HU185990B - Process for preparing new cefem-carboxylic acid derivatives - Google Patents

Abstract

Cephalosporins of formula (I) and their keto tautomers and salts (where Y is H or OMe; A is a 2,3-dihydro-2 (A'-imino)-4-thiazolyl gp., where A' is H, COCH2Cl, COCH2Br, COOCH2CCl3, CHO or trityl, or A can also be phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or 2- or 3-thienyl when Y is OMe; D is H, OCOMe, OCONH2, pyridinio, 4-carbamoylpyridino or SHet, where Het is 1,3,4-thiadiazol-5-yl 2-methyl-1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl, 3-methyl, -1,2,4-thiadiazol-5-yl, 5,6-dioxo-4H-1,2,4-traizin-3-yl, 4-methyl-5,6-dioxo- 1,2,4-triazin-3-yl or 1-D'-tetrazol-5-yl, where D' is vinyl, allyl, 1-4C alkyl, 2,3-hydroxypropyl or (CH2)nR1, where n= 1-3 and R1 is OH, NH2, NMe2, NHCOMe, CONH2, NHCONH2, SO2NH2, NHSO2NH2, COMe, NHSO2Me, CN, NHSO3H, SO2Me, SOMe or a carboxylic or sulphonic acid gp; R is NHR2, where R2 is a 3-pyridyl, 5-pyrimidinyl, 2-thienyl, 2-furylmethyl, 2-thienylmethyl, 2-imidazolylmethyl, 2-thiazolylmethyl, 3-pyridylmethyl or 5-pyrimidinylmethyl gp. op.t substd. by Cl, Me, NHCOMe, OH, SOMe, SO2Me, CONH2 or SO2NH2; E is H or a protecting gp.).

Description

The present invention relates to novel cephalosporins of the formula I, their possible tautomers, and to pharmaceutical compositions containing them.

In formula I, 5

Y represents a hydrogen atom or a methoxy group;

When Y is methoxy, phenyl, 4-hydroxyphenyl,

Represents a 2- or 3-thienyl group or, when Y represents a hydrogen atom or a methoxy group, represents a 2,3-dihydro-2-iminothiazol-4-yl group of the formula (a);

D is acetoxy or -SHet, whereby Seven is 2-methyl-1,3,4-thiadiazol-5-yl, 4H-5,6-dioxo-1,2,4-triazine-3- yl, 4-methyl-5,6-dioxol, 2,4-triazin-3-yl, 1- (C 1 -C 4) alkyl-tetrazol-5-yl or a group of formula II is g, wherein n is 1, 2 or 3 and R is hydroxy or acetylamino;

R is a group -NHR ₂ wherein R _{2 is} substituted or unsubstituted

3-pyridyl. 5-pyrimidinyl, 2-thienyl, 2-furylmethyl, 20

2-thienylmethyl, 2-imidazolylmethyl, 3-pyridylmethyl or 5-pyrimidinylmethyl and these groups may be substituted on the ring by methyl, hydroxy or aminosulfonyl;

It represents a hydrogen atom or an alkali metal atom. 25

For the preparation of the compounds of the present invention, as used in the starting compounds, the E 'carboxyl protecting group may also be used to date in the chemistry of penicillins and cephalosporins, in particular by hydrogenolysis or hydrolysis or other ester forming groups which may be removed slightly.

Easily cleavable protecting groups include benzyl, diphenylmethyl, trityl, tert-butyl, 2,2,2-trichloroethyl or trimethylsilyl; alkanoyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, 2-acetoxyethyl, pivaloyloxymethyl or phthalidyl.

In the formula I, the carbon atom represented by an asterisk represents an asymmetric carbon atom.

Particularly preferred are compounds of formula I wherein:

With the meaning given above,

Y and R have the meanings given above, and

D is acetoxy or -SHet where Sev is 2-methyl-1,3,4-thiazol-5-yl, 4-methyl-5,6-dioxo-1,2,4-triazine-3 il-45, alkyl-tetrazol-5-yl or tetrazol-5-yl of formula II wherein R is as defined above.

The cephalosporin compounds of formula I and the intermediates described below may exist in two tautomeric forms with respect to the pyrimidine ring. Particularly, depending on the particular solvent and the nature of the substituent R, which one of the structures of formula I or Γ predominates.

When A represents the thiazole group, two tautomeric forms of this ring, of formula (a) and (b), are also possible.

It is to be understood that the compounds of formula I given above always include each tautomer. 60

The compounds of formula I can exist in both possible R and S configurations due to the asymmetric carbon atom in the asterisk, but may also exist as mixtures thereof.

The compounds of formula I can be prepared by the following methods.

a) A 7-amino-cephalosporanic acid derivative of the Formula III wherein D is hydrogen, acetoxy or -SHet, E 'has the same meaning as E or a carboxy protecting group, Y has the same meaning as an ureidocarboxylic acid of Formula IV, wherein A and R are as hereinbefore defined, or a salt or reactive derivative thereof.

The reactive derivative of the ureidocarboxylic acid of formula IV is, for example, its acid anhydrides such as chloroformic acid esters, in particular ethyl or isobutyl chloroformate or reactive esters such as p-nitrophenyl ester or N-hydroxy-succinimide. or reactive amides thereof such as N'-carbonylimidazole or acid halides such as the corresponding acid chloride or acid azides. However, in principle any coupling method known in the art of β-lactam chemistry may be used.

The ureidocarboxylic acid, salt or reactive derivative thereof is reacted with the 7-aminocephalosporanic acid derivative in a solvent at a temperature of from -40 ° C to +40 ° C, optionally in the presence of a base. For example, when an anhydride of ureidocarboxylic acid, such as anhydride with chloroformate, is used, the reaction is carried out under cooling, for example at -10 ° C to + 10 ° C, in a solvent such as acetone, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, in a mixture of solvents. For example, when the N-hydroxysuccinimide ester of ureidocarboxylic acid is reacted with a derivative of formula III, the reaction is preferably carried out at a temperature of 0 to 20 ° C in the presence of a base such as triethylamine, solvent such as dimethylformamide, dichloromethane, dioxane mixture.

The reaction of the ureidocarboxylic acid itself or its salt with the compound of formula III is preferably carried out in the presence of a condensing agent such as N, N-dicyclohexylcarbodiimide.

b) A 7-aminocephalosporanic acid of formula V, or an inorganic or organic acid salt thereof, wherein A, D and Y are as defined above, with a pyrimidine derivative of formula VI, wherein R is as defined above and B is -NCO. or is a reactive derivative of the group -NHCOOH formula -NHCOC1- example, -NHCOBr- -NH-COOC ₆ H ₄ -NO 2 group of the formula (including in particular the radical of the formula preferred -NHCOC1) - acid. It is also possible to use mixtures of pyrimidine derivatives of formula VI in which B contains one or the other of the aforementioned groups, for example -NCO- and -NH-COCl simultaneously.

The reaction is preferably carried out in a mixture of water and water-miscible organic solvents (such as ketones such as acetone; cyclic ethers such as tetrahydrofuran or dioxane; nitriles such as acetonitrile; formamides such as dimethylformamide; dimethylsulfoxide; alcohols such as isopropanol or hexamethapol). finally. A tetrahydrofuran-water mixture is particularly preferred.

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In this case, the pH of the reaction mixture is maintained between 2.0 and 9.0, preferably 6.5 and 8.0, by adding a base or using a buffer solution.

c) A VII, a compound of formula - wherein, A, Y and R are as defined above - is reacted with - a VIII with a compound of ₅ formula - the formula wherein HET is as defined above, and M is hydrogen or alkali or alkáliföldfématomot.

