HU180307B - Process for producing new 7-beta-square bracket bracket-2,3-dioxo-1-piperazine-carboxamido-aracket closed-hydroxy-amido-square bracket closed-7-alpha-metoxy -ceph-3-eme-4-carboxylic acid derivatives - Google Patents

Abstract

There are provided 7a-methoxycephalosporins of the following general formula and salts thereof, wherein R & exp1! a hydrogen atom or a carboxyl-protecting group; R & exp2! an organic group bonded via oxygen or sulfur to the carbon atom; R & exp3! a lower alkyl group; n is 0, 1 or 2; A is a substituted or unsubstituted alkyl group; R & exp4! a lower alkyl group; and R & exp5! represent a hydrogen atom or a hydroxyl-protecting group. These compounds have a broad antibacterial spectrum and high bacterial beta-lactamase resistance and are well absorbed by the living organism.

Description

The present invention relates to novel 74- [2,3-dioxo-1-piperazinecarboxamido] -hydroxyamido [7-b] -7-methoxy-cef-5-ym-4-carboxylic acid derivatives. and salts thereof.

The compounds of the present invention have a broad spectrum of antibacterial activity against Gram positive and negative bacteria, in particular Escherichia coll, Klebsiella pneumoniae, Proteus, Serratia marcesens, Alkaligenes faecalis and others having excellent antibacterial activity. It is gram-negative against bacteria and stable to bacterial A-lactamase. Thus, the above compounds are very useful in the treatment of various infectious diseases.

While conventional 7 << - methoxycephalosporins are known to exert antibacterial activity on Gram-positive bacteria, the antimicrobial activity of these compounds against the said Gram-negative bacteria *, which would cause clinically serious infectious diseases.

The inventors of the present invention have carried out extensive research in the field of 70? -Methoxyl-cephalosporins. As a result, it has been found that the compounds of formula I to be described in more detail below, wherein the cephem ring is a 5-position. containing an oxy or thiomethyl group substituted with an organic group and the 7-position of the methoxy group, and the amino-position of the 7-position being linked to the group (a) wherein R 1, R 1, A and n are described below; and salts of these compounds are antibacterial, small

-1180.307 are toxic and well absorbed in the living body.

It is an object of the present invention to provide novel 7K-methoxy-1-cephalo-sporine 4k having a 2,3-dioxo-1-piperazinecxbonylaraino group and a group of formula (b) in their molecule. They contain.

Another object of the present invention is to provide novel 7P (-methoxycephalosporins) which have a broad antibacterial activity.

It is a further object of the present invention to provide novel [beta] -methoxy-cef alosporins which are highly resistant to γ-lactamase produced by bacteria.

It is a further object of the present invention to provide novel Te 6 -methoxycyclosporins which exhibit antimicrobial activity against highly isolated bacteria.

It is another object of the present invention to provide a process for the preparation of novel Tt-methoxyl-cephalospoxins.

It is a further object of the present invention to provide pharmaceutical compositions containing the novel N-N-ethoxycephalosporins or salts thereof.

According to the invention, the new N-methoxycephalospoxins of the formula I and their salts are prepared; in this formula r! a hydrogen atom or a diphenylmethyl * protecting group for the kaxboxyl group;

an Irish lower acylloxy group, a 5- (1,2,5,4-tetrazolyl) -tloo group or a 2- (1,5,4-thiadiazolyl) tioo group which may be substituted by a lower alkyl group or a lower hydroxyalkyl group;

C 1-8 alkyl;

lower alkyl;

a hydrogen atom or a hydroxyl protecting edge group as defined below.

The term lower alkyl as used herein denotes C 1-4 straight or branched alkyl, and may be methyl, ethyl, propyl or butyl, respectively; acyl oxy, as used herein, represents a monovalent O-acyl group, wherein is an acyl group; it is a C 1-4 acyloxy group. .

In this formula, R is hydrogen or a hydroxyl védőcsopoxt, i.e. C1-4alkyl, / 1-4 szénatomoe / -alkoxy / l to 4 carbon atoms / -alkllcsoport, lower alkyl occasions v ^u * noilcsoport formyl ^ y tetrahldropiranilcsoport.

The salts of the 7X-methoxyl-cephalosporins of Formula I according to the invention may be salts of the acidopoxton and the salts of the basic group. These salts are well known in the art of penicillins and cephalosporins. Among the salts, pharmaceutically acceptable salts are preferred. A. salts formed with an acid group with alkali metals such as sodium, potassium and the like; salts with alkali earth metals such as calcium, magnesium and the like; ammonium salts; and the nitroxogen content with organic bases such as procaine, dibenzylamine, N-benzyl-4-phenethyllamine, 1-ephenamine, N, N-dibenzylethylenediamine, trimethylamine, methyl triethylamine, methyl dimethyl, N-dimethylamine, N-dimethylamine, salts with molar, diethylamine and dicyclohexylamine.

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Salts formed with a basic group include salts with mineral acids such as hydrochloric acid, sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with organic sulfonic acids, such as methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and the like.

The invention also relates to the preparation of all optical isomers and racemic compounds of the ToG-methoxyl-cephalosporins of the general formula I and their salts, and the liver and hydrate of each crystal.

Of the various 7β-methoxycephalosporins prepared according to the invention, the compounds of formula Ia and their salts are preferred. In this formula, the lower alkyl, R> a methyl group, and IA, R _f © _n t; l report.

Most preferred among the 7- ^methyl -cephalosporins of the formula Ia and their salts are those wherein R 4 is hydrogen, especially those wherein R 4 is hydrogen and R 4 is aethoxyloxy substituted with 5- [1,2,3,4-tetrazolyl]. -thio or 2- (1,1,5,5-tladlazolyl) -tlo.

Preferred compounds of the present invention include, but are not limited to, the following:

Tfl - fp-C - (4 - e t11-2,3-dl oxo-1-piperazinecarbamide) -4- (S) or R-hydroxybutyramido-7H-methoxy-3-23- / 1-Nethyl-1,2,3,4-tetrazolyl-thiomide; 11M-4-carboxylic acid, or a pharmaceutically acceptable salt thereof;

74-? D-O-C- [N- or n-isopropyl-2,3-dloxo-1-piperazin? -? - n -cajeboxamido] -3- (S) or R -hydroxybutylramo-3-? 3-L5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -N * -cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof;

7-N-D-o-C- [4- (n- or 1-tert-butyl-2,3-dioxo-1-piperazinecase-8-carbamate) -4- (S) or N-hydroxy-butyxamla-3-7C-methoxy-3 -? 5 - (1-methyl-1,2,3,4-tetrazolyl-thiomethyl) ^-2H - ^oem -4-carboxylic acid, or a pharmaceutically acceptable salt thereof;

7β-H) -O- (4-ethyl-2,3-dloxo-1-piperazinecarboxamido) -N- (S) or N-hydroxy-butyraxide-7K-methoxy-3-acyl-9-oxo-methyl-methyl. N-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof;

-? - (J) -O- (4-methyl-1,2,3-dioxol-1-piperazinyl) oxamldo-4- (S) or (R) -hydroxybutylxamla <27-7K- methoxy-3- [p- (1-methyl-1,2,3,4-tetrazolyl) methyl] -2H-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof;

7a- [j) -o (.- / 4-ethyl-2,5-dioxo-l-carboxylic plper azln boxamldo / - / J / S and R / 7-7-hydroxy-butiramld £ ^ö C methoxycarbonyl -? -? - 1,3,4-thiadiazolyl? -1-methyl-o-methem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof;

trans-p-vin-4-ene 11-2,3-dloxo-1-piperazinecarboxamido [4- (S) or (R) -hydroxy-butyramide27-7 <'¢ -mθtoxi-3- £ 5 · -Γl- / 2 hldτoxiθtil / ^- -1,2,3 »4-tetrazollll tlometi] 3- to ^5-4--oefém Earbonsav or llag pharmaceutically acceptable salt thereof;

7 «- ΠΜ ^ - / 4-η-ο kt i 1-2,3-Dioxo-1-piper az> n -barbam oxamldo / - /} / 8 or R 1 -hydroxybutyram 1 dfj- N-methoxy-3- N - (1-methyl-1,2,2,14 * -tetrazolyl) -N-methyl-4-carboxylic acid, or a pharmaceutically acceptable salt thereof;

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7 - [(PX) - (4-Ethyl-2,3-dioxo-1-plperaginecarboxamido) -4- (S) or (R) -methoxy-butyramido] -7-methoxy-3- {4 - [ 1-methyl-1,2,3,3,10-etrazolyl] -Tloxyethyl] -2V-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof;

7 * £ J- pc <- / 4-ethyl-2 3-dioxo-l-piper in-arm boxamldo / -4 / S or lV-ötoxi butirainM 7oc- ^ _methoxy-3- β-. / 1-methyl-tetra 11-1.2,3,4 thiazolyl * / -ti ómét _ια- Δ ί cephem-4-carboxylic, or a pharmaceutically acceptable salt thereof El *;

7 (} - Zj) ~ 0 (- (4-ene-11-2,3-dioxo-1-piperaz η-1mr boxamido) -4- / S or R / -1 er cb ut oxi-b ut 1 r which do] -7 (X-nieth oxy-3- [4- (1-methyl-1,2,3,4-tetrazolyl) methyl] -1,215-cephem-4-carbonic acid, or a pharmaceutically acceptable salt thereof;

76- (5- [4- (4-yl) -1,2,3-dioxo-1-piperazinecarbamoyl] -2- (S) or N-formyloxy-butyramidyl-7-oxo-3-dioxo-3- (5-w / l-methyl-1,2,3,4-totrazole-1-thiomethyl) -4'-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof;

7 - [beta] -O-06- (4) 11-2,3-dioxo-1-plper is the indacarboxamido [4- (S) or R -acetoxybutyranide] -7-7 (X-methoxy-3- Z5 "/ l" ^me ^ ¹ ^ "^, 2,3, t-tetrazolyl / -tlometH7-A> cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof;

74-N-N-ethyl-2,3-dioxo-1-piperazinecarbamido [4- (S) or R - (2-tetrahydro-pyranloxy) -butyramido] -7-ol-methoxy. -3-2,5- (1-methyl-1,2,3,4-tetrazolyl) -methyl-3- [3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. ^T

The compounds of formula I or salts thereof may be prepared by the following processes: a compound of formula II wherein R 1 is hydrogen, an organic silyl group or a phosphorus organic group and R 1, R ² , R ^{4 are} as defined above; - where n A is reacted with a reactive derivative of a carboxyl group as defined above;

L 2 b / a compound of formula IV, wherein R, R and R-7 are as defined above, reactive with a compound of formula V wherein R 1, R ⁴ , n and A are as defined above, or a derivative thereof;

c / a VI oeíalosporlnt - wherein ^{RL, R2,} R ^, _{^R4, n} and A are as defined above - methanol in the presence of an alkali metal or alkaline earth metal-metHáttal VII - wherein KP alkali metal or alkaline earth metal and m · * · 1 or 2 and then reacting with a halogenating agent;

d / a 7X-methoxyl-cephalosporin of formula VIII wherein R ^{6 is a} readily available group with a nucleophilic reagent and R ¹ , R 4, r ⁴ , n aa are as defined above for a compound of formula IX wherein M ^{2 is} hydrogen, an alkali metal or an alkaline earth metal, m ² is 1 or 2 and R ^{2 is} as defined above.

