DE2731935A1 - ALPHA-ACYL-UREIDO-CEPHALOSPORIN, ITS SALT AND ESTERS, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

Brentford, Middlesex, UK

"CC-Acyl-ureido-cephalosporin, its salts and esters, process for their production and medicinal preparations containing these compounds "

Claimed priority: July 14, 1976, Great Britain,

No. 29 241/76

The invention relates to cephalosporins with a broad spectrum of antibacterial activity, which are used as therapeutic agents are valuable in humans, animals and poultry. The invention also relates to processes for the production of these cephalosporins and medicinal preparations containing these compounds.

In GB-PS 1 479 711 a class of cephalosporins of the general formula I is described

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R ³ .CH.CO.NH

KH

CO CO ₂ H

R ² - N - CR ¹

in the

Y is an oxygen or sulfur atom,

R denotes an organic radical with up to 20 carbon atoms,

R is the benzyl group or an alkyl radical with 1 to 3 carbon

1 2

represents material atoms, where the radicals R and R together with the adjacent carbon and nitrogen atoms can form a 5-, 6- or 7-membered ring, R * for alkyl radicals with 1 to 4 carbon atoms, cycloalkyl radicals with 3 to 7 carbon atoms, or for the 2- or 3-thienyl or the phenyl group, the phenyl group can be substituted by at least one halogen atom, one hydroxy, nitro and / or amino group and / or alkoxy radicals having 1 to 3 carbon atoms, and

R is the acetoxy group or a carbon, nitrogen and / or Is a nucleophilic radical containing sulfur atoms,

and their pharmacologically acceptable salts or esters.

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It has now been found that a compound not specifically described in this specification, although within the aforesaid definition, exhibits remarkable advantages over the other members of this general one Class not own.

The present invention is therefore a c ^ -acyl-ureidocephalosporin of the formula II

(D)

Ph.CH.CO.NH

N- N

CO

CH ₃ - N - COPh

or its pharmacologically acceptable salts or in vivo hydrolyzable esters.

Examples of such salts of the compound of the formula II are those with metal ions, e.g. aluminum, with alkali metal ions, such as sodium or potassium, with alkaline earth ions such as calcium or magnesium, and with ammonium or substituted ammonium ions, such as of lower alkylamines, for example triethylamine, of hydroxy (lower alkyl) amines, such as 2-hydroxyethylamine, Bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, of cycloalkylamines, such as bicyclohexylamine, or of procaine,

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Dibenzylamine, Ν, Ν-dibenzyl-ethylenediamine, 2-ephenamine, N-ethylpiperidine, N-benzyl-ß-phenethylamine, dehydroabiefcylamine, Ν, Ν'-bis-dehydroabietyl-ethylenediamine or bases of the Pyridine types, such as pyridine, collidine, or quinoline, or other amines that form salts with benzylpenicillin are useful.

In vivo hydrolyzable, pharmacologically acceptable esters of the compounds of formula II are those which hydrolyze in the human body to produce the parent acid. Examples suitable ester radicals are acyloxyalkyl radicals, such as the acetoxymethyl, Trimethylacetoxymethyl, ^ -Acetoxyäthyl-, o \ -Acetoxybenzyl- and the o (-Trimethylacetoxyäthyl group, also Alkoxycarbonyloxyalkylreste, such as the Äthoxycarbonyloxymethyl- and the cX -Äthoxycarbonyloxyäthyl group, also lactones, thiolactones and dithiolactones, i.e. ester residues of general formula

- CO.0. - CH - Z »

X «- C = Y ¹

in which X ¹ and Y ^{1 are} oxygen or sulfur atoms and Z ^{1 is} the ethylene or a 1,2-phenylene group, which latter can be substituted by halogen atoms, nitro groups or lower alkoxy radicals.

Preferred ester radicals are phthalide and 5,6-dimethoxyphthal i d groups.