For example, the compound of Formula VII with 1-methyl-5-mercapto-1,2,3,4-tetrazole in a solvent such as water, ·, θ methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran, acetonitrile, ethyl acetate, dimethoxy ethanol, dimethylformamide, dimethylsulfoxide, chloroform or a mixture of these solvents. Preferably a highly polar solvent such as 1 g of water is used; in this case, the pH of the reaction mixture is preferably maintained between 2 and 10, particularly preferably between 4 and 8. The desired pH can be adjusted by the addition of a buffer solution such as sodium phosphate. The reaction conditions are not particularly limited. The reaction is usually carried out at a temperature between 0 ° C and 100 ° C for a few hours. This provides compounds of formula I wherein D is -SHet.

d) A compound of formula I wherein Y represents a methoxy group may also be prepared by MOCH of a compound of formula IX wherein A, R, D and E 'are as defined above; with an alkali metal methylate of the formula EMI3.1 in which M ^{+ is} an alkali metal ion and then with 30 halogenating agents. For this purpose, a cephalosporin of formula IX is used in an inert solvent such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, dimethylformamide, methanol and the like. or dissolved or suspended in a mixture of two such solvents. To the resulting solution or suspension is added alkali metal methylate together with methanol, and the reaction mixture is reacted with a halogenating agent. In this reaction, methanol is used in excess and the amount of alkali metal methylate 40 used is 1 to 8 equivalents per equivalent of cephalosporin used. The term "excess" refers to more than one equivalent of cephalosporin equivalent. All reactions are carried out at temperatures between -120 ° C and -10 ° C, preferably between -100 ° C and -50 ° C 45. It is sufficient to react for 5 to 60 minutes. The reaction was quenched by acidifying the reaction mixture.

The halogenating agent used in this process is generally known as a positive halogen atom, for example CT, Br ⁺ or J ⁺ 50. Examples of such halogenating agents are elemental halogens such as chlorine, bromine, etc .; N-halogenimides such as N-chlorosuccinimide, N-bromosuccinimide, etc .; N-haloamides such as N-chloramide, N-bromoacetamide, etc .; N-halosulfonamides such as 55 N-chlorobenzenesulfonamide, N-chloro-p-toluenesulfonamide, etc .; 1-halo-benzotriazoles; 1-halo-triazines, organic hypohalites, such as tert-butyl hypochloride, tert-butyl hypoiodide, etc .; halohydantoin, such as Ν, Ν-dibromohydantoin and the like. Among such halogenating agents, tert-butyl hypochlorite is preferred. The halogenating agent is used in an amount sufficient to produce a positive halogen equivalent to the amount of cephalosporin of formula IX.

Suitable interrupts are acids which, when added to the cold reaction mixture, do not cause the reaction mixture to solidify or solidify to a dense viscous mass. Examples of suitable acids are 98% formic acid, glacial acetic acid, trichloroacetic acid and methanesulfonic acid. After the reaction is terminated, the excess halogenating agent is removed by reaction with a reducing agent such as trialkylphosphite, sodium thiosulfate or the like.

The compounds of formula I obtained by the above processes wherein E is other than hydrogen are deprotected in known manner. This provides compounds wherein E is hydrogen and which are particularly preferred end products in the present invention. For example, a compound of formula I wherein E represents a diphenylmethyl group is reacted with anisole and trifluoroacetic acid in a known manner to remove the ester protecting group or to remove the silyl protecting group by aqueous hydrolysis in a known manner.

The compounds of formula I obtained by the above processes, wherein A represents a protected aminothiazolyl group, are reacted in a known manner to cleave the imino protecting group. For example, a compound of formula I wherein A is a chloroacetyl-protected aminothiazolyl group and E 'is a diphenylmethyl group is first reacted with thiourea to cleave the chloroacetyl group and then with anisole and trifluoroacetic acid in a known manner. 296, or the ester protecting group is first cleaved, and then the chloroacetyl protecting group is removed with sodium N-methyldithiocarbanate (see European Patent Application 2586).

Compounds of formula I wherein E represents a sodium or potassium cation are prepared by reacting the corresponding free acid of a compound of formula I wherein E is hydrogen with the corresponding salt-forming ion. For this purpose, for example, reaction with sodium ethyl hexanoate in penicillin and cephalosporin chemistry is carried out, or with sodium bicarbonate and then freeze-dried.

Using the appropriate starting compounds, the compounds of formula I may be obtained in the form of the racemate or of the individual isomers. When the final product is formed in the D, L, form, the pure D and L diastereoisomers can be prepared by preparative liquid chromatography (HPLC). The invention also relates to racemates and isomers.

Uureidocarboxylic acids of formula IV wherein A is not an aminothiazolyl group are known in the art. These are described in German Patent Publication No. 29 24 296. In the case where A represents an aminothiazolyl group, these ureidocarboxylic acids are prepared by reacting an amino acid derivative of formula X or a salt thereof with an acid such as trifluoroacetic acid with a pyrimidine derivative of formula VI.

The reaction is carried out at a temperature of -20 ° C to + 40 ° C, preferably 0 ° C to + 20 ° C, in a solvent. Solvents include, for example, water and a water miscible organic solvent such as acetone, tetrahydrofuran, dioxane,

A mixture of acetonitrile, dimethylformamide, ethanol, dimethylsulfoxide can be used. Optionally, the use of a halogen hydrogen bonding agent may be necessary, for example, trialkylamines such as triethylamine or inorganic bases such as dilute sodium hydroxide solution.

The starting compounds of formula VI are prepared, for example, by reacting the corresponding 5-aminopyrimidines of formula XI, wherein R is as defined above, with phosgene. This reaction is preferably a solvent containing no hydroxyl functions per _10, such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol, preferably at temperatures between -10 ° C and + 20 ° C -40 ° C to + 60 ° C execute. In this case, the resulting hydrogen chloride ₁₅ in an inert organic base such as triethylamine or pyridine, an equimolar amount of a recommended cure. Excess pyridine may also be used as a solvent. If the aminopyrimidines of formula XI are difficult to dissolve in one of the solvents mentioned, the phosgenation may also be carried out in phase. In addition, according to a particularly preferred method, the aminopyrimidines of formula XI are reacted with a silylating agent such as hexamethyldisilazane, trimethylchlorosilazane triethylamine, trimethylsilyl diethylamine or N, O-bis-trimethylsilylacetamide. Reaction can be converted into the monosilylated aminopyrimidines, which are generally very soluble in the said solvents, either singly or according to the exchangeable hydrogen atoms present, and reacted with phosgene, without the addition of a preferred base, to afford the corresponding compounds of formula VI. Depending on the nature of the solvent, the temperature, the amount and the nature of the base optionally added, the appropriate isocyanate or carbamic acid halide or a mixture of these two compounds is formed. Depending on the circumstances, the isocyanate VI is partially or completely isomerized with the isocyanates to the 1 (H) -oxazolo [5,4-d] pyrimidin-2-one of the formula VI or, depending on the nature of the R substituent, mono or 40 produced.

The starting compounds of formula VI produced by phosgenation, or mixtures or silyl derivatives thereof, are generally readily soluble in the aforementioned solvents and, after removal of excess phosgene, can be converted directly to the corresponding cephalosporin V without further purification. However, it is also possible to isolate the VIA intermediate, optionally with a protic solvent such as methanol or water, to purify it, if necessary, according to its dissolution properties and to react as described above.

The synthesis of 2-substituted 5-amino-4-hydroxypyrimidines of formula XI is, in principle, known in the art. Specific examples are disclosed in German Patent Publication No. 29 28 344. The synthesis of starting compound V is described in the literature. For this purpose, for example, when A represents an aminothiazolyl group, a cephalosporin derivative of formula a is reacted under standard conditions in the cephalosporin chemistry with amino acid X protected by group A at the amino group and deprotected in the usual manner (see 29 24 296). German Federal Publication No.). 65

The 7-aminocephalosporanic acid derivatives of formula III are described in the literature.

Cephalosporins of Formula VII, which are useful as starting materials, may be prepared by the method described in the experimental section.

The preparation of cephalosporins of formula IX used as starting materials, when A is aminothiazole, is also described in the experimental section. Where A is another group according to the invention, its preparation is carried out according to Federal Patent Application Serial No. 29 28 344 or German Patent Publication No. 30 47 082.