In the above formulas, the R @ 4 organic silyl moieties and phosphorus-containing organic groups are commonly used as amino or carboxyl protecting groups in the synthesis of penicillins and cephaloaporins. Examples of such groups are:

-4180.307 / CH ^ / ^ Si, / CH / ^ GSL, groups of / e / e / f / formula, hereinafter the JJA ¹ / C ₂ HcjO / ₂ and P / CgH ^ / gP groups which for example, they can be easily removed by treatment with water or alcohol. "

B 'groups which are readily interchangeable with the nucleofl reagent may be halogen, such as chlorine, bromine or the like; * on a short. vidazene-chain alkanoyloxy groups such as formyloxy, aoethoxy, p-oplonloxy, bentyryloxy, pivaloyloxy and the like; aryl4 carbonylloxy groups such as benzoyloxl, naphtholoxyl and the like; aryllocarbonyl-oxy groups such as tlobenzoyloxy, tlonaphthoyloxy and the like; arylcarbonylthio groups such as benzoylthio, naphthoylthio and the like; axlocloctylthio groups such as thiobenzoylthio, thionaphthylthio and the like; karbamoiloxlcsoport; tlokarbánóiloxicsoport; pyridine-N-oxld-2-yl and pyridazine-N-oxld-6-yl. These are the R? groups may also have substituents such as halogen, nitro, lower alkyl, lower alkoxy, lower alkylthio, acyl and the like.

Compounds of Formula V can be readily prepared by reacting a compound of Formula X, wherein R 1 and R 4 are as defined above, with an alkali metal salt or an organic base thereof in an inert solvent, in the presence of an acidifying agent, to react with a carboxylic group.

The compounds of Formulas II and IV can be prepared in a manner known per se, for example, as described in the Journal of Synthetic Organio Ohemstry, Japan, Vol. 55, 568-57 ^J (1977).

A practical embodiment of the production processes a / b, o and d is described below.

Processes (a) and (b) can be performed under nearly the same conditions by dissolving or suspending the compound of formula II or IV in a solvent. Examples of such solvents are water, acetone, tetrahydrofuran, dioxane, aonetonitrile, dimethylformamide, dimethylaoetamide, methanol, ethanol, methoxyethanol, diethyl ether, diisopropyl ether, benzene, toluene, methylene chloride, chloroform, ethyl acetate * or methylisobutylketone. The solvents may be used alone or as a mixture of two or more solvents. To the resulting solution or suspension is added a reactive derivative of a compound of formula III on a carboxyl group, or a compound of formula V or a reactive derivative of a compound of formula V on a carboxyl group. The mixture optionally in the presence of a base at -60 - reacted at 50 ° C <A reaction time is usually from 5 minutes to 5 hours at - 80 ° C, preferably -40 _X. The bases used in the above reaction include inorganic bases such as alkali metal hydroxides, alkali metal hydrogencarbonates, alkali metal carbonates and alkali metal methoxides, tertiary amines such as methylmethylamine, triethylamine, tributylamine, plidine, m-N-methylpyridine, amlnok, so dicyclohexyllamine. dlethylamine and the like.

When the starting material of formula V is a compound of formula V or a salt thereof, the reaction may be carried out in the presence of a dehydrating condensing agent such as N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N, N * -diethylcarbodinamide, N, N * -5180.307

-carbonyl 1-bis (2-methyl-11-imidazole), trialkyl phosphates, ethylpolyphosphate? L 'is phosphorus oxychloride, phosphorus trichloride, ² hours 1, 5.2-dl oxaphospholane, oxazolyl chloride, dimethylchlorforminium chloride, and dimethyllethoxyphthalonium chloride.

Process o / is carried out as follows: In a laminated form, cefa% losporin VI of the Japanese Patent Application Laid-open Nos. 707-70 / 76 and 115890/76 is dissolved or suspended in a solvent. The solvent is, for example, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, dimethylformamide, methyl methyl acetate, acetonitrile, methanol or the like, or a mixture of two or more thereof. To the solution or slurry thus obtained is added, with methanol, an alkali metal or alkaline earth metal methylate of formula VII. In this reaction, an excess of the meta-female is used and the amount of alkali metal or alkaline earth metal methylate of formula VII is preferably 2 to 6 equivalents to the equivalent of cephalosporin VI of formula VI used. The term "excess" refers to more than 1 equivalent for 1 equivalent of oephalosporin VI. All of the above reactions are carried out at a temperature of - 120 ° C / 10 ° C, preferably - / ΙΟΟ - ^ Ο / θ. A reaction time of about 5 to 30 minutes is sufficient and the reaction is quenched by acidifying the reaction sequence.

Suitable acids for completing the reaction are those which, when added to the cold reaction mixture, do not cause the reaction mixture to solidify or lose to a dense viscous mixture. Examples of suitable acids are 98% formic acid, glacial acetic acid, trichloroacetic acid and methanesulfonic acid.

After completion of the reaction, the excess halogenating agent may be removed by treatment with a reducing agent such as trialkyl phosphite, sodium thiosulfate or the like.

In process d /, if the compound of formula VIII used is other than that in which R ^{6 is} a heterocyclic aromatic amine N-oxo-thio group, the thio group of which is on a carbon atom adjacent to the N-oxide group. Compound IX is reacted with a compound of formula IX in an inert solvent such as water, methanol, ethanol, propanol, isopropanol, butanol, acetone, methylethylketone, methyl, isobutylketone, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, 2-methoxyethanol, dimethoxy. ethane, dimethylformamide, dimethylsulfoxide. dimethyloethamide, dichloroethane, chloroform, dichloromethane, and the like, in the stomach or as a mixture of two or more solvents.

The above reaction is preferably carried out in a highly polar solvent such as water. The pH of the solvent is preferably maintained at 2-10, preferably 4-8. The reaction is buffered. This is done after the addition of sodium phosphate to maintain the pH at the desired level. Although the reaction conditions are not critical, the reaction is usually carried out at 0 to 100 ° C for a few hours and several times for ten hours.

By the use of a compound of formula VIII, wherein ^R5 heterocyclic aromatic amine N-oxide thio csopoft a thio group is adjacent the N-oxide group on carbon. then the compound of formula VIII and the compound of formula IX can be reacted in the presence of a divalent copper compound with the above inert solvents. This procedure is particularly useful when the general formula IX is used

-6180.307 alcohols such as methyl alcohol, ethyl alcohol, pxopyl alcohol, isopxopyl alcohol, n-butyl alcohol, benzyl alcohol * ethylene glycol and the like. In this eaetbe, the reaction proceeds smoothly in the excess alcohol used as the solvent. The bivalent xenyl compound useful in the process is an inorganic or organic divalent xylene compound. For example, xéz / II / -loxld. xes / II / -bromld, xes / II / -fluoride, copper / II / -nitrate, copper / II / -sulfate, xes / II / -boxate, copper / II / -phosphate, xes / II / -clanide, xeses Formula II, jeez / II acetate, xes / II xxopionate, lithium II, cytxate lithium II, taitaxate, copper II, salicylate. The amount of dichloride copper compound used is preferably 0.5 mol or more per mol of compound VIII. While the reaction conditions will vary depending on the type of compound VIII used, the duplex copper compound and the compound of formula IX, the reaction temperature will generally be 0-100 ° C and the reaction time will be from a few minutes to several days. .

The compound of formula I wherein R ^{1 is a} protecting group of kaxboxyl is conventionally converted to a compound of formula I wherein R 1 is hydrogen or the latter compound is a salt thereof.

a compound of formula wherein ^R1-kaxboxil védőcsopoit, a compound of formula I and its salt to the free acid.

If the starting materials have active groups, the active groups may be protected during the reaction with the groups commonly used to protect the kaxboxyl, amino or hydroxyl groups. After completion of the reaction, the protecting group is removed to give the compound of formula I. Examples of amine protecting groups include trichloroethoxyxbonyl, txibromomethoxyxbonyl, benzylloxylcarbonyl, p-toluenesulfonyl, p -nitoxobenzyloxycarbonyl, o -bromobenzyloxycarbonyl, o-nitrophenylacetyl, o -nitrophenylsulfenyl, o -nitrophenylsulfenyl, -, tert-butoxikaxbonyl, p-methoxylbenzylloxikaxbonyl, 5,4-dimethoxybenzylloxycarbonyl, 4- / phenylazo / benzyloxycarbonyl, 4- / 4-methoxyphenylazo / benzyloxycarbonyl, plxidln-1-oxide -2-benzylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 2-fuxyloxycoxylcarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylxopoxycarbonyl, isopxopoxycarbonyl, 1-cyclopxopyl-ethoxycarbonyl, phthaloyl, succinam, , 8-clenolyloxy-1-kaxbonyl, and the like * and other readily removable amyl-protecting groups, such as txityl, 2-nitrophenylthio, 2,4-dinitxophenylthio, 2-hydroxy-benzylidene, 2-hydroxy -5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pixidylmethylene. 1-methoxyxoxyl-2-pxopilidene, 1-ethoxyxoxyl-2-pxopilidene, J-ethoxycarbonyl-2-butylidene, 1-acetyl-2-pxopilidene, 1-benzoyl-2-pxqpilidene, 1 £ ft / 2-methoxyphenyl (cabamoyl) -2-pyropylidene, 1- (N- (4-methoxyphenyl) -caxbamoyl) -2-pxopillidene, 2-ethoxycafenylcyclohexylidene, 2-ethoxycapbonylcyclopentylidene, 2-acetyl- cyclohexylidene, 3,3-dimethyl-5-oxo-cyclohexylidene, di- or thioalkylsilyl groups and the like.

Examples of protecting groups for the hydroxy group include fl (-ethoxyethyl, benzyl, txityl, benzhydxyl, tetxahldxofuxll, tetxahydroxypylXanyl), optionally substituted acyl and alkoxyalkoxyl-oxo-xylcarboxyl-amino groups mentioned as amino-protecting groups.

With the kaxboxilcsopoxt protection group, they can be

U.S. Patent Nos. 3,499,909; 3,599,909; 3,573,296; and 3,641,018; U.S. Patent Nos. 2,301,014; 2,253,287; and 2,337,105.

The reaction conditions for the preparation are not limited to those described above and may be suitably varied according to the type of reagent used. "

The 7-methoxycephalosporins of the formula I or their salts can be isolated from the reaction by conventional means.

The N-methoxy-cephalosporins and their salts of the present invention are very useful in the treatment of human and mammalian diseases because of their broad antibacterial activity against Gram-positive and Gram-negative bacteria, such as Escherichia coli, Klebalella pneum Proteus species, Serratia marcescens, Alkali genes, etc. Gram-negatlv and are stable to Λ-lactamase.

⁰ The compounds of the invention are some pharmacological activities of typical compounds are described below.