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Chemically, the compound of formula II is 7- / ~ D, oi- (3-benzyol-3-methyl-ureido) -phenylacetamide £ 7-3- (2-methyl-1,3,4-thiadiazol-5-yl -thio) -methyl-ceph-3-em-4-carboxylic acid.

In Table I below is a comparison between this compound and three structurally similar compounds that in GB-PS 1 479 711 are mentioned with regard to their minimum inhibitory concentration indicated for various organisms. It can be seen from this Table I that the compound of Formula II exhibits remarkably superior antibacterial properties.

The present invention also relates to processes for the preparation of the compound of the general formula II « A method is characterized in that one compound of the general formula III or its on the nitrogen atom protected derivative

(in)

N-N

CH, S

in which R ^{x is} a hydrogen atom or a carboxyl protecting group, η has the value 0 or 1 and the dashed line denotes a double bond in 2- or 3-position, with an N-

acylating derivative of the acid of formula IV

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Ph.CH.CO-H

SH

(IV) CO

CH ₃ - N - COPh

implements and, if necessary, then carries out one or more of the following stages:

(1) Converting the Ceph-2-em isomer to the desired one Ceph-3-em isomers;

(2) splitting off the amino protecting groups;

(3) reducing the sulfoxide compound (n = 1) to form the desired sulfide compound (n = O);

(A) splitting off the carboxyl protecting groups and / or (5) converting the compound into a salt or ester.

Examples of "protected on the nitrogen atom derivatives ¹¹ of the compound of general formula III also include N-silylated and N-phosphorylated derivatives.

The term "N-silylated derivatives" of a compound of the general formula III means a reaction product of the 7-amino group of a compound of the general formula III with a silylating agent such as a halosilane or a silazane

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of the following formulas:

L ₃ Si U; L ₂ Si U ₂ ? L ₃ Si NL ₂ ; L ₃ Si NH Si L ₃ ; L ₃ Si.NH.COL; L ₃ Si. NH.CO.NH.Si L ₃ ; L NH.CO.NH.Si L-; LC.OSi L-.

Il

NSiL-

in which U is a halogen atom and the numerous radicals L, which can be identical or different, hydrogen atoms or Mean alkyl, alkoxy, aryl or aralkyl radicals. Preferred silylating agents are silyl chlorides, especially trimethylchlorosilane, and dimethyldichlorosilane.

The term "N-phosphorylated derivatives" of a compound of general formula III include those compounds in which the 7-amino group of a compound of general formula III with a group of the general formula

- ™ a ^R b

is substituted in which R_ is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino radical and R _{fe has} the same meaning as R

or denotes a halogen atom, where R _& and R _fe together can also form a ring.

Examples of suitable carboxyl protecting groups for the remainder

in the compounds of the general formula III

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Salts, esters and anhydride derivatives of carboxylic acids. Derivatives are preferred which in a later stage of the implementation in can easily be split off. Examples of salts are tertiary amine salts, such as those with tri- (lower-alkyl) amines, N-ethyl-piperidine, 2,6-lutidine, pyridine, N-methylpyrrolidine or dimethylpiperazine. A preferred salt is the triethylamine salt.

Suitable carboxyl protecting groups of the general formula -COpR ^X are also the following radicals:

(1) -COOCR _c R _d R _e , where at least one of the radicals R _c , R _d or

R is an electron donor, for example the p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthranyl, methoxy, acetoxy, methoxymethyl or the fur-2-yl group. The remaining radicals R _1, R _d or R can be hydrogen atoms or organic radicals. Suitable ester groups of this type are p-methoxy-benzyloxy-carbonyl, 2,4,6-trimethyl-benzylox-carbonyl, bis- (p-methoxyphenyl) -methoxycarbonyl and 3,5-di-tert-butyl -4-hydroxybenzyloxy-carbonyl group;