The compounds of formula I have been found to possess valuable pharmacological properties in addition to their good tolerability. Therefore, the active compounds of the present invention are useful in the prevention and medication of local and general infections in human and veterinary medicine. Examples of diseases that can be prevented or cured by the compounds of the present invention include diseases of the respiratory tract, pharynx, and urinary tract; the compounds are particularly effective against pharyngitis, pneumonia, peritonitis, nephritis, otitis media, cystitis, bronchitis, arthritis and general systemic infections. In addition, these compounds are inorganic or organic substances, in particular organic substances. such as polymers, lubricants, paints, fibers, leather, paper and wood and food preservatives.

Such use is possible because the compounds of formula I are very potent in vitro and in vivo against harmful microorganisms, in particular Gram-positive and Gram-negative bacteria and micro-organisms similar to bacteria, and at the same time exhibit particularly broad spectrum of activity.

For example, these cephalosporin derivatives can be used to treat and / or prevent local and / or systemic diseases caused by the following pathogens or pathogens; Micrococcaceae such as Staphylococci; Lactobacteriaceae such as Streptococci;

Neisseriaceae such as Neisserias;

Corynebacteriaceae such as Corynebacteria; Enterobacteriaceae such as Escherichiae from the Co1 group;

Klebsiella bacteria such as K. pneumoniae; Protea bacteria from the Proteus group, such as Proteus vulgaris;

Salmonella bacteria such as S.thyphimurium; Shigella bacteria such as Shigella dysenteriae; Pseudomonas bacteria such as Pseudomonas aeruginosa;

Aeromonas bacteria such as Aeromonas lique faciens;

Spirillaceae such as Vibrio bacteria such as Vibric cholerae;

Parvobacteriaceae or Brucellaceae such as Pasteurellabacteria;

Brucella bacteria such as Brucella abortus; Haemophilus bacteria such as Haemophilus influenzae;

Bordatella bacteria such as Bordetella pertussis; Moraxella bacteria such as Moraxella lacunata;

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Bacteroidaceae such as Bacteroides; FusiArm bacteria such as Fusobacterium fusiforri;

Sphaerophorus bacteria such as Sphaerophorus necrophnrus; 5

Bacillace you. thus, aerobic spore-forming agents such as Bacillus anthracis;

Anaerobic spore-forming Chlostridas such as Chlostridium perfringens;

Spiroehaetaceae such as Borrelia bacteria;

Treponema bacteria. for example Treponema pallidum; Leptospira bacteria such as Leptospira interrogans.

This list of pathogens is given by way of example only and is in no way restrictive.

In Table it is listed some characteristics, in particular good Selling ₁₅ ha, the compound of the invention.

Table I

.OH

nhr ₂

A Rj Y D

CHjCH; OH

-5A

R ₂

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HjNSOj

N-N

II '1

S <N \ _N /

CH, CH, NHCOCH,

H, F

N— s—!

H, NSO ₂

N-N

II> 1

-S <N

CH

N

OH 'OH

I

H ₂ USO | i il

HjNSOi-k ^> -CH ₂ h ₂ nso ₂ -1% _s ^ j-ch ₂ -ch ₂ o

MONTH

OCH,

OCH,

OCH,

OCH,

OCH,

SO ₂ NH ₂

OCH,

N O

CH

N - N

CH

--OCOCH,

N-N

CH ₂ CH ₂ OH

N-N 'V

OCH,

CH

CH, CH, OH

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ΗΟ

Ο

ΗΟ

Ο

ΗΟ

CH?

HjN-SOj Ο -CHj -OCHj -OCOCHj

For example, the efficacy of the lactam antibiotics of the present invention can be demonstrated by the following assays.

1. In vitro experiments

Serial dilution assay was performed using a microtiter system. The inhibitory effect of the compounds on bacterial growth was investigated in a liquid medium. Inhibitory activity was tested at the following concentrations: 128. 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06 / zg / ml.

The following medium was used: 10 g peptone, 8 g beef extract, 3 g sodium chloride, 2 g disodium hydrogen phosphate were made up to 100 ml with distilled water. The pH of the solution is 7.2-7.4. The primary cultivation period was 20 hours. The concentration of the cell suspension was adjusted using an Eppendorf photometer in a 14 mm diameter test tube with a 546 nm filter against a turbidity of 60 barium sulfate suspensions added to 3.0 mL of 1% sulfuric acid in 97 mL of 1% sulfuric acid. we got. After adjustment, the cell suspension was further diluted 1: 1500 with saline.

16 mg of each compound was weighed into a 10 ml volumetric flask and made up to volume with the solvent. Further dilution series were prepared with distilled water or the appropriate solvent.

To the wells of the microtiter plates was added 0.2 mL of medium, 0.01 mL of appropriately diluted compound and a drop (0.01 mL) of cell suspension and incubated for 18-20 hours at 37 ° C. As a control, solvent was always incubated.

Reading was performed with the naked eye and the respective 55 concentration limits (minimum concentration inhibiting bacterial growth) were determined.

The following microorganisms were used: Staphylococcus aureus SG 511, Escherichia. coli ATCC 11 775, Pseudomonas aeruginosa Hamburensis and Pseudomonas aeruginosa BC 19, Serratia marcescens ATCC 13 880, Klebsiella pneumoniae ATCC 10 031 and BC 6, Proteus mirabilis BC 17, Proteus rettgeri, Enterobacter cloaceae ATCC 13 047, Escherichia spp. lactamase producer), Klebsiella pneumonieae 65 1082 E (β-lactamase producer).

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Α II. Table I below summarizes the minimum inhibitory concentrations (LGK) determined for representative compounds of the invention. The numbering of the compounds corresponds to those in Table I.

Cefuroxime was used as comparator compound.

Acute toxicity was determined by oral and subcutaneous administration of the compounds of Table 2 in increasing doses in rats.

LD ₅₀ is defined as the amount of dose at which 50% of the animals die within 8 days of administration of θ. All compounds exhibited an LD ₅₀ of greater than 4 g / kg for oral administration and greater than 2 g / kg for subcutaneous administration, meaning that the compounds are considered to be substantially non-toxic. , c

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The effect of some of the compounds of the invention was investigated in vivo after experimentally induced infection in mice. Escherichia coli strain ATCC 11,775 was used as the pathogenic bacterium. 0.2 ml of bacterial suspension containing 5% mucin was administered intraperitoneally. This corresponded to about 1.4 · 10 ⁶ Escherichia coli cells per mouse. Female NMR1 strain mice were divided into groups of 10 animals; Two groups were left untreated, the other groups were treated subcutaneously with different doses to determine the ED _S0 (dose at which 50% of the animals survive) with the penicillins and cephalosproins of the invention. The animals were treated once an hour after the injection was absorbed.

The duration of observation in both cases was 7 days. The results of such experiments with representative representatives of the cephalosporins of the invention are shown in Table III. are summarized in Table.

III. spreadsheet

In vivo vehicle effect in mice - E coli infection (subcutaneous)

Compound ED, _n (mg / kg) First 0.8 4th 0.5 6th 0.5 11th 5 14th 2.5-5 Ccfuroxim 100

The invention further relates to a process for the preparation of a medicament for the treatment of infectious diseases of humans or animals.

Preferred pharmaceutical compositions are tablets, dragees, capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and sprays. In human or veterinary medicine, the active ingredient of the formula I, or a mixture of such active ingredients, is administered in an amount of 5 to 500 mg, preferably 10 to 200 mg, per kg body weight every 24 hours, optionally in several divided doses ^; t. Each dosage amount preferably contains from 1 to 250 mg, particularly preferably from 10 to 60 mg, of the active ingredient (s) according to the invention. However, depending on the weight and nature of the patient to be treated, the nature and severity of the disease, the formulation and administration of the drug, and the time and intervals of administration, it may be necessary to deviate from this dosage. Thus, in some cases less than the amount of active ingredient mentioned above may be sufficient, but in other cases more than this amount may be required. The best dose and route of administration of the active ingredient at any given time can be readily determined to the best of the art.

When used as a feed additive, the novel compounds can be administered in the usual concentrations and formulations together with the feed or feed composition, or in drinking water. In this way, infections caused by Gram-negative or Gram-positive bacteria can be prevented, reduced and / or cured, while at the same time promoting growth and better sales of feed.

The following examples illustrate the invention without limiting its scope. Temperature data is given in degrees Celsius.