1 / Minimum Inhibitor Concentration / LIIC,

The numbers in Table 1 represent the minimal inhibitory concentrations of each compound per µg / ml, as determined in a known manner by the Society of Chemotherapy, Japan, Vol 16, 98-99 / 1968/7. The culture obtained by culturing the experimental bacterium "Heart Infusion broth" (Elken Kagaku Co./) was inoculated into Heart Infusion agar medium (Elken Kagaku Co./). The inoculated medium was incubated at 37 ° C for 20 hours, and the minimum inhibitory concentration (Aig / ml) was determined by monitoring bacterial growth. The bacterial is inoculated at 10 ⁴ caira / plate. '!> ·

1 · Table

Compound THE B c D Bacterium CS-1170 / control / Escherichia coll NIHJ 0.39 rí.0,1 f ^ O, 1 O | X - 0.2 Klebsiella pneumoniae Y-50 0.39 0.1 ^ 0.2 0.2 0.2 Serratia marcescens W-35 100 6.25 6.25 6.25 50 Serratia marcescens IID620 3.13 0.2 0.2 0.2 1.56 Proteus morganii T-216 12.5 1.56 3.13 3.13 12.5 Aoir \ etobaoter oalooaoeticus A-6 50 12.5 50 50 50 Eacherlohia coli TK-3 / penicillinase producing bacterium / 1.56 -5 0.1 0.2 0.39 0.39 * '·> - Klebslella pneumoniae Jpeniollllnase-producing bacterium / 1.56 0.39 0.39 0.78 0.71

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Compound

Bacteria CS-1170 / control / &

Klebtlella spp. Y-72 12.5 0.39 0.78 X 56 ---- 12.5 Proteus vulgar 0-76 / cephalosporin producer bacterium / 3.13 1.56 1.56 3.13 Γ, Μ Serratla marcesoens W-8 / cephalosporinase producing bacterium / 200 50 50 100 200 Enterobacter oloacae IID977> 200 50 50 100 200

Escherichia coli 0-5482

/ cephalosporinase producing bacterium / / 1 Compound Bacteria 50 . spreadsheet E 6.25 6.25 12.5 resume / 12.5 H F G E. coli NIHJ = £ 0.1 <0.1 <0.1 0.2 KI.pneumoniae Y-50 0.2 0.2 0.2 250.1 Ser .mar cescena VJ-35 ... 6.25 6.25 3.13 3.13 Ser.maroescens IID620 0.39 0.78 0.39 0.1 ^ Pro.morganli T-216 3.13 3.13 12.5 . 1.56 Aci.calcoaoetlcus A-6 25 12.5 50 50 E. ooli TK-3 / penile cillinase producing bacterium / 0.1 ^ 0.39 = 93.1 = £ 0.1 KI.pneumoniae Y-4 / penicillinase producing bacterium / 0.78 0.78 0.39 Klebsiella spp. Y-72 3.13 0.78 0.78 1.56 Pro.vulgar GN-76 / Cephalosporinase-producing bacterium / 3.13 . θ »25 3.13 1.56 Ser.marcesoens W-8 / Cephalosporinase producing bacterium / 12.5 100 25 25 Self. oloaoae IID977 50 50 25 25 E. coli 0-5482 / cef alosporase-producing bacterium / 3.13 6.25 6.25

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Notes:

1 / A 03-1170 is a compound of formula K.

2 / The compound of formula A is 74- [beta] -o (- (4-ethyl-2,3-dioxo-1-pipe); -7 (1-methoxy-3- / 5- / 1-methyl 111-1,2,3, N-tetracol, 1 l / t, 11 cefemem-4-carboxylic acid sodium) in further references T-1982 /,

The compound of formula 3B is 74- (5-oC- (4-ethyl-2S-oxo-1-piperazinecarboxamido) - N - (S) -hydroxybutyl and the amido-7o-methoxy-3 -X5n .- / ~ 2 hidroxletil / l _í 2,3,4- tetrazolyl? yl thiomethyl-zj? -cephem * = 7 | —carboxylic acid sodium 6,

4) The compound of Formula C is a compound of formula 7-β-GC- (4) 11-2,3-dioxo-1-plper-4-one. - (S) -hydroxybutyric amido-7-C-methoxyl-3 - [(1,3,4) -adiazolyl] -1-a-a * -oephem-4-carboxylic acid sodium 1 * uniso.

The compound of formula 5 / AD is 7-methyl-4 - [(4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -N- (S) -hydro-oxybutamido] -70 (-methoxy-3-acetoxyl). -Methyl-4-carbamate-4-carboxylic acid, sodium salt.6 / The compound of formula E is 7-N-butyl-2,3-dioxo-1-piperazinecarboxamide. -4- (S) -hl <3r-oxy-b-iramido? -70-methyl-oxy-3 * -? - [5- (1-methyl-1,2,3,4-texazolyl) -thiomethyl] -Z-acephe ém-4-kar * b ons av-nát ri ums ó.

7 / The compound of formula F is 7A- (5-yl-4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -4- (R) -hydroxy-butyl amido / -7i. <methyloxymethyl oxy-3- 5- £ * / 1-methyl-t 111-1,2.3,4 etrazoll 1 / -1 i orne 111] - ^ y-ceph ^em-z l- carboxyiic acid sodium salt.

The compound of formula 8 / AG is a compound of the formula 7 - (-) - (-) - 1 - 2 - ³ - dioxo -? and which is dd? -7? -me toxl-3? -? - l -methyl-1,2,3,4-tetrazolyl-1-methylmethyl] -2H-cephem-4-carboxylic acid sodium.

The compound of formula 9A is 74-? -? -? -? -? - 11-2,3-dloxo-1-piperazinecarboxamido? -4-? 5 -? - rmloxy-butyramldox-7? -Methoxy-3. 3-methyl-1-1,2,3,4-tetrazolyl-1-methyl-4-carbonyl-4-carbonic anhydrous.

II. Stability to β-lactamase

Stability was measured for lactamase iodometrically at 30 ° C by the method of Perret / PerPer, OJ: Iodometric Plasma of Penicillin * Linase, Natura, 174, 1012-1013 / 1954/7, except that 0.2 M phosphate buffer solution (pH 6.5), 0.1 M phosphate buffer solution (pH b 7.0) was used. The stability of each compound is shown in Table 2 in terms of the relative degree of hydrolysis, the stability of cephalorldin / CER / 100 to oephalosporinase 100 and the stability of penicillin / G / PC-G /. peniQil- * llase to 100 ·

-10180,307

Table 2

Stability for? -Lactamase

Bacteria that produce cephalosporinase or penile IIIasease PC-G CER CEZ T-1982 E.ooll GN-5482 22 100 130 0.1 cephalosperinase Ser .maroescens W-8 21 100 94 0.04 E. coli TK-3 100 115 21 - <0.12 Peniclllináz Kl.pneumoniae Ύ-4 100 41 4 * 0.55

Note: CEZ stands for Cefazolin.

T-1982 is a compound of Formula A in Table 1.

III / Protection against infection

Groups of 4-week-old male ICR strains containing 5 mice per group were inoculated intraperitoneally with the indicated amounts of pathogenic bacteria suspended in 5% mucin. One hour after inoculation, the mice were treated subcutaneously with the experimental formulations to determine their protection against infection. The results obtained are shown in Table 3. The numbers in Table 3 · indicate the protective effect expressed in ED ^ _Q.

3 · Table

Protect against infection

Tribe

Trigger dose in germ / / mouse

Min.gátlókoncentráció

MIC / µg / ml / 5050 / subcutaneous / _____i bacterium- ¹ · ¹⁹⁸² T-19B2 CS-117Ö amount

pro.vulgáris 10 ^o'clock 0.78 1.56 (2T-3027 8.0x10 ° 0.06? 0.82 10 ⁵ 0.39 0.78 Ser.marcesoens 100 * <0.1 3.13 IID620 1.0x10 ' 10 ⁶ «<0.1 0.78 0.088 0.71 WHO. pneumonlae _R 10 ⁸ 0.1 ^ 0.78 Y_50 1.9x10 ° 10 ⁶ 0.1 ^ 0.39 0.10 0.73

Addition -11180.307: T-1982 is identical to the compound of Table 1.

CaJ-1170 is identical to the compound of Table 1.

The 7D (methoxycephalosporins) produced according to the invention have very low toxicity. For example, the T-1982 compound has an LD50 value of 5 g / kg or more / Ι0Ώ intravenously in mice.

The 7-methoxyl-cephalosporins of the formula I according to the invention and their salts are administered to humans and mammalian alleles in the form of free setv or a pharmaceutically acceptable salt or ester. The compounds are prepared in a variety of dosage forms conventional for penicillins and cephalosporins, such as capsules, syrups and injections, which are administered orally or parenterally.

When the compounds are administered to humans, intravenous injection (including drip injection) and intramuscular injection are preferred.

The antibacterial compounds of the invention may also be used in admixture with solid or liquid carriers or diluents commonly used in known antibiotic injections and the like.

The form of injection includes powders which are dissolved in a suitable solvent, such as sterilized water, saline or the like, before use. When the antibacterial compounds of the present invention are administered by injection, they may be used in combination with topical anesthetics such as lidocaln hydrochloride or other drugs.

The dosage of the antibacterial compounds of the present invention will vary depending upon whether it is administered to a human or mammalian animal and, when administered to a human, the appropriate dosage will be selected according to the age of the patient, the nature of the infectious disease and the symptom. For example, for injection, the appropriate dose for adults is 0.5 to 10 g daily. given in more details.

The invention is illustrated by the following examples, without limiting the scope of the invention. Unless otherwise noted, the percentages in the examples are in percentages. Temperatures are given in ° C.

Example 1

1 / 2.0 g of D-threonine is suspended in 50 ml of methylene chloride, 6.58 ml of trinethyl chlorosilane are added to the resulting suspension and then 7 x 01 ml of triethylamine is added dropwise at 0-5 °. The temperature of the suspension is gradually raised and the mixture is reacted at 20 ° for 1 hour, followed by 5 9 g of 4-ethyl-2,3-dioxopiperazinecarbonyl chloride / triethylamine hydrochloride / 4-ethyl 11-2.5 -di oxo-1-piper is added to the reaction mixture in an amount of 58.55% by weight. The mixture was reacted at 20 ° C for 1 hour and then distilled under reduced pressure to remove the solvent. Water (30 mL) was added to the residue, and the resulting solution was adjusted to pH 7.5 with sodium hydrogencarbonate, washed with 5 mL of ethyl acetate and 50 mL of acetonitrile. The resulting mixture was adjusted to pH 1.5 with 2N hydrochloric acid. Sodium chloride is added to the mixture

-12180.307, it is saturated with sodium chloride and the acetonitrile phase is separated.

The aqueous phase was extracted with acetonitrile (4 x 50 mL), the four acetonitrile extracts were combined with the above acetonitrile phase, the combined acetonitrile phases were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from n-butanol to give 5.6 g (75% yield) of Do (- (4-ethyl-2,3-dioxo-1-plperazinecarboxamido) - N - (S) -hydroxybutyric acid, m.p. 164). -166 DEG C. IR spectrum / KBr / cm @ -1 / cm @ -1 1740, 1710, 1670.