(2) -COOCR RjR, where at least one of the radicals R, R _d or

R represents an electron attractive group, for example

the benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulfonylmethyl, 2-dimethylsulfoniumethyl, o-nitro-phenyl or the cyano group. The remaining radicals R _c , R _d or R _ß can be hydrogen atoms or organic

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see be leftovers. Suitable esters of this type are the benzoyl-methoxycarbonyl, p-nitro-benzyloxy-carbonyl, 4-pyridyl-methoxycarbonyl-, 2,2,2-trichloroethoxy-carbonyl- and the 2,2,2-tribromoethoxycarbonyl group;

(3) -COOCR ₀ RoR. where at least two of the radicals R ", R, and R _Ä

c ex e L / u. e

Hydrocarbon radicals are, such as alkyl radicals, for example the methyl or ethyl group, or aryl radicals, for example the phenyl group, and the remaining radicals R_, Rj

C CL

or R - if present - 'are hydrogen atoms. Suitable esters of this type are the tert-butyloxy-carbonyl, tert-amyloxy-carbonyl, diphenyl-methoxy-carbonyl and triphenyl-methoxy-carbonyl groups;

(4) -COO-R ^, where R _{f is} the adamantyl, 2-benzyloxyphenyl, 4-methyl-thiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl and the pentachlorophenyl group;

(5) Silyloxycarbonyl groups obtained by reacting a silylating agent, as described above, having a carboxyl group;

(6) -COOP.R.Rv ,, where R _e and Rv. the above meanings

α D el D

own ;

(7) trialkyl tin ester or

(8) Oxime esters of the general formula -CO ₂ N «CH.R, in which

R is an aryl or heteroeyelic radical.

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The carboxyl group can be generated from one of the aforementioned esters by customary processes corresponding to the respective R ^x radical, for example by an acid or base catalyzed hydrolysis. Further processes for cleavage are once the reaction with Lewis acids, such as with trifluoroacetic acid, formic acid, hydrochloric acid in acetic acid, zinc bromide in benzene and with aqueous solutions or suspensions of mercury (II) compounds, the reaction with a Lewis acid by addition a nucleophilic compound such as anisole can be facilitated; secondly, reduction with agents such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohol, zinc / pyridine, palladium on charcoal (or other hydrogenation catalysts on support materials) and hydrogen; third attack by means of nucleophilic compounds, such as those containing a nucleophilic oxygen or sulfur atom, for example alcohols, mercaptans and water; fourth, by oxidative processes, for example those in which hydrogen peroxide and acetic acid are used; and fifth, by irradiating with light or ultraviolet rays.

In the aforementioned processes, a reactive, N-acylating derivative of the acid of the formula IV is used. The choice of reactive derivative is of course influenced by the chemical nature of the substituents on the acid.

Examples of suitable N-acylating derivatives are acid halides, preferably the acid chloride or bromide.

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Acylation with an acid halide can be carried out in the presence of an acid binder, for example a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium bicarbonate, or an oxirane which binds hydrogen halide released during the acylation. The oxirane is preferably a 1,2-alkylene oxide having 1 to 6 carbon atoms, such as ethylene oxide or propylene oxide. The acylation using an acid halide may be carried out at temperatures from -50 ⁰ C to +50 ⁰ C, preferably from -20 tamid ⁰ C to +30 ⁰ C, in an aqueous or non-aqueous medium such as aqueous acetone, ethyl acetate, Dimethylace, dimethylformamide , Acetonitrile, dichloromethane, 1,2-dichloroethane or mixtures thereof can be carried out. The reaction can optionally be carried out in an unstable emulsion of a water-immiscible solvent, in particular an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate.