Synthesis of Iureidocarboxylic Acids of Formula IV, where - is -thiazothyl) la) D, La- {3- [2- (5-S-thdfamoyl-2-thienylmethyl-amino) -4-hydroxy-5-pyrimidinyl] ureido} -2,3-dihydro-2-imino-4-yl-acetic acid

D, L-α-amino- (2,3-dihydro-2-imino-4-thiazolyl) -acetic acid (1.73 g, 0.01 mol) was dissolved in 60 ml of tetrahydrofuran and 20 ml of water together with 10 ml of sodium hydroxide solution.

5-Amino-2- (5-sulfamoyl-2'-thienylmethylamino) -4-hydroxypyrimidine (3.01 g, 0.01 mol) was suspended in 50 ml of anhydrous tetrahydrofuran and refluxed with 6 ml of diethylaminotrimethylsilane. The reaction mixture was concentrated in vacuo and the dry residue redissolved in tetrahydrofuran (50 mL) and a solution of phosgene (1.05 g) in anhydrous tetrahydrofuran (1.05 g) added dropwise to this solution while cooling with ice. After cooling and stirring for 15 minutes, the reaction solution was concentrated in vacuo to half its volume.

This solution is added dropwise with ice-cooling to the above solution while maintaining the pH of the reaction mixture at 8.0. After cooling, the reaction mixture was stirred at room temperature for an additional hour, diluted with water (30 mL) and the tetrahydrofuran removed in vacuo. The aqueous phase was extracted twice with ethyl acetate and the pH of the aqueous phase was adjusted to 3.8 with 2N hydrochloric acid. The precipitate was filtered off with suction and dried in vacuo.

Yield: 3.12 g (62%).

IR: 3300 (wide), 1640-1650, 1530 (wide signal), 1155 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO + + CD, OD) in ppm: 4.65 (s, broad, 2H), 5.15 (s, 1H), 6.5 (s, 1H), 7.05 (d, 1H), 7.45 (d, 1H), 8.15 (s, 1H).

The ureidocarboxylic acids (A represents hydrogen) of the following table are prepared analogously.

ARC. spreadsheet

r ₂ Yield. % Nuclear Magnetic Resonance Spectrum (DMSO + CD3OD) (ppm) lb. 3-pyridyl-methyl 56 4.5 (br, 2H), 5.15 (s, 111), 6.45 (s.H), 7.25 (mlH), 7.7 (m.H), 8.1 (s, 1H), 8.5 (m, 2H). juice. 2-furyl-methyl 64.5 4.4 (s, 2H). 5.10 (s. 1H), 6.3 (m. 2H); 6.5 (s. 1H); 7.5 (s. 1H); 8.05 (s, 1H). ld. 6-hydroxy-3'piridil 41 5.2 (S, 1H), 6.4 (s, 1H), 6.55 (s, broad (1H), 7.55 (q.H), 7.8 (d.H), 8.2 (s, lH). juice. 4-methyl-2-imidazolyl-thiomethyl 58 2.1 (s, 3H), 4.4 (s, 2H), 5.15 (s.H), 6.80 (s.H), 7.3 (s.H), 8.05 (s) , H). If. 3-methyl-5-pyrimidinyl · methyl 60 2.5 (s, 3H); 4.4 (s, 2H). 5.15 (s.H), 6.4 (s.H), 805 (s.H). 8.6 (s, 2H).

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II Preparation of Cephalosporins Example 1

7 (3- \ D, L-a- [3- (4-hydroxy-2-) 3-pyridyl-methyl-amino) -5-pyrimidinyl) -ureidof2,3-dihydro-2-imino-4-thiazolyl) acetamido \ -3 - [(l-methyl-tetrazol-5-yl) -tiometilJ-ceph-3-em-4-carboxylate

The ureidocarboxylic acid (2.08 g, 0.005 mol) obtained in Example I (1b) was dissolved in 50 ml of anhydrous dimethylformamide. A solution of 7-amino-3 - [(1-methyltetrazol-5-yl) thiomethyl] -ceph-3-em-4-carboxylate (2.5 g) in methylene chloride (30 ml) was added thereto, followed by cooling with ice. 1.15 g of dicyclohexylcarbodiimide are added. The ice-cooled reaction mixture was stirred overnight and then concentrated in vacuo. The dry residue was stirred with methanol (50 mL) followed by methylene chloride (100 mL) and the solid isolated by filtration was chromatographed on a silica gel column eluting with 5: 1 methylene chloride / methanol.

The resulting diphenylmethyl ester was treated with 10 ml of trifluoroacetic acid and 4 ml of anisole in the usual manner and the residue was converted to the sodium salt in dimethylformamide-methanol with sodium ethyl hexanoate.

Yield: 1.90 g (31%).

IR: 3340, 1765, 1660, 1540 ^cm-first

Nuclear Magnetic Resonance Spectrum (DMSO + + CD ₃ OD), ppm: 3.50 (m, 2H), 3.95 (s.3H), 4.4 (m, 4H), 5.0 (m, 1H), 5.4 (s, 1H), 5.6 (m, 1H), 6.45 (d, 1H),

7.25 (m, 1H), 7.65 (m, 1H), 8.1 (s. 1H), 8.5 (m. 2H)).

By this method, the following cephalosporins of general formula I are synthesized (A '= hydrogen; E = = sodium ion; Y = hydrogen). (See table on pages 30-31.)

Example 9

7otrMetoxi-78- \ D, La-3- (2- / 5-szidfamoil trimethylmethylsilyl indenyl-2-methyl-amino) -4-hydroxy-5-piriinidinil) ureido] - (2,3-ilihidro-2-imino-4-thiazolyl ) acetamido \ -3 - [(l-methyl-tetrazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate

A solution of 1.8 g (0.002 mol) of the diphenylmethyl ester of the cephalosporin of Example 4 is dissolved in 70 ml of anhydrous tetrahydrofuran and a solution of 500 mg of lithium methoxide in 20 ml of anhydrous methanol is added at -70 ° C. stirred. Thereafter, 300 mg of tert-butyl hypochlorite are added at -70 ° C, stirred at -70 ° for a further 45 minutes, then 0.6 ml glacial acetic acid and 150 mg triethyl phosphite are added. Phosphate buffer pH 7.0 (100 mL) was added to the reaction mixture at room temperature, followed by extraction with methylene chloride (3x). The organic extracts were separated, dried and the solvent evaporated in vacuo. The residue was chromatographed twice on a silica gel column, eluting with 1: 6 methanol: methylene chloride, to give 530 g (30%) of the desired diphenylmethyl ester.

Conversion to the acid followed by the sodium salt is illustrated in FIG. is carried out according to example.

IR: 1765. 1670, 1155 ^cm-first

-101

185,990

r ₃ D Yield % IR spectroscopy. cm ' ¹ NMR Spectrum (DMSO + CDJOD) ppm: -N N-N 7 \ II I | // ^CH2 ' -S- N 44 1765, 2.1 (s, 3H), 3.50 (m, 2H), 3.95 (s, 3H), // \ / 1650 4.4 (m, 4H); 5.05 (broad d, 1H). -N N 1520th 5.40 (sJH), 5.60 (m. 1H), 6.80 (s, 1H), ch ₃ I 7.3 (s, 1H), 8.5 (s, 1H). CH? 8 / Γ, Ν-ΧΧ N-N 49.5 1765, CHREN 7-CH II 1655, 2.45 (s, 3H), 3.45 (m, 2H), 3.95 (s, 3H), V kJ -Sr N 1540th 4.3-4.5 (m, 4H), 5.0 (m, 1H), 5.40 (s, 1H), 5.65 (m, 1H), 6.45 (broad s, 1H), I 8.10 (s, 1H), 8.55 (s, 2H). CH?

Nuclear Magnetic Resonance Spectrum (DMSO + + CDjOD), ppm: 3.40 (s, 3H), 3.55 (m, 2H), 3.95 (s, 3H), 4.35 (m, 2H), 4, 7 (s, 2H), 5.05 (broad, s, 1H), 5.35 (s, 1H), 6.45 (d, 1H), 7.05 (d, 1H), 7.45 (d) , 1H), 8.15 (s, 1H).