Nuclear Magnetic Resonance Spectrum (CD3 / CDCl3) ppm: 1.11 (3H, t, CH1), 1.13 / 311, d, CH1 /, 3.28-3.75 (4H, m, CH). x 2 /, 3.78-4.30 (4H, m, CH., CH x 2). ² *

2-1.0 g of D-OC - [1 H] -ethyl 11-2,3-dloxo-1-plperazinecarboxamido [1 H] -hydroxybutyric acid are suspended in 15 ml of methylene chloride and 0.38 ml of —Motylmorpholine is added to make the suspension a solution. Ethyl chlorocarbonate (0 * 35 mL) was added at -15 to 20 [deg.] C. and the solution was reacted at the same temperature for 1.5 hours. Then, 1.67 g of diphenylmethyl-7H-amino-3- [5- (1-methyl) -1,2,2,4,4-tetrazolyl] -1X-7,4-cephem-4-carboxylate are added to the reaction mixture. and the mixture is reacted at the above temperature for 1 hour and at -10 to 0 ° for 1.5 hours. The resulting mixture was distilled under reduced pressure to remove the solvent, and to the residue was added water (30 mL) and ethyl acetate (30 mL), and the resulting solution was stirred. The precipitated white crystals were collected by filtration to give 2.5 g (95% yield) of diphenylmethyl-7β, β-β-4-ethyl-2β-dioxo-1-piperazinecarboxamido / 4H-5H-hydride. ^ xv ^: -butiramldqj / 5 ~ / l -meth 11-1,2,3,4-batch xazolyl] -dimethyl 11J-ΔD-oephem-4-carboxylate, m.p. 121-125 ° / dec. . IR-Spectrum / KBr / cm ^-1 : YQ_Q 1785, 20-20, 1680.

MLIR Spectrum / CD, S0CD, / ppm values: 1.00 / 3H, t, CH, /, 1.16 / 3H, d, CHY, 3.4-4.0 / 1 OH, m, ₂ x CH 4, CH x 2 /, 3.85 / JH, s,

CH, /, 4.25 / 2H, q, CH ₂ /, 5.10 / 111 'd, CH /, 5.8 (1H, m, CH), 6.85 / 111, s, CH / 7 , 2-7.45 / 1011, a CH x 2 / 8.91 / 1H, a, NH /, 9.26 / 1Η, s, NH /. ° ^?

3 / 1.0 g of diphenylmethyl-7ZL / P '- [4-ethyl-2,3-dloxo-1-piperazinecarboxamide] - N - (S) -hydroxy-p-butyramid-7- [beta] -1-methyl-1,2,3 4-tetrazolll / -tlomét 117- / V ^{"cephem-4-carboxylate} was dissolved in a mixture of 30 ml of dry methylene chloride and 2 ml of dry tetrahidorfurán, and the resulting solution was cooled to -70 °. To the cooled solution was added lithium methoxide (3.55 ml / 1.66 mmol / ml / methanol) at the same temperature, the reaction mixture was stirred for 3 minutes, and tert-butyl hypochlorite (0.18 ml) was added. After stirring for 15 minutes at the above temperature, 0.39 ml of acetic acid was added to the resulting solution and the temperature of the solution was raised to room temperature. The solution was distilled under reduced pressure to remove the solvent, the residue was dissolved in ethyl acetate (20 mL) and water (20 mL), and the pH of the solution was quenched with aqueous sodium hydrogencarbonate solution.

Set 6.5-ίθ. The organic phase is separated off, washed with water,

-13180.307 vizmcntui u ... ··; After washing with sulfuric acid, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography Λ / aco silica gel C-200, eluent benzene / ethyl acetate 1: 2 t / tooth /. Yield: 0.6 g of (40.8 H) diphenylmethyl-7? - [4- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -8H-hydroxy. -b ut Irish amida7-70 (r -methoxyl-5- [3- (1-methyl] -1,2,3,4-tetrazolyl] -1-yl) -1H-7-cephem-4-carboxylate, which has the following physical properties:

IB spectrum / KBr / ^cm-1: V _{C Q} _ 1760, 1710, 1670th

EW spectrum (CDCl3): ppm: 1.20 (3H, t, CH3), 1.25 (5H), d, CH3 (5.5), 311 (s), CH3 (3.79), 3H (s). , CII j /, 3.2-4.0 (8H, m, CII ₂ x 4), 4.3-4.6 (4H, m, CH ₂ , CII x 2), 5.02 / 111, a , CH 2, 6.85 (111, s, NH), 7.2-7.4 (10H, a, C 8 H 12 x 2), 8.52 (1 H, a, NH), 9.55 (H 1, d). , NH /.

4 / 0.5 g of diphenylmethyl-76-ZHOH - (4-ethyl-2,3-dloxo-1-plperazole) carbamido-1- (1-S) -hl-droxy-b ut Irish doj-7 N-Methoxy-5- {5- [1-methyl-1,2,3,4-tetxazolyl] -thiomethyl] -N-cephem-4-carboxylate was dissolved in 5 ml of anlzole, and 5 ml of trifllaoroacetic acid was added under ice-cooling. and then stir the resulting solution at the same temperature for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent, and to the residue were added 10 mL of ethyl acetate and 10 mL of water, followed by stirring with saturated sodium bicarbonate,

Set to 6.5 to dissolve the residue. The aqueous phase was separated and methyl acetate (10 mL) was added. The resulting mixture was adjusted to pH 2.0 with 2N hydrochloric acid. The organic phase was separated. The aqueous phase was extracted with methyl acetate (2 x 10 mL) and the two extracts were combined with the above organic phase. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated with diethyl ether to give 0.25 g (65.5% yield) of 74- (1H) -N- (4-ethyl-2,5-dloxo-1-oiperazinecarboxamido) -N- (S) -hydroxybutyramido-7,7-g-methoxy. ^Methyl 1-5-2,5,4-tetrazole-1-yl is obtained from 117-5 N-cephem-d-carboxylic acid, m.p. 118-120d (with decomposition).

IB Spectrum / KBr / _σ __θ 1770, 1705, 1675 ·

MMB Spectrum (CD3SOCD3) ppm: 1.10 / 5H, t, CII, /, 1.15 / 5H, d, CH3 /, 5.40 / 511, s, CH3 /, 5.95 / 5H, s, CH /, 5.5 to 4.0 / 811, m, CH ₂ x 4 /, 4.1-4.4 / 4H, m, CH, CH x 2 /, 5.05 / s 1 H,

CH /, 9> 2 / 2H, d, NH x 2 /.

The following compounds are prepared in the same manner as above: .......................................

74-Zp-κ- (4-η 11 -2,3-dioxo-1-piper) is the anchor boxamido / - / - / δ-hldr oxybutyr and amido7-7 (k-methoxyl-5). - £ 2- / 1,5, 4-t iadiazolil / iometilJ -t-ZV-cephem-4-carboxylic acid, mp 108-112 ° C / dec / IB-spectrum / KBr / om "θ ^ ^1,.. 1780, 1720, 1680 MMB-NMR / D ₂ 0 CDjSOCDj / ppm-values: '1.02 to 1.59 / 6H, m,

-14180,307

GH ₅ x 2 /, 3.50 (3H), a, CH ₃ /, 3.3-4.5 (12H, m, CH ₂ x 5, CH x 2 /, 5.05 (1H, s, CH) , 9.42 (1H, a, CH);

74-IP- (E) - (4-n-Octyl-2,3-dioxo-1-piperazinecarboxamide) - (2S) -hydroxy-butam! dq7-7K-Methoxy-3β- (1-methyl-1,2,3,4-tetrazole-1-yl) -1H-N- ^cephem -4-carbonic acid, m.p. 113-115 ° (decomposition) IR spectrum / KBr / GirT? V 1780, 1660-1720.

IiU.'iR Spectrum / CD COCD ^ ^ / from 0.80 to 1.60 ppm vascular bowling / 18H, m, CH ₂ x 6, CH x 2 /, 3.30 to 4.50 / 12 H, m, CH ₂ x 5, CH x 2 /, 3.48 (3H, s, Cl- ₃ ), 3.95 / 3H, a, CH ₃ /, 5.00 (1H, a, CH), δ , 37 / Hi, 0, NH /,

9.40 / 111, d, W.

7 - [(J) -o-C- (4-n-butyl) -1,2,3-dioxo-1-piperazinyl] -N, N-oxo-1β-hydroxy-1-carboxamide. -3- (5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl) -N-cephem-4-carboxylic acid, m.p. 125-133 ° C (dec.) IR -spektrum / KBr / cm ^-1 Y _{Q Q} _ 1785, 1710, 1680th

NMR apéktrum / CD SOCD ^ ^ / ppm 0.80 to 1.60 over plows / 1CH, m, 2 x CHG, CH ₃ x 2 /, 3.20 to 4.40 / 12 H, m, ₂ x Cl 5, CII x 2 /, 3.41 (3H, s, CH *), 3.94 (3H, s, CH),, 5.08 (1H, a, CH), 9.27 (1H, a, NH /, 9.30 / 111, d, NII /.

74- [mu] - (4-ene-11-2,3-dloxo-1-piperazinecarboxamido) -Z, N- (R) -hydroxybutyl-1 H -amido [7-b] -methoxy] -3- [beta] -N- m.p. 111-1,2,3,4-tiol-ylmethyl-N-N-cephem-4-carboxylic acid, m.p. 144-150 ° (with decomposition), IR spectrum / KBr / cm ^-1 : V 1700 , 1735-1660.

MMR spectrum / CD ₃ COCD ₃ : CD ₃ SOCD ₃ = 4: 1 v / v. ratio (ppm ore frogs: 0.96-1.37 (OH, m, CH ₃ x 2), 3.30-4.92 (12H, m, CH 8 x 5, CH x 2), 3.54 / 3H , a, CH3, 4.04 (3H, 0, CH3), 5.10 (1H), a, CH (9.23), bs, NH (9.46 (1H), d, NH).

Example 2

1 / 4.5 g of DP (- (4-ethyl-2,3-dioxo-1-piperazinecarboxaniloyl) -1- (S) -hydroxybutyric acid is suspended in 45 ml of methylene chloride, and 1.60 g of N-methyl are added to the resulting suspension. morpholine is added to convert the azo suspension into a solution. The solution was cooled to -20 DEG C., 1.78 g ethyl chlorocarbonate was added and the resulting solution was reacted at -13 DEG -16 DEG for 1.5 hours. Subsequently, 6.50 g of diphenylmethyl-7-amino-3-acetoxymethyl-11 N-cephem-4-carboxylate are added to the reaction mixture at -30 °. The mixture is reacted at 10 ° to 15 ° for 30 minutes and then at -10 to 0 ° for 30 minutes, after which the solvent is distilled off under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), methyl acetate (50 mL) and water (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and the solvent removed by distillation under reduced pressure. The residue was purified by column chromatography (Wako silica ··· C-200, 60: 1 v / v chloroform / ethanol) to give 8.2 kg / 78.2% yield / diphenylmethyl 11-70- / 0-C. (- (4-Ethyl-2,3-dioxo-1-piperazinecarboxamido-4- (S) -hydro-oxybutramido) -3-aoethoxymethyl-2H-oephem-4-carboxylate) powder.

-15180,307

Tii-srvv.txvr. ·. / KBr / cm ^-1 : y _c _ ₀ 17780, 1705, 1670.