The acid halide can be prepared by reacting the acid of the formula IV or its salt with a halogenating agent, such as a chlorinating or brominating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Optionally, the N-acylating derivative of the acid can Formula IV can be a symmetrical or mixed anhydride. Examples of mixed anhydrides are alkoxyformic anhydrides or anhydrides with, for example, carboxylic acid monoesters, Trimethyl acetic acid, thioacetic acid, diphenylacetic acid,

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Benzoic acid »phosphoric acids (such as phosphorous or phosphoric acid), Sulfuric acid or aliphatic or aromatic sulfonic acids (such as p-toluenesulfonic acid). The mixed or the symmetrical anhydrides can be generated in situ. For example, one can use a mixed anhydride win from N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. If a symmetrical anhydride is used, the reaction can be carried out in the presence of 2,4-lutidine as a catalyst will.

Other N-acylating derivatives of the acid of Formula IV are Acid azides or activated esters, such as esters with 2-mercaptopyridine, Cyanmethanol, p-nitrophenol, 2,4-dinitrophenol, Thiophenol, halophenol (including pentachlorophenol), methoxyphenol or 8-hydroxyquinoline, furthermore amides, such as N-acyl-saccharine or N-acyl-phthalimide, or else Alkylidene imino esters which have been prepared by reacting the acid of the formula IV with an oxime.

Some activated esters, such as those with 1-hydroxybenzotriazole or esters formed with N-hydroxy-succinimide can be prepared in situ by reacting an acid with the corresponding Hydroxy compound in the presence of a carbodiimide, preferably dicyclohexylcarbodiimide, are prepared.

Other reactive N-acylating derivatives of the acid of formula IV are reactive intermediates that are produced by a reaction formed in situ with a condensing agent

such as a carbodiimide, for example

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Ν, Ν'-diethyl-, -dipropyl- or -diisopropyl-carbodiimide, NtN'-di-cyclohexyl-carbodiimide or N-ethyl-N'-jf -dimethylamino-propyl-carbodiimide, also a suitable carbonyl compound, such as N, N ^1- carbonyldiimidazole or Ν, Ν'-carbonylditriazole, furthermore an isoxazolinium salt, such as the N-ethyl-5-phenyl-isoxazolinium-3-sulfonate or N-tert-butyl-5-methyl-isoxazolinium perchlorate, or finally one N-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline, such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Other condensing agents include Lewis acids such as BBr, -CgHg, or a phosphoric acid condensing agent such as diethylphosphoryl cyanide. The condensation is preferably carried out in an organic reaction medium, for example in methylene chloride, dimethylformamide, acetonitrile, an alcohol, in benzene, dioxane or tetrahydrofuran.

If the compound obtained after the N-acylation is in the 1-position contains a sulfoxide group, this can according to customary Processes, for example with triphenylphosphine and acetyl chloride, can be reduced. In the aforementioned procedure the acylation can result in a migration of the double bond into the 2-position of the cephem core, whereby one a mixture of 2-cephem and 3-cephem isomers is obtained. In this case, the mixture of the 2-Cephera and 3-cephem isomers are converted into the 3-cephem isomer, by oxidizing the mixture to sulfoxides and then reducing the sulfoxides. This is of course a common process for the production of 3-cephemes from 2-cephe-

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men, as described for example in GB-PS 1,280,693 is. Again, such a method is treatment with triphenylphosphine and acetyl chloride.

The compounds of the formula II can also be prepared by reacting a compound of the general formula V

(V) .OCOCH ₃

in which R ^{x is} a hydrogen atom or a carboxyl protecting group, η has the value O or 1 and the dashed line denotes a double bond in the 2- or 3-position, or its ester salt or its nitrogen-protected derivative with the thiol of the formula VI

BS

N-N

(VI)

and performing at least one of the following steps

(1) Converting the Ceph-2-em isomer to the desired one Ceph-3-em isomers;

(2) splitting off the amino protecting groups;

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(3) Reduce the sulfoxide compound to produce the desired one Sulfide compound;

(A) Cleavage of the protective groups on the group -COpR and / or

(5) converting the compound obtained into a salt or an ester,

produce.