Example 10 25

7α-Methoxy-7 - {D, La- [3- (2- / 5-sulfamoyl-2-thienyl-1-ethylamino) -4-hydroxy-5-pyrimidinyl) -ureido] - (2,3-dihydro) -2imino-4-thiazolyl) acetamido} -3 - [(l- / 2-hydroxyethyl / tetrazol-5-yl) -tiometilJ-ceph-3-em-4-korbonsav iidtriumsó

1.0 g (1.5 mmol) of 7α-methoxy-7β - [[D, Lα-amino- (2,3-dihydro) -2-imino-4-thiazolyl] -acetamido) -3-j [1- (2-Hydroxyethyl) -tetrazolyl-5-yl] -thiomethyl (-epheph-3-em-4-carboxylic acid trifluoroacetate) was dissolved in 60 ml of tetrahydrofuran and 20 ml of water and the pH of the solution was adjusted to ca. adjust to pH 8.5 with hydroxide solution 35

450 mg of 5-amino-4-hydroxy-2- (5-sulfamoylthienylmethylamino) pyrimidine were silylated in the usual way and reacted with 150 ml of phosgene. The reaction mixture was added to the cephalosporin solution while maintaining the pH between 7.5 and 8.0 with sodium hydroxide solution. After the addition, the mixture was stirred at room temperature for 1 hour, water (10 ml) was added, the insoluble material was removed by filtration and the tetrahydrofuran was distilled off in vacuo. The aqueous phase was extracted twice with ethyl acetate and adjusted to 3.5 with dilute hydrochloric acid while cooling with ice. The precipitate was collected by filtration, dried and converted to the sodium salt in the usual manner.

Yield: 655 mg (44.5%).

IR: 1765, ^1775> crn ^'first 50

Nuclear Magnetic Resonance Spectrum (DMSO + + CD.OD), ppm: 3.43 (s, 3H), 3.7 (m, 2H), 4.3 (m, 2 + 2 + 2H), 4.65 (s) , 2H), 5.1 (s. Broad. 1H), 5.4 (s, 1H), 6.5 (s, 1H), 7.05 (d, 1H), 7.4 (d, 1H) , 8.13 (s, 1H).

In analogy to Example 9, the following 7a-methoxy-cephalosporins were prepared.

Example 11

7arMetoxi-70 \ DL-a- [3- (4-hydroxy-2- / 3-pyridyl inetilamino / -5-pyrimidinyl) -Ítreidol- (2,3- (polyhydric-2-imino-4-thiazolyl) acetamido Sodium salt of 3 - [(1-methyl-tetruzol-5-yl) -thioethyl] -ceph-3-ene-4-carboxylic acid

Yield 36.5%.

IR: 1765, 1660, 1540 ^cm-first

Nuclear magnetic resonance spectrum (DMSO + CDjOD) ppm: 3.40 (s, 3H), 3.55 (m, 2H), 3.95 ⁶⁵ (s, 3H)), 4.4 (m, 4H); 5.0 (s, broad, 1H) -, 5.35 (s, 1H), 6.45 (s, broad, 1H), 7.25 (m, 1H), 7.65 (m, 1H), 8.1 (s, 1H), 8.5 (m, 2H)).

Example 12

7a-Methoxy-78- [D, La- [3- (4-hydroxy-2- / 4 ^: methyl-2'-imidazolylmethyl-amino) -5-pyrimidinyl) -ureido] - (2,3-dihydro-2-imino) 4-thiazolyl) acetamido} -2 - [(l-methyl-tetrazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate

Yield: 34%.

IR: 1765, 1655, 1535 ^cm-first

Nuclear Magnetic Resonance Spectrum (DMSO + + CDjOD), ppm: 2.1 (s, 3H), 3.40 (s, 3H), 3.50 (m, 2H),

3.95 (s, 3H). 4.4 (m, 4H), 5.0 (s, 1H), 5.35 (s, 1H), 6.85 (d, 1H), 7.3 (s, 1H), 8.05 (s) , H).

Example 13

73- {D, La-3- (2- / 5-sulfamoyl-2-thienylmethyl-amino / -4-hydroxy-5-pyrimidinyl) -ureidol- (2,5-dihydro-2-imino-4- thiazolyl) -acetamido-3 - [(] / 2 ^: hydroxyethyl / -tetrazol-5-yl) -thiomethyl] -ceph-3-em-4-carboxylic acid sodium salt

600 mg of cephalosporin of Example 5, together with 220 mg of 1- (2 ^L -hydroxyethyl) -5-mercapto-tetrazole in 40 ml of nitromethane, are heated at 80 ° for 6 hours and then evaporated in vacuo. The dry residue was dissolved in a mixture of acetone and glacial acetic acid and diphenyl diazomethane was added while cooling with ice until the violet color remained. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (5: 1 methylene chloride / methanol). The resulting ester is hydrolyzed in the usual manner and converted to the sodium salt.

Yield: 280 mg (43%).

IR: 1765, 1660, 1540, 1155 cm ^1st

Nuclear magnetic resonance spectrum (DMSO + CD ₃ OD) ppm: 3.55 (m, 2H), 4.1-4.7 (m.8H), 5.05 (m.lH), 5.35 (s, 1H), 5.60 (e.g., 1H). 6.45 (broad, s, 1H), 7.05 (d, 1H), 7.45 (d, 1H), 8.15 (s, 1H).

The following compounds were prepared analogously.

Example 14

73- \ D, La-3- (2- / ^{5: 1} SzulfoinoiÍ 2-thienylmethyl omino / -4-hydroxy-5-pyrimidinyl) -ureidtí / - (2,3-dihydro-2-imino-4 thiazolyl) -acetamino \ -3 - [(2-methyl-l, 3,4-thiadiazol-5-yl) -tiometilJ-ceph-3-em-4-karboiisav nátriuinsó

Yield 46.5%.

IR: 1765, 1660, 1535, 1160 ^cm-first

-11185 990

Nuclear Magnetic Resonance Spectrum (DMSO με CD, OD). ppm: 2.75 (s, 3H), 3.50 (m, 2H), 4.25 (m, 2H), 4.65 (s, 2H), 5.05 (m, 1H), 5.40 (s) , 1H), 5.60 (m. 1H), 6.45 (d, 1H), 7.05 (d, 1H), 7.45 (d, 1H), 8.00 (S, 1H). ₅

Example 15

7- [3- (D, La- [3- (2-S-5-sulfamoyl-2-thienylmethylamino) -4-hydroxy-5-pyrimidinyl) -ureido] - (2,3-dihydro-2-imino- 4-Thiazolyl) -acetamido} -3 - [(1- (2-acetylaminoethyl) -tetrazo-T-5-yl) -thiometh-cef-3-em-4-carboxylic acid, sodium salt ₁ θ

Yield 42%.

IR: 1760, 1655, 1610 cm

Nuclear Magnetic Resonance Spectrum: 1.85 (s, 3H), 3.6 (m, 2 + 2H), 4.2-4.7 (m.6H), 5.05 (q. 1H). 5.40 (s, broad, 1H), 5.70 (q, 1H), 6.50 ( _s , 1H), 7.05 (d, 1H), 7.45 ₍₅ (d, 1H), 8.15 (s, lH).

Example 16

704D-7a-methoxy-a- [3- (2/5-szidfamoil-2-thienylmethyl-amino / -4-hydroxy-5-pyrimidinyl) ureidophenyl-phenyl-acetamido} -3 - [( 1-methyl-tetrazol-5-yl) -thioethyl-cef-3-em-4-20

carboxylic acid sodium salt

1.9 g (0.004 mol) of 7α-methoxy-7β- (Da-aminophenylacetamido) -3 - [(1-methyltetrazol-5-yl) thiomethyl] -epheph-3-em- 4-Carboxylic acid was suspended in a mixture of 60 ml of tetrahydrofuran and 20 ml of water and, after cooling with ice, added n sodium hydroxide until dissolution occurred.