2 / h, oh g / 1 /; Prepared diphenylmethyl-7A- (DX / 4-ethyl-2,3-dioxo-1-piperazinecarboxamido) - N - (S) -hydroxy-butyrar, η 5 -3 -acetoxymethyl-4-cephem-4-carboxylate in 80 ml. Methylene oxide solution was dissolved and 26 ml of methanolic lithium methoxide solution (lithium methoxide content 1.51 mmol / ml) was added at -70. The solution is stirred at - 65-70 / ⁰ for 3 minutes, then 1.60 g of tert-butyl hypochlorite is added and reacted at the above temperature for 15 minutes. Thereafter, 3 ml of acetic acid were added to the reaction mixture, the temperature of the mixture was gradually raised to 0 °, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and water (10 mL), the organic layer was separated, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel C-200, eluting with ethyl acetate, to give 2.65 g (31.8% yield) of diphenylmethyl-74-ZM- / 4-ethyl-2,3-dloxo-1 Piperidine is obtained in the form of a white powder in the in-box boxaldehyde - [4- (8-hydroxybutyl) -amido] -7X-methoxy-3-acetoxymethyl-Zb-cephem-4-carboxylate. .

IB spectrum / KBr / cm -1: 80/1740,1710,1680.

3.65 g of diphenylmethyl 11-74-d-D-O-4-yl-2,3-di-o-piper-1-piperazinyl prepared according to 2/2 are: - (S) -hydroxy-butyl oxide which do7 -7 (A-methoxy-3-ace't-oxime) 1-ac ephem-4-carboxylate under ice-cooling with 26 ml of anisole and Trifluoroacetic acid (3 ml) was added and the resulting mixture was reacted at this temperature for 30 minutes and the reaction mixture was distilled under reduced pressure to remove the solvent and the residue was washed with diethyl ether to give 2.0 g (97%) of a white powder. po (- (4-cis-11-2,3-dioxo-1-piperazinecarboxamido) -N- (1,3) -hydroxybutyl) and araido-7c (~ methoxyl-3-acetoxymethyl-z) -celem-4-carboxylic acid, m.p. 142-145 ° (dec.).

IB spectrum / KBr / cm ^-1 : 1780, 1705, 1670.

V V

CDCl3 / CDCl3: v / v: ppm: 0.85-1.45 (6H, m, Q1 ^ x2), 2.03 / 3H, s, CH ^ /, 3.15-4.95 / 12H, m, CH ₂ x 5, CH x 2 /, 3.48 / 311, s, GH _? (, 5.06 (1H, S, CH), 8.84 (111, s, NH), 9.54 (111, d, NH).

Example 3

0.71 g of 74- (p-O-tert-4-ethyl-2,3-dioxo-1-piperazinecarbosamido) -4- (5H) -hydroxy-buty-amido-7c (-methoxy-3-acetoxymethyl) Il-4-cephem-acetic acid and 0.22 g of 1- (2-hydroxyethyl) -5-mer-captto-1H-tetrazole are dissolved in 24 ml of nitromethane and the resulting solution is reacted at 80 ° for 5 hours. The residue was dissolved in ethyl acetate (20 ml) and acetone (20 ml), diphenyldiazomethane was added until the reddish violet color persisted and the solvent was distilled off under reduced pressure. silica gel C-200, eluent chloroform-ethanol 20: 1 by volume /, thus a pale yellow powder

-16180.307. To the powder was added anlzole (5.5 mL) and trifluoroacetic acid (3.5 mL) under ice-cooling, and the resulting mixture was reacted at the above temperature for 30 minutes and then the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate to give 0.28 g (34%) of N- (p-β-β-4-ethyl-2,3-dloxo-1-piperazinecarboxamido) -1H-hydroxy-butyramido] -7 ° C. methoxy-3 ^ - £ L / 2-hydr oxy-et 11 / etrazoliÍ7 -1,2,3,4-t-t Lome HJ - ^ - i ^z cephem-carboxylic acid as a pale yellow powder. 128-135 ° (dec.).

IR spectrum / KBr / cm -1: V 1700, 1/10, 1675 »

I.MR spectrum (CD ^ COCD ^: CD ^ OCD ^ - 4: 1 / v / v ppm: 0.9-1.4 / 611, m, CII ^ x 2), 3.47 / 5H , s, CH 2, 3.20-4.50 (16H, m, d ₂ x 7, CH x 2), 5.03 (1H, s, CH), 9.01 (MI, s, NII). , 9.51 / MI, d, NH /.

The above procedure is repeated except that 1-methyl-4-mercapto-1H-tetrazole is used in place of 1- (2-hydroxyethyl) -5-inertcapto-1 H-tetrazole. 4-Ethyl-2,3-dloxo-1-piperazinecarboxamido [4- (S) -hydroxyl-butyramido] 7'-7K-meboxi-3E-n-methyl-1,2,3,4-tetrazolyl] -thiomethyl-τΔ / -cefem-4-kaxb on acid is obtained.

The product had a melting point and IR and <RTI ID = 0.0> 1 H </RTI> NMR spectra similar to that of Example 1.

Example 4

0.20 g DK- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2- (S) -tert-butoxybutyric acid are dissolved in 7 ml of anhydrous methylene chloride, to which 0.10 g of oxalic chloride is added. 1 drop of methylformamide was added under ice-cooling and the reaction mixture was reacted at room temperature for 30 minutes. The reaction mixture is then distilled under reduced pressure to remove the solvent. The residue was dissolved in 8 ml of anhydrous methylene chloride and the solution was cooled to -50 °. To this solution was added 0.3 g of diphenylmethyl-70-amino-7OC-methoxy-3-Z5- (1- ^methyl -1,2,5,4-tetrazolyl) -methyl] -cephem-4-carboxylate followed by 0.1 g. dlmethylaniline (ml) was added and the mixture was reacted overnight at -20 °. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in a mixture of water (10 ml) and ethyl acetate (15 ml), the ethyl acetate layer was separated, washed well with water and the solvent was distilled off. The residue was purified by column chromatography (Wako silica gel C-200, 2: 1 v / v benzene / ethyl acetate) to give 0.31 g (63%) of diphenylmethyl 11-74- [4- (4-ethyl-1-2)]. 3-Dloxo-1-plpgx azinecarboxamido [4- (S) -tert-outoxyl-butyric ₍ mid-7? -? - (methoxy-5-Z5- / 1-methyl) -1-1,2,3,4-1 ether] b oxllátot ol of the 1 / -1 i ome 11 1J-A ° ^c ~ em-4-carboxylic ester of melting point 109-115 ° C / dec / IR / KBr / cm ^ ^_. V * Q_Q 1780, 1720-1680;

1 H NMR (CDCl 3, δ ppm), 30 / 9H, s, CH, x 3 /, 1.03-1.55 / 611, m, CH 2 _x 2, 3.51 / 311, s, dl, /, 3.72 / 311, 8, CH, /, 3.18 to 4.68 / 12 H, m, _CH2 X 5, X 2 dl / 4.98 / H 8, CH / , 6.76 / MI, s, CH /, 7.22 / 1011, bs, Ο, θΗ ^ x 2 /, 8.04 / MI, bs, NH /, 9.50 / 1H, d, NH /.

-17180,307

The above product is 2 ml. The anlzole is dissolved in 2 ml of a mixture of trifluoroacetic acid and reacted at room temperature for 30 minutes. The reaction mixture was evaporated to dryness under reduced pressure, ethyl acetate (10 ml) was added to the residue and the mixture was stirred for 1 hour. The precipitated crystals were filtered off and dried, yielding 0.21 g (55.7% yield) of 7 J - D - O (- (4-ethyl-2,3-dioxo-1-plperazine carboxamido) - N- (S) -hydroxybutylramine-7-P (-methoxy-3β - (1-methyl) -1,2,3,4-1 etrazo-11,11 -111'-cesium-4-carboxylic acid is obtained. melting point / roll-over · /, ¹ ea IIlIí IR spectrum of the product obtained in example 1. Kevei same.

Example 5

G, 7-methyl-4- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) - N, S -hydroxybutyramido-3- [5- (1-methyl) -1,2,3 Dissolve 4-Tetrazolyl-t-methyl Δ-Δ * -cephem-4-carboxylic acid in a mixture of 40 ml of anhydrous methylene chloride and 20 ml of anhydrous methanol and cool to -75 °. To the solution was added lithium methoxide solution in methanol (3.7 mL) (lithium methoxide, 9.2 mmol) and reacted at -75-70 ° C for 3 minutes, followed by addition of t-butyl hypochloride (0.22 mL) and the reaction mixture for 15 minutes. . To the reaction mixture was added 0.28 ml of formic acid and the temperature of the mixtures was raised to room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was dissolved by addition of 4 ml of water, 4 ml of saturated aqueous sodium chloride solution and 20 ml of acetonitrile. To this solution, 6 N hydrochloric acid was added dropwise to adjust the pH to 1.2. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue was added acetone (14 mL) and the resulting mixture was stirred. The precipitated crystals were filtered off to afford 0.71 G of 7 - [? - X- ^z -methyl-2,3-dloxo-1-piperazinecarboxamido] -4- (S) -hydroxy-but-lramine as an acctonic adduct. The yield of η 5 -7 Lö - ηη 1 -O-O- (1-methyl-1,2,3,4-tetrazolyl) -methyl-n-zx ′ -cephem-4-carboxylic acid is obtained.

The above adduct is suspended in 4.3 ml of 20% aqueous acetone and adjusted to pH 5.0 by the addition of sodium bicarbonate. 70 mg of activated carbon is added to the suspension, the mixture is stirred for 3-4 minutes and then the activated carbon is filtered off over celite. The filtrate was adjusted to pH 1.5 with 6N hydrochloric acid and stirred at room temperature for 30 minutes and ice-cooled for 3 hours. The precipitated crystals were filtered off and dried, yielding 0.5 g (45%) of [74- [4- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -1 H] hydroxy-butyl] _! m.p. 173-175 [deg.] C., m.p. 173-175 [deg.] C., m.p. 173-175 [deg.] C., m.p. 173-175 [deg.] C. dec /. Ί / · '

IR / KBr / ^cm: Ύ _c _q 1775, 1710, 1675, 1660th

The MMR spectrum of the textiles was identical to that of Example 1. Melting point of its sodium salt decomposes 164θ0. -------- Ultraviolet spectra at K _max / nm / / in water /: 229,269, / gC] 20_ ₊ ^ ₀ o

EXAMPLE 6 g of N, N-c - [(4-Ethyl-2,3-dloxo-1-piperazinecarboxamido) -4 ', 5'-hydroxy] -beta-amide] -3- [5- (1-methyl)] -1,2,3,4-tetrazolyl-thiomethyl-1-N-cephem-4-carboxylic acid is suspended in 20 ml of anhydrous methylene chloride, and 0.8 ml of vinyl acetate are added to the suspension, and