Process for converting the Ceph-2-em isomers to the Ceph-3-em isomers and the reduction of the sulfoxides are described above. The explanations regarding the amino protective groups and their separation also apply in the present case.

A third process for the preparation of the compounds of formula II is that one

(a) a protected 7-acylamino-ceph-3-em of the general formula VII

(VII)

rP J j CH ₂ . S.
X N- N ο * CO ₂ R S.

in which R ^{p is} an acylamino group and R ^x , η and the dashed line have the meanings given above, with the formation of an imino bond on the 7-amino atom

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lets react

(b) the compound obtained for introducing the radical of the general formula QR ^ on the imino carbon atom, in which Q is an oxygen, sulfur or nitrogen atom and R _{f is} an alkyl radical having 1 to 12 carbon atoms or an aralkyl radical having 5 to 14 carbon atoms, reacts with the formation of an imino ether, iminothioether or amidine (depending on whether Q is an oxygen, sulfur or nitrogen atom),

(c) the compound obtained is reacted with a reactive derivative of the acid of the formula IV;

(d) treating the reaction product with water or an alcohol and

(e) where appropriate, one or more of the above Performs steps (1) to (5).

A fourth process for the preparation of the compounds of formula II is that one

(a) a compound of the general formula VIII

(VIII)

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in which R ^x , η and the dashed line have the meanings given above, or their nitrogen-protected derivatives with an N-acylating derivative of the acid of the formula IX

CO-H

² (IX)

CH ₃ -N- COPh

implements.

The statement regarding the N-acylating derivatives, the N-protected Derivatives and the carboxyl protective groups and their cleavage can also be used in this case.

Another object of the present invention are medicinal preparations, the a <* -acyl-ureido-cephalosporin of the formula II optionally together with pharmacologically acceptable carrier materials, diluents and / or excipients, and optionally contain other active ingredients.

The medicinal preparations can be formulated for administration in any desired way and used for use in human or veterinary medicine. It can be used locally or by the oral or parenteral route. The medicinal preparations can be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations such as oral or sterile parenteral solutions or suspensions.

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Tablets or capsules for oral administration can be in In the form of single doses and contain customary excipients, such as binders, for example syrup, acacia gum, Gelatine, sorbitol, tragacanth or polyvinyl pyrrolidone, also fillers such as lactose, sugar, corn starch, calcium phosphate, Sorbitol or glycerin, furthermore lubricants such as magnesium stearate, talc, polyethylene glycol or silicon dioxide, furthermore Disintegration aids, such as potato starch, or finally pharmacologically harmless wetting agents, such as sodium lauryl sulfate. The tablets can be coated according to methods which are known per se in standard pharmaceutical practice be. Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, Syrups or elixirs, or they can be as dry products for reconstitution with water or other suitable ones Vehicles are offered before use. Such liquid preparations can contain conventional additives, such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, Aluminum stearate gel or hardened edible oils, emulsifiers, for example lecithin, sorbitan monooleate or acacia gum, further non-aqueous vehicles, which may include edible oils, for example almond oil, fractionated coconut oil, oily esters, such as of glycerol, propylene glycol or ethanol, and also preservatives, for example p-hydroxy-benzoic acid methyl ester or propyl ester or sorbic acid, as well as, where appropriate, customary flavor corrections or dyes, contain.

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Suppositories contain common suppository bases, such as Cocoa butter or other glycerides.

For parenteral administration, liquid unit doses are prepared using the compounds and a sterile vehicle produced, whereby water is always preferred. Depending on the vehicle used or the concentration used, can the compound is either suspended or dissolved in the vehicle. When making solutions, the connection can dissolved in water for injection purposes or sterilized by filtration before filling into suitable vials or ampoules and sealing. Advantageously, adjuvants such as local anesthetics, preservatives and / or buffer substances can be used in the vehicle be resolved. To increase stability, the drugs can be frozen after filling into vials or ampoules and the water can be removed under reduced pressure. The dry, lyophilized powder is then in a Vial or ampoule sealed, with a vial or ampoule of water for injections attached to reconstitute the liquid before use will. Parenteral suspensions are prepared in virtually the same manner, with the proviso that the compound is suspended in a vehicle rather than dissolved, and that sterilization is not combined with filtration. the Sterilization of the compound can be accomplished by exposure to ethylene oxide prior to suspending in the sterile vehicle. Preferably in the preparations to facilitate a

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uniform distribution of the compound, a surface-active compound or a wetting agent is also used.