To this solution was added dropwise a solution of the phosgene adduct prepared in analogy to Example 10 from 5-amino-4-hydroxy-2- (5-sulfamoylthienylmethylamino) pyrimidine (1.2 g, 0.004 mol) and while maintaining the pH at 8.0 by the addition of sodium hydroxide.

Further reaction and work-up were carried out analogously to Example 10.

Yield: 1.53 g of sodium salt (46%).

IR: 1760, 1660 ^cm-first

Mass Magnetic Resonance Spectrum (DMSO + +. CD3OD), ppm: 3.4-3.6 (m, 2H), 3.50 (s, 3H), 3.95 (s.3H), 4.2 (m, 2H). , 4.6 (m, 2H), 5.05 (s, 1H). 5.55 (s, 1H), 7.05 (d, 1H). 7.5 (m, 6H), 8.15 (s, 1H).

In analogy to Example 16, the following compounds were prepared: (A = phenyl, Y = methoxy, E = hydrogen).

-12185 990

Example 23

7ot-Methoxy-78-lD-a-3- (4-hydroxy-2- / ^4:> N-ethyl-2-imidazolyl ^1-methyl amino / 5-pyrimidinyl) -ureido> lp-hydroxy-phenyl-acetamido } -3 - [(1-Methyl-tetrazo} -5-yl) -methyl-cef-3-ene-4-carboxylic acid sodium salt g

a) D-α- [4-Hydroxy-2- / 4-methyl-2-yl (iso (transylmethylamino) -5-pyrimidinyl) -ureido] -p-hydroxy-n-acetic acid

1.1 g (0.005 mole) of 5-amino-4-hydroxy-2- ^(4-methyl-2: imidazolyl-methylamino) pyrimidine in 60 ml of anhydrous tetrahydrofuran with 4 ml diethyl amino silane trimctil jq with v boil under reflux until dissolving. The solution was concentrated in vacuo and the dry residue redissolved in 50 mL of tetrahydrofuran dropwise to a solution of 525 mg of phosgene in tetrahydrofuran under ice-cooling and then evaporated to half volume under vacuum after 15 minutes. This solution was added dropwise at 5 ° to a solution of p-hydroxyphenylglycine (850 mg) in tetrahydrofuran (40 ml), water (5 ml) and sodium hydroxide (5 ml). After the addition was complete, the pH was adjusted to 8.0 and stirred at room temperature for 1 hour. The reaction solution was diluted with water (20 mL), the tetrahydrofuran was distilled off in vacuo, and the residue was extracted twice with ethyl acetate. The aqueous phase was acidified to pH 2.9 with 2N hydrochloric acid with cooling, and the precipitate was filtered off with suction and dried. 25

Yield: 1.45 g (70.5%).

Infrared spectrum 3350. 1660. 1540. 1530 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (DMSO + + CD 3 OD), ppm: 2.1 (s, 3H). 4.4 (s. 2H). 5.15 (s, 1H),

6.75 (m, 2H + 1H), 7.3 (d, 2H), 8.15 (s. 1H). 30

b) 1.25 g (0.003 mol) of the thus obtained ureido-carboxylic acid are dissolved in 40 ml of anhydrous dimethylformamide and 1.5 g of 7-amino-3 - [(1-methyltetrazol-5-one) is dissolved in 20 ml of methylene chloride. il) -thiomethyl-ethyl-3-em-4-carboxylic acid diphenylmethyl ester followed by cooling with ice (650 mg) dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The dry residue was stirred with 50 ml of methanol, then 100 ml of methylene chloride, and then chromatographed on silica gel with 5: 1 methylene chloride / methanol to remove minor impurities. In this way, the non-methoxylated diphenylmethyl ester of the title compound at 7a is obtained.

Yield: 1.62 g (62%).

c) 890 mg of this ester are dissolved in 50 ml of anhydrous tetrahydrofuran, -70 ml of lithium methoxide in 10 ml of methanol are added and stirred for 3 minutes, then -750 ° C is added with 150 mg of tert-butyl hypochlorite. After stirring for 45 minutes at -70, 0.3 ml of glacial acetic acid and 75 ml of triethyl phosphite are added. To the reaction mixture was added 70 ml of a pH 7.0 bisphosphate buffer at room temperature and extracted three times with methylene chloride. The organic layer was separated, dried and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with 6: 1 methylene chloride / methanol to give 350 mg (38.5%) of the title compound diphenyl ester.

This ester was stirred under ice-cooling with 4 ml of trifluoroacetic acid, 2 ml of anisole and 10 ml of methylene chloride, then concentrated in vacuo and diethyl ether was added to the dry residue. The solid product is filtered off with suction and reacted with dimethylformamide / methanol to give the appropriate amount of sodium hexanoate to afford the sodium salt. The salt was precipitated with diethyl ether, filtered off and dried in vacuo.

IR: 1765, 1660, 1550 ^cm-first

Magnetic Resonance Spectrum (DMSO + + CD, OD), ppm: 2.1 (s, 3H), 3.45 (s, 3H), 3.55 (m, 2H),

3.95 (s, 3H), 4.35 (m, 4H), 5.0 (s, 1H), 5.40 (s, 1H), 6.75 (m, 2t-1H), 7.30 (d, 2H), 8.05 (s, 1H).

In a manner analogous to Example 16 or 23, the cephalosporins are summarized in the following table. The synthesis of the corresponding ureido-carboxylic acids and the synthesis of 7H-benzhydryl ester are described in German Patent Publication No. P 29 28 344.

-13185 990

Example Yield IR Spectrum NMR Spectrum (DMSO + CD., OD) 'A K2 L * _Λ .

% ·% cm ¹ ppm:

I n ± Γ-. __

r * í 't

Ξ £

V) <n r- ~ x x - Γ4 'is

A +

M tr, v *> 1/1 r * i Nf

X <1 * X X X f * 1 Ή £ T3 X ΜΊ nf SHE Vi i / i nf + rf r < 00 r * i π + u r ' X X X rí X X X X r ~ X C f f * 1 © CM • d Ό ©, N3 £ V) nf v> V> r \ £ rí nf 'SHE

X cn

1/1 f * 1 t * v

Nf e * i

Nf ©

Ό <5

Nf and>

1/1 i / 1

O </ 1 ι / l VI sC V

V, r * i

ΓΛ

Nf f * 1

nf

X o „£

X r * y £

© r <

X

C4 ε

rí

nf

X

C4 ε

+ x

X

ΜΊ σ '

nf

X

C4

X ^r I

P

1/1 Ά, - Nf O _r © f * 1 N · r * '

nf

VI £

1765, 3.45 (s, 3H), 3.50 (m, III), 3.95 (s, 3H),

1660, 4.40 (III.4H), 4.95 (\ .III). 5.35 (i.e. (-1),

155 ». 6.3 6.75 (4,211), 7.25 (4,211).

7.45 (s. 1H). 8.1 (s. 1H).

ό

X

-i

Q

ÛC ©

X z

u

Q 'rj

ΓΊ

-14185 990

ANCESTOR

Α £ χ * ϊ f χ ^rl ί; 3 ϊ έ «<9 =

X- -, Ο Ο. * Τ · ν-, ₂ τ. X -t X γ * 'χ X a XX t ~. <Ν Λ> 5 ρ £ 3 * tT) Ά

W, 3 * · «-“ Γ η t «ί - = -3 <τ x X XX r, ± i

Ο u-i —r o <X

(Z) X

X υ

u

Example 32

7a-Methoxy-7S- {Da - [(2- / 5 ^: Aminosulfonyl-2-thienylmethylamine / 4-hydroxy-5-pyrimidinyl) -ureidoph-p-hydroxyphenylacetanido} -3 -f (1/2-Hydroxyethyltheirazole-5-id-dome-5-yl)] - cef-3-em-4-carboxylic acid sodium salt

500 mg of the cephalosporin of Example 26 and 180 mg of 1- (2-hydroxyethyl) -5-mercapto-tetrazole in 40 ml of methanol are heated at 80 for 6 hours and then concentrated in vacuo. The dry residue is dissolved in a mixture of acetone and ethyl acetate and diphenyl diazomethane is added to the solution while cooling with ice until the violet color remains.