-18180.307 mg of pyrldlnium p-toluenesulfonate are added and the resulting mixture is refluxed for 50 minutes to give 7,3-b-oC- (4-θ 111-2,3-dl) oxo-1p iperazinecarboxam 1do / -. N- (S) -N- (1-ethoxyethyl) -oxyl-N-butyramol-3-ol- (1-methyl) -1,2,3,4-tetrazolyl] -methyl] -4-oxephem -4-carbonate is obtained. The reaction mixture was cooled to -75 ° C, 0.5 ml of methanolic lithium methoxide (0.5 ml) was added, followed by dropwise addition of lithium methoxide methanol (2.7 ml) (7.52 mmol of lithium methoxide). The reaction mixture is reacted at - 75-70 ° C for 3 minutes and then 3 ml of anhydrous methylene chloride containing 0.25 ml of tert-butyl chlorochlorite is added dropwise over 10 minutes. After stirring at the above temperature for 5 minutes, acetic acid (0.34 mL) was added and the temperature of the resulting mixture was raised to 0 °. Water (5 mL) was added to the reaction mixture, the mixture was stirred and the organic layer was separated and the solvent was distilled off under reduced pressure. The residue thus obtained, 7? -DD-o (- (4-ethyl-2,3-dioxo-1-piperazine-carboxamido) -4- (S) -? -1- (1-ethoxyethyl). -oxyl-butlramido $ -70 (-methoxy-3- [5- (1-methyl] -1,2,3,4-tetrazolyl) -1-methyl-17 -? - cephem-4- carobic acid is dissolved in 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate is added and the solution is stirred at room temperature for 2 hours and then allowed to stand overnight at 5 ° C. The precipitated crystals are filtered off and washed with water. 0.85 g of 9β-N-N- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -N- (S) -hydroxy-butylramid-β-7α-cyano-ethoxyl-3-β-1-methyl is added as an adduct. -1,2,3,4-Tetrazol-1-ylmethyl] -2X-cephem-4-carboxylic acid is obtained.

The adduct was suspended in 5 ml of 20% aqueous acetone, the pH was adjusted to 5.0 by the addition of sodium bicarbonate, 85 mg of active carbon was added to the resulting mixture.

Stir for 3-4 minutes and then filter the activated carbon over Celite. The filtrate was adjusted to pH 1.5 with 6N hydrochloric acid, and the filtrate was stirred at room temperature for 30 minutes and ice-cooled for 3 hours. The precipitated crystals were filtered to obtain 0.66 g / yield 60% / 7 ^ - / P- <K- / ^z i-ethyl-2,3-dioxo-carboxamido lrpiperazln * / A- / S / -hydroxy-butiramldo7 7-methoxy-3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -N-cephem-4-carboxylic acid dihydrate is obtained, m.p. 173-175 ° C. / decay /. IR spectrum / KBr / onT ¹ : '!? _n 1775, 1710, 1675, 1660.

The product had the same NMR spectrum as the product of Example 1.

7 · example

1 / 2.5 g of diphenylmethyl D - () -1- (4-ethyl-2,3-dloxo-1-piperazinecarboxamido) -4- (S) -hydroxy-butyrate is dissolved in 50 ml of anhydrous methylene chloride, Boron trifluoride diethyl ether complex (BF content 47% by weight) followed by 50 ml diethyl ether diazomethane solution / dlazomethane content ca. 1.4 g / g is added. After the reaction mixture was gradually warmed to room temperature, water (20 mL) was added, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (Wako silica gel C-200, 5: 1 v / v benzene / ethyl acetate). The yield was 0.68 g (26.4%) of diphenylmethyl-IMC * / 4-ethyl-2,3-dioxo-1-pi

-19180.307 per az in i.ux b o xam 1 do / - $ - / S / -me b oxl-b ut Transcribe.

0.6 g of diphenylmethyl-IM (- / 4-11-2,3-dioxo-1-plper) prepared from 2A-Aa 1/5 ml of the sugar boxamido (-) - (S) -methoxyl-b Anisole was dissolved in a mixture of 5 ml of trifluoroacetic acid, and the solution was reacted for 30 minutes under ice-cooling and the solvent was distilled off under reduced pressure, 10 ml of diethyl ether and 10 ml of diisopropyl ether were added and stirred for 1 hour. the precipitated crystals were collected by filtration, yielding 0.37 g / 95.8% yield / D-o (- / 4-ethyl-2,

m.p. 132-133 °.

D-t- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -4- (S) -methoxybutyric acid (3) (0.18 g) is suspended in 3 ml of anhydrous methylene chloride and 0 1 g of oxalyl chloride is added. A drop of Ν, Ν-dimethyl chloroform was added to the suspension, the temperature of the suspension was raised to room temperature, and the suspension was reacted for 1 hour. The reaction mixture was distilled under reduced pressure to remove the solvent, and the residue was dissolved in anhydrous methylene chloride (5 mL) to give 0.28 g of diphenylmethyl-7-methyl-7-methyl-4-methoxyl. -3- (5-µm) et 11-1,2,3,4-tetrazole-1-thiomethane cephem-4-carboxylate, followed by 0.086 g of methyl methaniline. The mixture is reacted at ~ 20-10 ° for 12 hours and the solvent is distilled off under reduced pressure. The residue was dissolved in a mixture of 5 ml of water and 10 ml of ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The organic phase was distilled under reduced pressure to remove the solvent and the residue was purified by column chromatography (Wako silica gel C-200, 1: 1 v / v benzene / ethyl acetate / eluent) to give 0.28 g / 57.8% yield / diphenylmethyl -7H-Zp-O1- (4-ethyl-2,3-dloxo-1-piperazinecarboxamide) - 3 - [(S) -methoxy-butyramido] -7PC-methoxyl-3-yl] -N-methyl -1,2,3,4-Tetra-azolyl-thiomethyl-N, N-cephem-4-carboxylate is obtained.

4 / 0.18 g of diphenylmethyl-7H-ene - (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -N- (S) -methoxy-butyramido-7-C-methoxy-3- ( 5- (1-Methyl-1,2,3,4-tetrazolyl) -methyl] -7,7-cephem-4-carboxylate was dissolved in a mixture of 2 ml of anisole and 2 ml of trifluoroacetic acid, and the solution was reacted under ice-cooling for 30 minutes. The solvent was removed by distillation under pressure, ethyl acetate (10 ml) was added to the residue, and the mixture was stirred for 30 minutes, and the precipitated crystals were collected by filtration to give 0.1 g / 70% yield of [74-] -4- (4-ethyl-2,3). -dioxo-1-piperazinecarboxylamido [4- (S) -methoxy-butyramido] -7C-methoxy-3- [5- (1-methyl-1,2),

3,4-Tetrazolyl-thiomethyl] -5-cephem-4-carboxylic acid is obtained, m.p. 130-136 ° (dec.).

H spectrum / KBr / ONT ^1: 1790, 1720 -16,801

MMH Spectrum (CD ^C COCDjj: CD ^ So SoCDCD = 4: 1 v / v): 1.17 / 3H, t, CH, /, 1.23 / 3H, d, CH, /, / 3.33 / 3H, α, CH, /, 3.45 / 3H, α, CH ^ /, 3.96 / 3H, α, CHj /, 3.25-4.60 / 12H, m, CHg x 5, CH × 2 /, 5.08 (1H, a, CH) ^; 8.97 (1H, a, NH), 9.31 (1H, d, NH) ·

-20180,307

In the same manner as above, the following compounds are prepared: -

74 - {- [(4-ethyl-2,3-dloxo-1-piperazinecarboxamido) -4- (S) -ethyl] -butylmethyl # -TX-methoxyl-3- (1 - [- t-meth 11-1.2,5,4 © trazolll / -tiometirj- * ^ x-cephem-4-carboxylic, mp, 110-119 ° C / dec / apektrum IR / KBr / ^cm-1 _{<c = 0} 1780, 1720-1670;

MMR spectra (CD3COCD, OD: SOCl4? 4: 1 v / v): 1.10-1.35 (9H, m, CH3 x 3), 3.50 (3H, S, CH3), 3.98 / 3H, s, OH ₅ /, 3.30 to 4.70 / 14 H, m, CH ₂ x 6, CH x 2 /, 5.03 / 1H, s, CH /, 8.95 / 1 H , a, NH /, 9.40 (1H, d, NH);

7β-tert-butyl (4/4-et 11-2,3, -dioxo-1-ylperazinecarboxamide) -4- [N-tert-butoxybutyrimido] -70 70-methoxy-3 - (5- / l-me 111-1,2,3,4-tetrachloride) -l-methyl-2-N- ^cephem -4-carboxylic acid, m.p. 110-115 ° (with decomposition), IR spectrum / KBr / om ~ ¹ : Υ * 1780, 1730-1680;

NMR apektrum / CD COCD ^ ^ / ppm values: 0.82 to 1.42 / 15 H, m, CH x 5 /, 3.50 / 3H, s, CH at ₅ /, 3.94 / 3H, s , CH, /, 3.22-4.58 (12H, m, CH ₂ x 5, CH X 2 /, 5.04 / 1H, a, CH /, 8.48 / 1H, a, NH / 9, 40 (1H, d, NH).

Example 8

To 1 / 0.5 g of Dc <- (4-ethyl-2,3-olloxo-1-plperazinecarboxamido) - [beta] - [S] -hydroxybutyric acid is added 5 ml of formic acid and the mixture is reacted at 50 for 2 hours, followed by distillation under reduced pressure to remove the solvent. Ethyl acetate (5 mL) was added to the residue and the precipitated crystals were filtered off. Yield: 0.45 g (82%) of D-α- (4-ethyl-2,3-dloxo-1-plperazinecarboxamido) -β- (S) -formyloxyacid, m.p. 170175 °.

IR spectra / KBr / 1740-1710, 1660;

Ppm: 1.15 / 3H, t, CH3 /, 1.35 / 3H, d, CH3 /, 3.10-3.72 / 4H, m, 0¾ x 2), 3.72-4.10 (2H, m, CHV), 4.40-4.70 (1H, m, CH), 5.28-5.64 (1H, m, CH), 8.15 (1H, a, δ-Η), 9.41 (1H, d, NH).

2 / 0.3 g of D-η 4 - (4-ethyl-2,3-dioxo-1-plperazinecarboxamido) -β- (S) -formyloxy-butyric acid are suspended in 5 ml of anhydrous methylene chloride, and the suspension is ice-cooled to 0.14. g of oxalyl chloride followed by 1 caenp of dimethylformamide. The temperature of the fluorescent suspension was raised to azo temperature and the suspension was reacted for 30 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was dissolved in anhydrous methylene chloride (5 mL) and cooled to -40 °. To this solution 0.45 g dlfenilmetil-7FL-amino-7o <'-methoxy-3-I5' 7 methyl ^1-f 111-1,2,3,4-1etrazolil / -tlométΙΓ / -2Ρ- oefém-4 carboxylate followed by 0.12 ml of Ν, Ν-dimethylaniline. The reaction mixture was reacted at -20 ° C overnight and then the solvent was distilled off under reduced pressure. The residue was dissolved in water (10 mL) and ethyl acetate (20 mL), and the organic layer was separated.