The pharmaceutical and / or veterinary preparations can contain 0.1 to 99 percent by weight, preferably 10 to 60 percent by weight of active substance, depending on the method of administration, contain. If the preparations consist of individual doses, each dose preferably contains 50 to 500 mg of active substance. When treating adults, the daily dose used is 100 to 3000 mg, for example 1500 mg, depending on the route of administration and the frequency of Administration.

The esters of general formula I can be the only active ingredient be in the medicinal preparations of the present invention or be used in combination with other antibiotics. The medicinal preparations of the present invention advantageously also contain a compound of the general formula X.

IIV = H-CH ₂ B _(x)

CO ₂ H

in which B is a hydrogen atom or the hydroxyl group, or their pharmacologically acceptable salts or esters.

The compound of the general formula X is preferably the Clavulanic acid of formula XI

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CH ₂ OH

H CO ₂ H

or their pharmacological salt or ester.

The production of these compounds is described in BE-PS 827 926
and 836 652 as well as in DT-OS 26 16 088.

The following example illustrates the invention.

example

7- / ~ D, oC - (3-Benzoyl-3-methyl-ureido) -phenylacetamido_7-3- (2-methyl-1,3,4-thiadiazol-5-yl-thio) -methyl-ceph ^ -em - ^ carboxylic acid.

5.91 g (0.01 mol) of the trifluoroacetic acid salt of 7- (D, OC-amino-phenylacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl-thio) -methyl-ceph -3-em-4-carboxylic acid are suspended in 25 ml of tetrahydrofuran and 50 ml of water. The pH is then adjusted to 6.5 using 2.5N sodium hydroxide solution. Then drip
a solution of N-chlorocarbonyl-N-methyl-benzamide, which has been prepared from 2.7 g (0.02 mol) of N-methyl-benzamide, in
25 ml of tetrahydrofuran are added, while the pH value of 6.5 is maintained by simultaneous addition of sodium hydroxide solution. After the addition is complete, the solution is twice with each
50 ml of ethyl acetate washed, covered with 100 ml of ethyl acetate and acidified to pH 2.0. Then the ethyl acetate is separated

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layer off and extract the aqueous layer twice with each 50 ml of ethyl acetate. The combined extracts are washed twice with 100 ml of water each time and once with 50 ml of saturated sodium chloride solution washed, dried over anhydrous magnesium sulfate and treated with 5 ml of a 2N solution of the sodium salt of Treated 2-ethylhexanoic acid in methyl isobutyl ketone. The mixture is then diluted with anhydrous ether and filtered precipitated sodium salt, washes it with anhydrous ether and dries it under reduced pressure. 4.96 g are obtained (= 75 »2 percent of theory) of the desired cephalosporin.

NMR spectrum in (CD ^) ₂ SO ι

S = 9.77 (1H, d, J = 8 Hz, -NH-); 9.52 (1H, d, J - 8 Hz, -NH-); 7.65 (5H, s, Ph-); 5.77 (1H, d, J - 8 Hz, coincides with D ₂ O to a singlet, ⁰ C proton); 5.8 to 5.5 (1H, m which coincides with D ₂ O to a doublet at 5.72, J = 4 Hz, C ₇ proton); 4.98 (1H, d, J = 4.5 Hz, Cg proton); 4.8 to 4.2 (2H, m, -CH ₂ S); 3.7 to 3.2 (2H, m, C ₂ ~ methylene protons); 3.15 (3H, s, ^ N-CH,); 2.72 (3H, s, thiadiazole-methyl- Pro tone).