The reaction mixture was evaporated and the dry residue was purified by silica gel column chromatography (5: 1 methylene chloride / methanol). The resulting ester was cleaved as described in Example 1 and the acid converted to its sodium salt.

The yield of the sodium salt is 230 mg.

IR: 1765, 1660, 1540, 1155 ^cm-first

Nuclear Magnetic Resonance Spectrum (DMSO + 20 + CDjOD). ppm: 3.45 (s, 3H), 3.55 (m, 2H), 4.0-4.7 (m.8H), 5.0 (s.H). 5.45 (s, 1H). 6.75 (d, 2H). 7.0 (d, 1H),

7.25 (d, 2H), 7.45 (d. 1H). 8.15 (s, 1H).

The following compound was prepared analogously.

Example 33

7a-Methoxy-7 @ - {D, LA [3- (2- / ^5: szidfonil amino-2-thienylmethyl-amino / -4-hydroxy-5-pyrimidinyl) -ureido] -p-Hydroxy- fe> III-acetamiáo} -3-f (2-methyl-l, 3,4-thiadiazol-5-yl) -tiometilj-ceph-3-em-4-carboxylic acid nátriamsó

Synthesis was carried out with the cephalosporin of Example 26 and 2-methyl3G-5-mercapto-1,3,4-thiadiazole.

The yield of sodium salt is 44%.

IR: 1765. 1655, 1610, 1540 ^cm-first Nuclear Magnetic Resonance Spectrum (DMSO + + CD., Δ H), ppm: 2.75 (s, 3H), 3.45 (s.3H), 3.50 (m.2H), 4.25 (m, 2H). . 4.65 (s, 2H), 4.95 (s, 1H), 5.45 (s, 1H), 6.75 (d, 2H). 7.05 (d, 1H). 7.25 (d. 2H). 7.45 (d.H), 8.15 (s.H).

The compounds of formulas I and Γ can be formulated into standard pharmaceutical compositions such as tablets, dragees. it can be processed into capsules or ampoules. Generally, the dose for each adult is 50 to 1000 mg, preferably 100 to 500 mg, and the daily dose is 100 to 4000 mg, preferably 250 to 2000 mg.

Example I

7a-Methoxy-7S- [D - [3- (4-hydroxy-2- (4-methyl-2-imidazolyl) ethyl] -5-pyrimidinyl) -trido [d] p -hydroxy-phenylacetamide) - Tablets containing 3 - [(1-methyl-tetrazol-5-yl) -thiomethyl] -cef-3-em-4-carbophysic acid

From 2 kg of active ingredient. A mixture of 5 kg of lactose, 1.8 kg of potato starch, 0.1 kg of magnesium stearate and 0.1 kg of talc is conventionally compressed into tablets so that each tablet contains 200 mg of the active ingredient.

II. example

7 (x-Metoxi7l3- \ D - {(- L3 (4-hydroxy) oxy-2- / ^4: methyl-2-amino-iinidazfílil-nieiil / S piritnidiiiib ureidof-p-hydroxy-phenylacetamido 4 -3-1 (J-Methyl-tetrazol-5-yl) -Tiomethyl-cef-3-em60 -4- ^l ''n;nn:;

In a manner analogous to Example 1, tablets are compressed and then coated with sugar, potato starch, talc and tragacanth.

-15185 990

III. example

7a-Methoxy-7f3- \ D-a- [3- (4-hydroxy-2- / 4-methyl-2-imidazolyl ^{1-methyl-amino} / 5-pyrimidinyl) -ureido-p-hydroxyphenyl-acetamido \ -3 - [(1-Methyltetrazol-5-yl) -thiomethyl] -cef ^: 3-em-4-carboxylic acid sodium capsule

Five kg of active ingredient are conventionally filled into hard gelatin capsules such that each capsule contains 500 mg of active ingredient.

ARC. example

7ct-7-methoxy $ - \ D-a- [3- (4-hydroxy-2- / 4-methyl-2-imidazolyl-methyl-amino / 5-pyrimidinyl) -ureido] -p-hydroxyphenyl acetamido} Dry ampoules containing sodium salt of -3 - [(1-methyltetrazol-5-yl) thiomethyl] -ceph-3-em-4-carboxylic acid

251 g of the active ingredient are dissolved in 200 ml of distilled water for injection under aseptic conditions. The solution was filtered through a 0.22 µm Millipore filter (Millipore Corporation, Bedford, USA). The solution was filled into 1000 x 10 mL vials at 20 ml and lyophilized. The vials were sealed with a rubber stopper and an aliquot. so each bottle of A is '50. contains the active ingredient.

Alkyl for injection; fi * Alcoholic saline solution is filled in 2.0 ml ampoules and the ampoules are sealed so that impulse B ·. <pjiA physiological kitchen in ampoules B '' ilc Jtoi poured into vials A, intravenous l. e ^{<RTI ID} = 0.0 ^{> j </RTI> is} injected.

Dissolve 1 ml of distilled water for injection in 20 ml of vial A and 250 ml of a 5% solution for injection in water. In this way, suitable solutions for the process are prepared.

Also, tablets, dragees, capsules, etc. are ampu'Lüat á '. which may contain one or more other active ingredients or their physiologically physiologically active compounds. .b + contains its salable salts.

Claims (8)