It was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (Wako Silica Gel C-200, 10: 1 v / v chloroform: acetone) to give 0.5 g / 64% yield of dif-enzyme 11-7A-β- (4 - 4-ethyl). 2,3-Dloxo-1-plperazinecarboxamido [4- (S) -1-phenyloxy-butyramo] -N-t-methoxy-3-p- (1-methyl-1,2,3,4-tetrazolyl) -methyl] -N-2-yl. This gives C 4 -methyl 4-carboxylate.

5 / 0.2 g of diphenylmethyl 11 - [4- (4'-6'-yl) -2,3-dioxo-1-plperazinecarboxamide] - [4- (S) -f or -molyloxy] b and iddo The phosphorus-methoxy-5- 7β- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -acephem-4-carboxylate was dissolved in a mixture of 2 ml of anisole and 2 ml of trifluoroacetic acid and the The solution was reacted under ice-cooling for 15 minutes, and the reaction mixture was distilled under reduced pressure to remove solvent, to the residue was added ethyl acetate (10 mL) and the mixture was stirred for 50 minutes to form crystals which were filtered to give 15 g / 94% yield / 7 - (4-Ethyl-2,5-dloxo-1-piperazinecarboxamide) - N - (N-formylhydroxy-butyramide) -7 K-methoxy-5- (p-1-methyl) -1-1,2,3,4 -1 etrazo 111 / -1 iome 11Π cef ε-4-carboxylic acid, m.p. 147-155 ° (with decomposition). IR spectra / KBr / οιη '' ¹ ·: Υ ^ _θ 1730, 1720 - 1680;

NMR apektrum / CD ^ ^ SOCl? / Ppm values: 0.90 to 1.35 / 6H, m, CH x 2 /, 3.20-3.80 / 6H, m, CH ₂ x 3/3, 40 / 3H, s, CH, /, 3.80-4.10 / 2H, 'm, _CH2 /, 3.94 / 3H, s, CH /, 4.20-4.40 / 2H, m , CII ₂ /, 4.50-4.90 (1H). m, CH /, 5.07 (1H, a, CH), 5.20-5.50 (1H), m, CH (CH), 8.20 (1H), a, CH (CH), 9.43 (1H), s, NH, 9.54 (1H, d, NH).

In a similar manner, the following compound was prepared: 7 * 1- [p- (K- [4-ethyl] -2,3-dioxo-1-piperazinecarboxamido) -N- (S) -acetoxyl-oxide. -7 < - &gt; -methoxy-3- {N- [1-methyl-1,2,3,4-tetrahydro-azolyl] -thiomethyl] -Z, - cephem-4-carboxylic acid, m.p. . 136-142 ° (with decomposition). MMH Spectrum (CDOCCOCD ^ ^ SOC ^ SOC SOC SOCDDDj =: 4: 1 v / v ppm: 1.06-1.35 (6H, m, CH ^ × 2), 2.01 (3H, α, CH ^), 3.45 / 3H, s, CH at ₅ /, 3.98 / 3H, s, oy, from 3.35 to 5.00 / 12 H, m, 5 x CH _2, CH x 2 / 5.02 / lH, s, CH /, 9.37 (1H, s, NH), 9.45 (1H, d, NH).

9 »example. 1 / 0.5 g of 74- [M - (4-ethyl-1,2,5-dioxo-1-piper)] anchor boxamido [4- (S) -hydroxybutyramide] -3- [5-] -methyl-1,2,3,4-tetrazolyl-1-ylmethyl] -2,6-cephem-4-carboxylic acid is suspended in 20 ml of anhydrous methylene chloride and 0.76 ml of 2,3-dihydro-plant is added to the suspension. and 0.021 g of plridinum-l-p-toluenesulfonate are added. The mixture was heated at reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to -75 °, 1.5 ml of methanolic lithium methoxide solution (3.725 mmol of lithium methoxide) was added and the reaction mixture was reacted for 3 minutes. Then 0.123 ml. tert-butyl hypochlorite is added to the reaction mixture and the mixture is reacted for 15 minutes. 0.12 ml of ant for the reaction mixture—

-22180.307 acid was added and the temperature was raised to room temperature and the solvent was distilled off under reduced pressure. The residue is dissolved in a mixture of 10 ml of water and 10 ml of ethyl acetate and the pH of the solution is adjusted to 7.5 with dilute aqueous sodium bicarbonate solution. The aqueous layer was separated, ethyl acetate (10 mL) was added and the pH was adjusted to 1.5 with ice-cold 2N hydrochloric acid. The organic layer was separated, washed with water, brine, and dried over anhydrous sodium sulfate. The organic phase was distilled under reduced pressure to remove the solvent. Diethyl ether was added to the residue, and the crystals formed were filtered off to give 0.42 g (70.6%) of 7F- [beta] - (4-ethyl-2,5-dloxo-1-piperazole). - N - (S) - (2-tetrahydro-opixanyloxy) -butam-M-methoxy-5- [5- (1-methyl) -1,2,5,4-tetrazolyl] -thi 1 - (N-cephem-4-carboxylic acid), m.p. 152 ° (dec.).

IB spectrum / KBr / ra ¹ / _{G =} 1770, 1710-1670;

MMR Spectrum: CDCl3 + D2 O / ppm: 1.20 / 5H, t, CH2 /, 1.25 / 5H, d, CHy, 1/1-1.9 / 6H, m, CIL ·, x 3 /, 5.52 / 5H, s, CH 2 /, 5.89 / 5H, s, CH, /, 5.5-4.9 / 15H, m, CE? x 6, CH x 5 /, 4.98 / 1Η, s, CH /. ' ^pd

2 / 0.5 g of 7β - [5- (4-ethyl-2,5-dioxo-1-pyrazerazinecarboxamido) -β- (S) -2-tetrahydro-pyrrolooxy] -butyramide-4-methoxyl -5- [5- (1-Methyl-1,2,5,4-tetrazolyl) -thiomethyl] -cephem-4-carboxylic acid was dissolved in 20% aqueous acetone and the solution was treated with 6N hydrochloric acid. The reaction mixture was stirred at room temperature for 2 hours, then the reaction mixture was distilled under reduced pressure to remove the solvent, dissolved in a mixture of 8 ml of acetonitrile and 2 ml of saturated aqueous sodium chloride solution, and the organic phase was separated. Extract with 2 x 4 mL of acetonitrile and combine the two acetonitrile phases with the organic layer above, dry the combined organic layers over anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, add acetone (7 mL) and stir until the crystals precipitate. the crystals are filtered off adduct in the form of 0.4 g of 7? - / Ρ ^"ί ^ - / 4 βΙ; _{11-2.3-ΰ1οχο-Μ} Γ ρ1ρθΧazlnkarboxamido / -4 / S / T-buHramidqJ -hydroxy-yloxy ^ -methoxy oxy 5- (5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl) -2H-cephem-4-carboxylic acid is obtained. This product is suspended in 2.4 ml of 20% aqueous aoetone and the suspension is adjusted to pH 5.0 with sodium bicarbonate and 40 mg of activated carbon is added. The reaction mixture is stirred for 5 to 4 minutes and the activated carbon is filtered off on a cell. The pH of the filtrate was adjusted to 1.5 with 6N hydrochloric acid, and the filtrate was stirred at room temperature for 50 minutes and then with ice cooling for 5 minutes. The resulting crystals were filtered off to give 0.52 g (68.7%) of (74- (pK-) - 4-ethyl-2,3-dioxo-L-iperazine zincboxamido) - (N -) - S -hydroxybutyl kr which is d.q77'-1-methyloxy-5-15-l-methyl-1,2 |

5.4-Tetrazolyl (thiomethyl) -N-cephem-4-carboxylic acid dihydrate, m.p. 175-175 ° (dec.).

IR spectrum / KBr / ππΓΓΓθθθ 1710, 1675, 1660; NMR / CD SOCD ^ ^ / ppm 1.10 / 5H, t, CH /, 1.15 / 5H, d, CH at ₅ / 5.40 / 5 H, s, C _5/5 , 93 (3H, s, CH 2), 3.5-4.0

-23180.307 / 8Η, m, CH ₂ x 4 /, 4.1-4.4 / 4H, m, CH ₂ , CH X 2 /, 5.0? (1H, s, CH), 9.2 (211, d, NH x 2).

Example 10

0.58 g of 7β- (10C-amyl) -N- (S) -hydroxy-butyrimino-7H-methoxy-5-L5- (1N) -N-1,2,3,4-t of ethanol was suspended in 10 ml of 80% aqueous tetrahydrofuran, and the pH of the suspension was 7.0-

Set to 7.5. To the resulting solution was added 0.48 g of a mixture of 4-ethyl-2,3-dloxo-1-piperazinecarbonyl chloride and trlethylamine hydrochloride (58% w / w 4-ethyl-2,3-dloxo-1-piperazinecarbonyl chloride) at 3-5 ° C. , while the addition of trlethylamine has a pH of 7.0 -7? 5- * ®. The mixture was reacted at the above temperature for 1 hour and then adjusted to pH 5.5 with 6N hydrochloric acid. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was dissolved in 4 ml of 20% aqueous acetone and the pH of the solution was adjusted to 1.5 with 3N hydrochloric acid at 3-5 ° C. Is the solution stirred for 5 hours? and filtering off the formed crystals. 054 g (65.1% yield) of 74- [beta] - (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) - N - [(S) -hydroxybutyl-amide] -7-C-methoxy-3- 5- / l-methyl-l, 2,3,4-tetrazolyl / -tiometifJ ^{Zr-cephem-4-carboxylic} acid dihydrate, melting at 173-175 ° C / dec · /.

IB spectrum / KBr / cm ^"1: / ^ 1775, 1710, 1-657, 1660th

The product has the same ΜΜΙΐ-spectrum as the product of Example 1.

· Medicinal product

7 - Z - [5- (4-Ethyl-2,3-di-oxo-1-piperazinecarboxyl) -6- (S) -hydroxy-oxide and amide Sodium hydrogencarbonate was added to the N-methyl-3-oxy-3H, 4'-1-methyl-111-1,2,3,4-trimethyl-1,1'-zephem-4-carboxylic acid and the mixture was treated with The product is treated in the usual manner to form the sodium salt of the product, lyophilized and sterilized by dissolving 1 g of the above sodium salt (expressed as active ingredient) in 20 ml of brine.

2. pharmaceutical composition

1 g of compound (1) (expressed as active ingredient) is dissolved in 3 ml of 0.5% aqueous solution of lidocaln hydrochloride to form an injection solution.

· Medicinal product

1 g of compound (1) (expressed as active ingredient) is dissolved in 20 ml of 5% aqueous glucose solution to give an injectable colloidal solution.

In a manner analogous to that of Pharmaceutical Formulation 1, lyophilized sodium salts of the other compounds of the invention can be prepared and salts prepared for injection.

