presence of an aqueous alkali solution, the chloride of an acid of formula (III) wherein R and R 1 are as defined in claim 1 With a compound of formula II wherein X is as defined in claim 1. (Priority: June 3, 1977) Processes a) and b) according to claim 1 or steps 2 to 3 A process according to any one of claims 1 to _{4 for the preparation of} compounds of formula I wherein R ₄ and X are as defined in claim 1, and their salts and hydrates of the salts thereof, wherein R is furyl as starting material. a compound of formula (III) or a reactive functional derivative thereof or a compound of formula (IV): wherein R 1 is and Y is as defined in claim 1. (Priority: June 3, 1977) Processes a) and b) according to claim 1 or steps 2-4. A process according to any one of claims 1 to 4 wherein R _x is a methyl group containing a compound of formula I wherein R and X are as defined in any one of claims 1-4. A compound of formula (III) or a reactive functional derivative thereof or a compound of formula (IV), wherein R is a compound of formula (III) or a salt thereof and a hydrate of a salt thereof. in the latter, Y is selected from 1-4. A process as claimed in any one of claims 1 to 6. (Priority: June 3, 1977) Processes a) and b) according to claim 1 or steps 2-5. A process according to any one of claims 1 to 4, wherein X is represented by the general formula (c) Compounds of formula (I) and salts thereof containing -713 groups or a group of the formula (a) wherein one of the substituents R _a and R ₃ , or R ₄ and R ₅ represents a hydrogen atom and the other a methyl group; for the preparation of hydrates of the salts, wherein R and R ₄ are 1-5. A process according to any one of claims 1 to 3, wherein the starting material is a compound of formula (II) or (V) wherein X is as defined in the scope of this claim. (Priority: June 3, 1977) Processes a) and b) according to claim I or a A process according to claim 6 for the preparation of compounds of formula I wherein X is 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-triazin-3-yl wherein R and R , as defined in claim 1, characterized in that starting materials are compounds of the formulas (TI) and (V) wherein X is as defined in the scope of this claim. (Priority: June 3, 1977) Processes a) and b) according to claim 1 or a A process according to claim 6 for the preparation of a compound of formula I wherein X is 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-triazin-3-yl wherein R and R ₄ and the hydrates of their salts, wherein the starting materials are the compounds of formula (II) and (V) wherein X is as defined in the scope of this claim. (Priority: June 3, 1977) Processes a) and b) according to claim 1 or a A process according to claim 7 for the preparation of (7R) -7- [2 - (- furyl) -2- (methoxyimino) acetamido] -3 {[(1,2,5,6-tetrahydro-2-methyl- 5,6-dioxo-triazin-3-yl) thio] -methyl} -3-cephem-4-carboxylic acid, and its salts and hydrates of the salts, characterized in that starting materials of the general formula (II) and (III) or a reactive functional derivative of a compound of formula (III) or a compound of formula (IV) or (V) wherein R is furyl, R 1 is methyl and X is 1,2,5,6-. tetrahydro-2-methyl-5,6-dioxo-triazin-3-yl and Y is according to claim 1. (Priority: June 3, 1977) The process of claim a) and b) according to claim 1 or the process of claim 8 according to (7R) -7- [2- (carbamoylmethoxyimino) -2- (2-furyl) acetamido] -3 - {[(1,4,5,6-Tetrahydro-4-methyl-5,6-dioxo-triazin-3-yl) thio] methyl} -ceph-3-em-4-carboxylic acid, e salts of compounds of formula (II) and (III) - or reactive functional derivatives of compounds of formula (III) - or compounds of formulas (IV) and (V) wherein R is furyl; R ₄ is aminocarbonylmethyl; and X is 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-triazin-3-yl; and Y is according to claim 1. (Priority: March 22, 1978) 11. A process for the preparation of a pharmaceutical composition, which process comprises the preparation of a compound of the formula I according to claim 1, wherein R is furyl, thienyl or phenyl, R ₄ is lower alkyl or aminocarbonylmethyl, and X represents a group of the general formula (a), (b) or (c) (wherein one of R ₂ and R ₃ or R ₄ and R ₅ represents a hydrogen atom and the other represents a lower alkyl group) - or a pharmaceutically acceptable salt thereof; mixing the hydrate of the salt with a pharmaceutically acceptable carrier and / or excipient and converting it into a pharmaceutical composition. (Priority: June 3, 1977)