A process for the preparation of a new cephem carboxylic acid derivative of the formula I or -, wherein: Y represents a halogen atom or a methoxy group; When Y is methoxy, phenyl, 4-hydroxyphenyl, 2- or 3-thienyl when Y is hydrogen or methoxy, 2,3-dihydro-3-iminothiazol-4-yl; D is acetoxy or -SHet, whereby Seven is 2-methyl-1,3,4-thiadiazol-5-yl, 4H-5,6-dioxo-1,2,4-triazine-3. -yl, 4-methyl-5,6-dioxo-1,2,4-triazin-3-yl or alkyl having 1 to 4 carbon atoms, or a group of formula II cs is in this group n is an integer from 1 to 3 and R is hydroxy or acetylamino; R is -NHR ₂ wherein R _{2 is} substituted or unsubstituted 3-pyridyl, 5-pyrimidinyl, 2-thienyl, 2-furylmethyl, 2-thienylmethyl, 2-imidazolylmethyl, Represents a 3-pyridylmethyl or 5-pyrimidinylmethyl group and may be substituted by methyl, hydroxyl or aminosulfonyl groups, It represents a hydrogen atom or an alkali metal atom, characterized in that: a) a 7-amino-cef-3-em-4-carboxylic acid derivative of the formula ΙΠ in which Y and D are represented by E and E is the same as E or a carboxyl protecting group, preferably diphenylmethyl; With ureidocarboxylic acid of formula IV, wherein A and R are as defined above, or with a salt or reactive derivative thereof, between -40 ° C and + 40 ° C in the presence of a solvent and optionally a base; obsession b) a 7-amino-cef-3-cm-4-carboxylic acid of formula V, wherein A, D, and Y are as defined above, or an inorganic and organic base thereof with a pyrimidine derivative of formula VI; wherein R is as defined above and B is a group -NCO or a reactive derivative of the group NHCOOH formula or -NHCOC1, -NHCOBr -NH-COO-C ₆ H ₄ -p-NO ₂ group -, or a mixture of pyrimidines of formula VI, wherein one of B has the meaning given above, and the other has the meaning given above, and these compounds are partially or completely isocyanates. The <1 isomer may be in the form of 1 (H) -oxazolo (5,4-d) pyrimidin-2-one in a solvent between 2.0 and 9.0 pi, or between -20 ° C and + 50 ^D C reacted; obsession c) for the preparation of compounds of formulas I and Γ in which D is -SHet and E is hydrogen, a compound of formula VII, in which A, Y and R are as defined above, is prepared according to general formula VIII; with a compound of the formula: In this formula, Sev is a hydrogen atom or an alkali metal or alkaline earth metal atom of the above meaning in a solvent at a temperature between 0 ^° C and 100 ° C and a pH of 2 to 10: or d) I or olyan? for the preparation of compounds of formula I wherein Y is methoxy, a compound of formula IX, wherein A, R, D cs 5 'as hereinbefore defined, in the presence of methanol is a MOCH _; - a'káblém metiláttnl - wherein, M * Alkali ifématomot present ^- - Monkey nalogénező agent inert oidoszmben -120 ° C to -10 ° C was reacted under, and one received L and Γ chin compound of formula ¹ ÁNOS. wherein E is an easily cleavable protecting group, is converted into the free carboxylic acid of formula I and II, respectively, wherein E is hydrogen, optionally a compound of formula I or Γ is converted to its alkali metal salt. (Priority: 12/01/1981) 2. A process according to claim 1 for the preparation of a novel eephem carboxylic acid derivative of the formula I or Γ. which formula Y is methoxy. Phenyl. 4-hydroxyphenyl, 2- or 3-thienyl; D is acetoxy 'or -SHet, and in this group Seven are 2-methyl-1,3,4-thiadiazol-5-yl, 4H-5,6-dioxo-1,2,4-triazine -3-yl. 4-methyl-5,6-dioxo ;, 2,4-triazin-3-yl or 1- (1-4 s. denotes a group wherein n is an integer from 1 to 3, R 1 is hydroxy or acetylamino: R is -NHR ₂ , wherein R _{2 is} optionally substituted 2-thienyl, 2-furylmethyl, 2-thienylmethyl. 3-pyridylmethyl, 5-pyrimidinylmethyl, 3-pyridyl or 5-pyrimidinyl, and these groups may be substituted on the ring by methyl, hydroxy or aminosulfonyl. and -161 185,990 It is a hydrogen atom or an alkali metal atom, characterized in that: a) an ureidocarboxylic acid of formula IV, wherein A and R are as defined above, or a salt thereof and a reactive derivative thereof with a 7-amino-cef-3-em-4-carboxylic acid derivative of formula III, wherein Y is methoxy; or an acetoxy group -SHet group of the general formula E 'are identical to those defined above or represents a carboxyl protecting group, - _base-1 was reacted in the presence of fibrosis in the presence of a solvent and optionally between 40 ° C to 40 ° C; obsession b) a salt of a 7-amino-ceph-3-em-4-carboxylic acid of formula V, wherein Y is methoxy, A and D, as defined above, or an inorganic or organic base thereof with a pyrimidine of formula VI; derivative - wherein, R is as defined above and B is a group -NCO or a reactive derivative of -NHC00H group or -NHC0C1, -NHCOBr -NH-COO-C _fi H ₄ -p-NO ₂ group - or a general IP pyrimidine of formula with a mixture of TSI, p of the formula wherein B is partially reacted with between one and partly the other above-mentioned meanings, in a solvent of 2.0 to pH 9.0, and from -20 ° C to 50 C ^Q; obsession c) for the preparation of compounds of formulas I and Γ in which D is -SHet as defined above and E is hydrogen, a compound of formula VH, in which A and R have the same meaning as Y, is a methoxy group. A compound of Formula VIII, wherein Sev is as defined above and M is hydrogen or an alkali or alkaline earth metal atom, is reacted in a solvent at 0 ° C to 100 ° C and at a pH of 2 to 10; obsession d) a compound of formula IX, wherein A, R, D and E 'are as defined above, in the presence of methanol, with a MOCH, an alkali metal methylate of the formula: M ⁺ an alkali metal atom, then a halogenating agent in an inert solvent; Between -10 ° C and -10 ° C, the resulting compound of formula I or,, wherein E 'is an easily cleavable protecting group, is converted to the free carboxylic acid of formula I or Γ, where E is hydrogen In this case, a compound of formula I or Γ in which E is hydrogen is converted to its 4 alkali metal salts. (Priority: December 12, 1980) 3. A process according to claim 1, wherein the cephem carboxylic acid derivatives of formula I or illetve 2,3-dihydro-2-iminothiazol-4-yl of formula (a); A hydrogen atom or a methoxy group at the Y-position; D is acetoxy or -SHet; and in this group, Seven is 2-methyl-1,3,4-thiadiazol-5-yl; í R is -NHR ₂ wherein R _{2 is} optionally substituted 2-thienyl, 2-furylmethyl, 2-thienylmethyl, 2-imidazolylmethyl, 3-pyridylmethyl, 5-pyrimidinylmethyl -, 3-pyridyl or 5-pyrimidinyl and these groups may be substituted on the ring by methyl, hydroxy or 1-amino sulfonyl; and E is hydrogen or an alkali metal atom is - GENERATED characterized in that a) a IV of ureidocarboxylic acid of formula - wherein, A and R are as defined above - action derivative or salt or re- ^{{-amino-ceph-3-em} 7 a of formula III With a -4-carboxylic acid derivative - in which E 'has the same meaning as E above or a carboxy protecting group, Y and D have the same meaning as above - 40 ° C 5 to +40 ° C in the presence of a solvent and optionally a base; obsession b) a compound of formula V, wherein A, D and Y are as defined above, a pyrimidine derivative of formula VI, wherein R is a compound of formula θ and B is -NCO or a reactive derivative of -NHCOOH; or NHCOC1, -NHCOBr -NH-COO-C ₆ H ₄ -p-NO ₂ is a group - or a pyrimidine of formula VI with a mixture of wherein B is one part, In 5 portions of the other solvents mentioned above having a pH between 2.0 and 9.0 and between -20 ° C and + 50 ° C: or c) for the preparation of compounds of formulas I and Γ in which D is -SHet, E is hydrogen, a compound of formula VII, wherein R and Y are as defined above, is a compound of formula VIII, wherein Seven having the meaning given above and M in hydrogen or an alkali or alkaline earth metal solvent - 0 ° C 5 to 100 ° C and pH 2 to 10; obsession d) for the preparation of compounds of formula I or illetve in which Y is methoxy. a compound of formula IX wherein A, R, D 0 and E 'have the meanings given above - M'OCH in the presence of methanol; with an alkali metal methylate of the formula - M ⁺ alkali metal - and then with a halogenating agent in an inert solvent at a temperature of -120 ° C to -10 ° C. and a compound of formula I or kapott, Wherein E 'represents an easily cleavable protecting group, it is converted into the free carboxylic acid of formulas I and Γ, where E is hydrogen, optionally the alkali metal salt of a compound of formula I or Γ where E is hydrogen. (Priority: December 12, 1980) 4. Process a) according to any one of claims 1 to 3, characterized in that the reactive derivative of the ureidocarboxylic acid of the formula IV is an acid anhydride, a reactive ester, a reactive amide, an acid halide or an acid azide, and the 7-amino-cef-3 wherein E 'is as defined above with the exception of hydrogen and the reaction is optionally carried out in a solvent in the presence of a base and / or a condensing agent. (Priority: 12/01/1981) 5. Process b) according to any one of claims 1 to 5, characterized in that the compound of the formula V or an inorganic or organic base salt thereof with the compound of the formula VI in the presence of water in water or in a water-miscible solvent At pH 6.5-8.0 or in anhydrous solvent or in a mixture of water and water immiscible solvent at pH 6.5-8.0, or a compound of formula V wherein the hydrogen atom on the carboxyl group is readily substituted with a protecting group, with the compound of formula VI in a solvent free of water and hydroxy or in an aprotic solvent, optionally in the presence of a base. (Priority: 12/01/1981) -171 185,990 6. Process c) according to any one of claims 1 to 3, characterized in that the reaction is carried out in a highly polar solvent at a pH of 4-8. (Priority: 1981. 12/01) 7. Process d) according to any one of Claims 1 to 3, characterized in that the compound of formula IX is dissolved or suspended in an inert medium with an excess of 2 to 6 molar equivalents of alkali metal methylate in methanol followed by halogenation at -100 ° C to -50 ° C. after which time it is terminated by the addition of acid. (Priority: 12/01/1981) 8. A process for the preparation of a pharmaceutical composition comprising an cetematic carboxylic acid derivative of the formulas I and F, as defined above, wherein A, Y, D, R and E are as defined above. The active ingredient produced by the process according to any one of claims 1 to 6, together with the usual carriers, diluents, excipients and / or other excipients of the pharmaceutical compositions. (Priority: 12/01/1981) (4 pieces of drawing)