UV spectrum in 95 percent ethanol: ^275nm < ^{£ e 15 100} >

Biological data:

(a) Comparative results with compounds from GB-PS 1 479 711.

Table I below shows a comparison of the er

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inventive connection with the three below, structurally related compounds from the aforementioned British patent:

(D)

Ph.CH.CO.CH

bra

°

CO

", - i.e ..

CH.

CO ₂ H

Comparison connection A:

Comparison connection B:

R = -Ph

χ s -OCOCH-

R = -CH ₂ Ph X «= -OCOCH-

Comparison connection C:

OCH.

OCH-

X s -OCOCH-

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Tabel

Minimum inhibitory concentration (/ ug / ml) Comparison compounds A. B. C. 25th O organism Connection of the 5.0 12.5 125 O Example 25th 125 50 B. coli JT 1 5.0 12.5 12.5 12.5 E. coli JT 425 5.0 2.5 5.0 125 SaIm.typhi 5.0 50 25th - Shig. sunny ² F ⁵ 25th - - Ps. Aeruginosa 10 25th 25th 12.5 25th Serratia marcescens US 5.0 5.0 12.5 50 Klebsiella aerogenes A 5.0 5.0 12.5 50 Enterobacter cloacae Nl 5.0 5.0 12.5 50 P. mirabilis C977 2.5 50 50 5.0 P. morganii 2.5 0.5 1.25 125 P. rettgeri 12.5 50 25th - Staph, aureus Oxford 0.5 0.12 0.12 Strep.faecalis 12.5 β-hemolytic Strep CN10 0 _r 05

(b) Combinations with clavulanic acid of formula XI.

In Table II, the activities of the compound of the example alone and in combination against various bacterial strains are given.

It can be seen from this table that the compound according to the invention together with clavulanic acid shows a synergism at a concentration of 1.0 / Ug / ml, which results in an improved effectiveness against R-factor strains of E. coli and resistant strains of Klebsieila aerogenes and Proteus mirabilis. Some synergism can also be seen in certain Pseudomona strains.

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Tabel

II

Activities of the compound according to the invention alone and in combination with clavulanic acid against a number of bacterial strains in agar (minimum inhibitory concentration (/ Ug / ml)

organism Connection of the example (1, C / Ug /
and ml)
Clavulanic acid (/ Ug / ml) 1.0 5.0 10.0 E. coli JTl
JT415C +
JT425C +
JT4R +
JT20R +
JT39R +
JT56R +
JT68R + 0 s | o
12.5
5.0
5.0
5.0
12.5
5.0 2.5
5.0
12 5
5.0
2.5
2.5
2.5
2.5 HN) HHN) UlN) N)
1OUtN) IOUlOUIUI Pseudomonas aeruginosa 10662
LO3425
BR016
Dalgleish
PU .11
FRlI
Pr5 5.0
12 5
12.5
500
25th
25th
25th
25th 25th
125
125
25th
125
25th
125 H N)
UI Ul N) Ul Ut Ul Ul
O O Ul O O O O 125
125
125
125
125
50
50 Klebsiella aerogenes Ba95R +
1112
T312
T216
1281
A. 25th
500
125
125
125
500
125 5.0
5 0
5.0
5.0
5.0
2.5 N) N) N) Ut N) Ul
UlUl Ul O Ut O O N) N) N) N) N)
Ul UIUlUt UlUI Proteus mirabilis BS66
247
R254
H-WP
P. morganni IDUlO
1580
P. rettgeri T238 H
N) N) N)
Ut Ul Ut Ul Ul Ul
·· «· · *
OO O in in in in cm m in
CN CN CN CN H CN CN in in in in mmm
CN CN CN CN O CN CN HN) O HHN) H
N) UlUl N) N) Ul N) Staphylococcus aureus MB9
C444
T50
Oxford 12.5
5.0
125
50
5.0
12.5
50 OOOH
ro cn cn to 40.1
40.1
<° ι
40.1 40.1
40.1
40.1
40.1 O N) N) Ul
N) UiUi O

*) Serial dilution in nutrient agar. Inoculation 0.001 ml a culture broth prepared overnight.