Claims (12)

Patent claims A process for the preparation of the 70 - [2,3-dioxo-1-piperazinecarboxamido] -hydroxy-amldol-7'-methoxy-cef-3-ye-4-carboxylic acid derivative of the formula I and its salts, wherein -24180,307 R ^{1 is} hydrogen or a diphenylmethyl protecting group for the carboxyl group; ^R2 alkanoyloxy lower alkyl, 5- / 1,2,3,4-tetrazolyl / -tióvagy 2- / l, 3,4-tiadlazolil / -tiocsoportot ring that may be substituted with lower alkyl or lower hydroxyalkyl; C 1-8 alkyl; C 1-4 alkyl, and R 1 is hydrogen or C 1-4 -alkyl, C 1-4 -alkonate-alkoxy-C 1-4 -alkyl, lower alkanoyl, formyl or tetra-tetrahydropyranyl protecting group, characterized in that a compound of formula II a cef-3-em-4-carboxylic acid derivative wherein R ¹ , R ² , R ⁴ and R ⁴ are as defined above, r 5 is hydrogen or an organosilyl group or an organic phosphorus group 2 * Reacting a 3-dioxopperazine derivative of the formula A in the formula with a reactive derivative of the carboxyl group of A; or b) a cef-3-em-4-carboxylic acid derivative of the Formula IV, wherein R 1, R 6 and R 5 are _as defined above, with a 2,3-dioxp-plperazine carboxamido derivative of the Formula V, wherein wherein R * and R 4 are as defined above - or. reacting with a reactive derivative of a carboxyl group; or an o-C - [2,3-dloxo-1-plperazine-carboxamido] -hydroxy-amldo '- cef-3-ym-4-carboxylic acid derivative of formula C / VI in which R1, R2 _} R3, p ⁴ and A are reacted in the presence of methanol with an alkali metal or alkaline earth metal methate of formula VII in the presence of methanol, wherein M ^{1 is} an alkali metal or alkaline earth metal atom, m ⁴ is 1 or 2; or d / for the preparation of compounds of formula I wherein R 2 is other than lower alkanoyloxy and R 1, R 1, R 4 and A are according to the present invention, a 7-t-methoxyl-cef-3-em-4-carboxylic acid of formula VIII a compound of formula R ^{6 which is} readily substituted with a nucleophilic reagent R ⁶ , e.g. R ¹ , R ¹ , R ⁴ and A are as defined above, wherein a compound of Formula IX is wherein M ^{2 is} hydrogen, alkali or alkaline earth, m ² is 1 or 2 and R 2 is of a compound of formula I, if desired, optionally present the dose groups are cleaved and / or a compound of formula I is optionally converted into its salt. / Priority: October 5, 1979 · / 2. A process for the preparation of N, N-dioxo-1-piperazinecarboxamido-N-hydroxyamido-N, N-ethoxy-cer-p-em-4-carboxylic acid glazes and salts thereof. in the formula -25180 307 Η uh · · υ protective -unatomot or karboxilosoportot, diphenyl me- _c. methyl-uaoportot; R ^{4, as} alkenoloxyl, 5- (1, 2, 3, 4, 4) -tetrazolyl / t-substituent means 2-, 1,3,4-thiadiazole-1-thio, which may be substituted by lower alkyl or lower hydroxyalkyl. ; C 1-8 alkyl; iP is C 1 -C 4 alkyl and r 4 is hydrogen, characterized in that a cef-3-um-4-carboxylic acid derivative of the general formula II is represented by the formula R 1, R 2, R 6; and r4 has the meaning given above, R- ^? hydrogen is a reactive derivative of the carboxyl group of a 2,3-dloxopiperazine derivative of the Formula III in which A is as defined above, or b / a cef-J-ye-4-carboxylic acid derivative of the Formula IV wherein R ¹ and R ^{2 are} as defined above, by reacting a 2,3-digoxopiperazine carboxamldo derivative of general formula V with a reactive derivative of A ₍ and F as defined above) or its carboxyl group; or o / - / 72.3 "dioxo-plpθrazin-karboxamldo / amidóJ hydroxymethyl-ceph-3 · ^em-J ^ -karbon8av derivative - in which R ^, ^R2, R ^, ^R4 and A with an alkali metal methate of formula VII, wherein M ¹ is an alkali metal and m ¹ is 1, in the presence of methanol, or d / for the preparation of compounds of formula I wherein R ² is a lower alkane nolloxl, and R 1, R ⁴ , R ⁴ and A are a tert-methoxyceph-3-ym-4-carboxylic acid derivative of Formula VIII, wherein R ^{6 is} nucleophilic reagent is a readily displaceable group such a halogen atom, a lower alkanolloxlcsoportot, sjciíkarboniloxlcsoportot, ariltlokarboniloxicsoportot, arilkarboniltiocsoportot, ariltlokarboniltiocsoportot, karbamoiloxicsoportot, tiokarbamoiloxiosoportot, pyridine-N-oxide-2-yl or pyridazin-N-oxide-6-yl group, R ^1, R5, R4 and a are as defined above - is reacted with a compound of formula ιχ - wherein, m ² represents a hydrogen atom, an alkali metal or alkáliföldfématomot, m ² is 1 or 2, and Ti is as defined in this method; and, if desired, deprotecting the resulting compound of formula I, and / or converting a compound of formula I, if desired, into its * salt. / Priority: April 23, 1979 3. A process for the preparation of the 70- [2,3-dioxo-1-piperazinecarboxamido] -hydroxyamido [K-methoxy-o-3-em-4-carboxylic acid derivatives of the formula I] and salts thereof, in which képl is hydrogen or a diphenylmethyl protecting group for a carboxy group; -26180.307 ο I? lower alkanoyloxy, 5- (1,2,3,4-tetrazolyl) -thio or 2- [1,3,4-thiadiazolyl] -thio which may be substituted by lower alkyl or lower hydroxyalkyl; C 1-8 alkyl; - C4-C4 alkyl and B ^{2 is a} C 1-4 alkyl protecting group, C 1-4 alkoxy (C 1-4) alkyl, lower alkanoyl, lower alkanoyl or tetrahydropyranyl protecting the hydroxy group, characterized in that a Cef-5- and the 4-carboxylic acid derivative wherein R 1, b 3 and I 4 are hydrogen as defined above, is a compound of formula III Reacting a 2,5-dioxo-piperazine derivative of the formula (A) as hereinbefore defined with a reactive derivative thereof; or b / a cef-3-em-4-carboxylic acid derivative of formula IV, wherein R1 and R2 are as defined above, with a 2,3-dioxo-piperazine carboxamido derivative of formula V reacting a compound of formula A, IP and In with a reactive derivative of the above or carboxyl group; or c / a of formula VI 'A / - // 2,3-dioxo-piperazlnkarboxamido / -hydroxy-amidóJ-ceph-3-em-4-carboxylic acid szarniaz Ekoton the formula wherein R ^1, R ^2, R >, Β ² * · and A having the same meaning - one With an alkali metal or alkali metal salt of Formula VII - in this formula, jelent represents an alkali metal or alkaline earth x atom, the value of m ¹ being reacted in the presence of 1 or 2 - methanol; or d / for the preparation of compounds of formula I wherein R ² is lower from lower alkanoyloxy and R ¹ , r ³ , r 4 and A are selected from the group consisting of 70 (-ethylethoxy-3-ye-A-carboxylic acid derivative of the Formula VIII) in which R6 is an easily substituted group, e.g. , pyridine-N-oxide-2-yl or pyridazine-N-oxide-6-yl, R ^{1 -} R 4 and A are reacted with a compound of formula IX as defined above - in which M ^{2 is a} hydrogen atom is an alkali or alkaline earth metal, m2 is 1 or 2, and R 2 is as _{defined in Qzen} ; and, if desired, deprotecting the resulting compound of formula I, and / or converting a compound of formula I, if desired, into its salt. / Priority: August 7, 1979 · / The process for the preparation of any of the processes according to claim 2, which is 7 - [(j) - ( ^z - 1-ethyl-2,3-dloxo-1-plperazine carboxamido) - (S) -hydroxybutyram] -TPI-methoxy-3- £ A process for the preparation of 5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -ceph-J-a-carboxylic acid by reacting appropriately substituted starting materials. / Priority: April 23, 1979 · / -27180.307 ^l j. The process according to any one of claims 2 to 7) - f) -o - [4- (4-ene] -2,3-dioxo-1-piper is the carboxamido [4 R] -hydroxybutyl]. ramldoj-7 (ε-methoxy-3-η 5 - (1-methyl-1,2,5,4-tetrazolyl) -thiomethyl) -epheph-3-ε-4-carboxylic acid, characterized in that the appropriately substituted starting materials / Priority: April 23, 1979 6. A process for the preparation of any of the processes according to claim 2, which is 74- [beta] - [4- (4-ethyl-2,3-dioxo-1-piper)] and amido-7? -methoxy-3-? 5 -U- (2-hydroxyethyl) -1, The preparation of 2,3,4-tetrazolyl] -thiomethyl-ceph-3-ym-4-carboxylic acid is characterized by reacting appropriately substituted starting materials. / Priority: April 23, 1979 · / 7. A process for the preparation of any of the processes according to claim 2, which is selected from the group consisting of N, N-O-G, 4-ethyl-2,3-dloxo-1-piperazinecarboxamido, and N, N-hydroxy-butyramido. -7t (-methoxy-3-acetoxymethyl-cef-3-ym-4-carboxylic acid, characterized by reacting appropriately substituted starting materials. / Priority: 1979 · April 23 · / 8. A process for the preparation of any of the processes according to claim 2, which is 7 - {(J) - {{- (4-ethyl-2,3-cLioxo-1-piperazinecarboxamido) -4- [S] -hydroxybutyl-amide] -7- -methoxy-3-Z2- [1,3,4-tladlazolyl] -methyl] -J-cef-3-em-4-carboxylic acid, characterized by reacting appropriately substituted starting materials. / Priority: 1979 · April 23 · 9. A process for the preparation of any of the processes according to claim 2, which is N - [5 - [(4-n-butyl-2,3-oxo-1-piperazinecarboxamido) - [beta] - (S) -hydroxybutyramide For the preparation of -7 H -methoxy-3- {5- [1-alpha] 11 -1,2,3,4-tetrazolyl] -thiomethyl] -ceph-3-yl "4-carbonic acid, characterized in that the appropriately substituted starting materials are with. / Priority: April 23, 1979 · / 10. The method of any of claims 3 to 7, wherein the compound is 73-QH- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -F (S) -methoxy-butyramide-7G-6-methoxy. -3-G2 / 17metil-l, 2,3,4-tetrazolyl / -tlométf | ceph-3-Eui-4-carboxylic acid, which comprises that substituted starting compounds are reacted in accordance with ^r. / Priority: August 7, 1979 · /. ...... -......- _ 11. The method of any of the methods of Claim 3j, which is an ancillary partner, is 7A- [pc (r- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) - 4 - (-) -] -b ut and producing d -jO-methoxy-1-1,3-β- (1-methyl-1-1,2,3,4-etrazolyl-thiomethyl) -oef-3-ym-4-carboxylic acid characterized by reacting an appropriately substituted starting compound * / Priority: 1979 · August 7 · / 12. Process as an active ingredient of the formula 7 for the preparation of pharmaceutical compositions containing -dioxo-1-piperazinecarboxamido / -hydroxyamido-7- (c-methoxy-oef-3-em-4-carboxylic acid derivatives or a salt thereof, wherein R *, R 1, R ² , R * and The active ingredient of any one of claims 1 to 11, as defined in claim 1, is formulated together with the usual carriers, diluents, γ, excipients and / or other excipients of the pharmaceutical compositions. · 5 / -------