709883/1082

Claims (1)

Claims Λ. ' © C-acyl-ureido-cephalosporin of the formula (II) Ph.CH.CO.NH f | _N _ _N 4 ^ k \ J ^ (II) CH f | - S ~ \ S CH ₃ - N - COPh or its pharmacologically acceptable salts or in vivo hydrolyzable esters. 2. Cephalosporin according to claim 1 in the form of the free acid or an alkali metal salt. 3. Process for the preparation of the compounds according to claim 1, characterized in that one (A) a compound of the general formula (III) or its derivative acylated on nitrogen H, N ^ Sv. (III) 2 "Π Γ ΊΙ N - N -O- CH in which R ^{x is} a hydrogen atom or a carboxy1 protective group »η has the value O or 1 and ge · 709883/1082 ORIGINAL INSPECTED The dashed line denotes a double bond in the 2- or 3-position , with an N-acylating derivative of the acid of the formula (IV) Ph.CH. ₂ Century CO CH -N- COPh implements or (b) a compound of the general formula (V) or its salt or derivative protected on the nitrogen atom CH-. -N- COPh H OCOCH (V) in which R ^x _t η and the dashed line have the meanings given in (a), with the thiol of the formula (VI) N - N (VI) implements, or 709883/1082 O - 2T-
3 ! (N— ISt 27 31935 y-acylamino-ceph-J-em CO ₂ R ^X S the general (c) a protected one
Formula (VII) (O) _n (VII) _R P Ή in which R ^{p is} an acylamino radical and R ^x , η and the dashed line have the meanings given under (a), can react with the formation of an imino bond on the 7-amino atom, the compound obtained introducing the radical of the general formula QR _f on the imino carbon atom , in which Q is an oxygen, sulfur or nitrogen atom and R _{f is} an alkyl radical with 1 to 12 carbon atoms or an aralkyl radical with 5 to 14 carbon atoms, with the formation of an imino ether, iminothioether or amidine (depending on whether Q is an oxygen , Sulfur or nitrogen atom is allowed to react, the compound obtained is reacted with a reactive derivative of the acid of the formula (IV) and the reaction product is treated with water or an alcohol; or (d) a compound of the general formula (VIII) 7 0 9883/1082 (ο) α η Ph.CH.CO.NH ^ ^S ν. (VIII) / ""] Γ ί) ^Ν —Ν MH ι I ¹ I. ° C ^ in which R ^x , η and the dashed line have the meanings given under (a), with an N-acylating derivative of the acid of the formula (IX) CO ₂ H CH ₃ - N - COPh (IX) implements and after one of the preceding steps (a) to (d), optionally carrying out one or more of the following steps : (1) Converting the Ceph-2-em isomer to the desired one Ceph-3-em isomers; (2) splitting off the amino protecting groups; (3) reducing the sulfoxide compound to form the desired sulfide compound; (4) splitting off of the protective groups on the group -COpR; and or 709883/1082 (5) converting the obtained compound to its salt or ester. H. Medicinal preparations containing a cC-acyl-ureido-cephalosporin of the formula (11) or its pharmacologically acceptable salt or in vivo hydrolyzable ester, optionally together with pharmacologically acceptable carrier materials, diluents and / or excipients, and optionally other active ingredients. 5. Medicinal preparations according to claim 4, containing a compound of the general formula (X) as an additional active ingredient j = r> (X) CH.CH A 2 in which A is a hydrogen atom or the hydroxyl group, or their pharmacologically acceptable salts or esters. 709883/1082