DE2753220A1 - NEW CEPHALOSPORIN DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF - Google Patents

Description

description

The invention relates to improvements related to cephalosporin compounds, and more particularly relates to a new one Class of cephalosporin compounds that have valuable antibiotic properties.

The present cephalosporin compounds are incorporated herein by reference referred to as "Cepham" according to J.Amer.Chem.Soc., 1962, 84, 3400, where the term "cephem" refers to the basic cepham structure with a double bond.

The cephalosporin antibiotics are widely used in the Treatment of diseases caused by pathogenic bacteria in humans and animals and are used in particular Useful in treating diseases caused by bacteria that oppose other antibiotics such as penicillin compounds resistant, as well as in the treatment of penicillin-sensitive patients. In In many cases it is desirable to use a cephalosporin antibiotic that is both gram-positive as well as against gram-negative microorganisms has an activity and extensive studies have been carried out on the Development of various types of broad spectrum cephalosporin antibiotics directed.

A particular interest is currently directed to the development of broad spectrum cephalosporin antibiotics that oppose the Gram-negative organisms have a high level of activity. Existing commercially available ß-lactam antibiotics tend to be in addition, towards certain gram-negative organisms, such as e.g. ß-lactamase producing organisms, the one to an increasing extent common sources of infection in humans are to show a comparatively low level of activity. The practical therapeutic Applications of aminoglycoside antibiotics such as gentamicin, which are active against gram-negative organisms, tend to be due to the high toxicity of these antibiotics

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becoming restricted or difficult to administer. It is well known that cephalosporin antibiotics normally have low toxicity in humans, so that the development of broad spectrum cephalosporin antibiotics with high activity against gram negative organisms such as strains of Escherlchia coil has met an essential need in chemotherapy.

The present invention relates to Tß-acylamidoceph - ^ - em - ^ - carboxylic acid antibiotics and their non-toxic derivatives, which are characterized in that the acylamido part has the formula

R.C.CO.NH-

f \. (CH ₂ ) _m .C (CH ₇ ) ^ CO.N.CO.NR ^C R ^d

R »

has [where R is a phenyl, thienyl or furyl group

away

means; R and R, which can be the same or different, are each selected from hydrogen, C ^ -alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or butyl), C ₂ _ ^ - alkenyl (e.g. vinyl or allyl), Ο, ™ -Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), phenyl, naphthyl, thienyl, puryl, carboxy, C ₀ ^ -alkoxycarbonyl (e.g. ethoxycarbonyl) and

away
Cyano, or R and R together with the carbon atom to which they are attached form a C 1 -C cycloalkylidene or cycloalkenylidene group (eg a cyclobutylidene, cyclopentylidene or cyclohexylidene group); R ^c and R, which can be the same or different, each represent a hydrogen atom or a substituting group, for example an alkyl group or substituted alkyl group (for example a methyl, ethyl, propyl, isopropyl or t-butyl group), or R ^c and R together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which contains 5 to 7 ring members and which can contain further heteroatoms, such as N, O or S, and substituted by lower alkyl

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can be tuated; R ^e denotes hydrogen or Cj ^ -alkyl (for example methyl ethyl, n-propyl, isopropyl or butyl); and m and η each represent 0 or 1 such that the sum of m and η is 0 or 1].

The antibiotic compounds according to the invention can are represented as compounds of the general formula

H H

R.C.CO.NH ^

. _{2 / m} .'c. (CH ₂ ) _n .CO.N.CO.NR ^C R ^d

R ^b

[where R, R ^a > R » R °» R * R ^e , m and η are as defined above and Y represents the residue of an oxygen or sulfur nucleophile] and their non-toxic derivatives.

These compounds are syn isomers or are present as mixtures of syn and anti isomers with at least 75 % of the syn isomer, preferably at least 90 % of the syn isomer.

The antibiotic compounds of formula I can be used to treat a variety of diseases caused by to treat pathogenic bacteria in humans and animals, such as infections of the respiratory and urinary systems.

These compounds show broad spectrum antibiotic activity. The connections have a Activity against microorganisms that form ß-lactamases and have a very high stability towards ß-lactamases, produced by a wide variety of gram negative organisms.

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It was found that the compounds according to the invention have good activity against numerous members of Enterobacteriaceae (for example "strains of Escherlchia coil, Klebsiella aerogenes and Proteus mirabills ).

ab The compounds in which at least one of the radicals R and R has a different meaning than that of hydrogen also showed activity against Pseudomonas organisms, for example against strains of Pseudomonas aeruglnosa .

The compounds according to the invention are defined in such a way that they have the syn -isomeric form with regard to the configuration of the group

R ^a R ^e

0. (CH ₂ ) .C. (CH ₂ ) _n .C0.N.C0.NR ^C R ^d

with reference to the carboxamido group. In the present case, the syn configuration is structurally called

R.C.CO.NH-tt

NR ^a R ^e

\ ^R f

0. (CH ₂ ) _m .C. (CH ₂ ) _n .CO.N.CO.NR ^C R ^d

This configuration is based on the work of Ahmad and Spenser in Can.J.Chem., 1961, 22, 1540 is assigned.

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As indicated above, the compounds can exist as mixtures of syn and anti isomers, provided that these mixtures contain at least 75% of the syn isomer, preferably at least 90 % of the syn isomer. However, it is preferred that the compounds be syn isomers that are substantially free of the corresponding anti isomer.

The term "non-toxic derivatives" is to be understood as meaning those derivatives which are physiologically acceptable in the administration dose. Such derivatives can e.g. salts, biologically acceptable esters, 1-oxides and solvates (especially

away

Hydrates). It can be seen that when R or R represents carboxy, derivatives such as salts and esters are reacted one or both of the carboxy groups present in such compounds of formula I can be formed.

Non-toxic salt derivatives which can be formed from the compounds of general formula I include salts of inorganic bases, such as alkali metal salts (eg sodium and potassium salts) and alkaline earth metal salts (eg calcium salts); Salts of organic bases (for example procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine salts) ; and, if suitable, acid addition salts, for example with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, toluene-p-sulfonic acid and methanesulfonic acid. The salts can also be in the form of resinates which, for example, with a polystyrene resin or crosslinked polystyrene-divinylbenzene mixed polymer resin containing amino or quaternary amino groups or, if suitable, sulfonic acid groups, or, again, if suitable, with a resin which contains carboxyl groups , for example a polyacrylic acid resin. In general, the use of highly soluble salts with bases (e.g. alkali metal salts such as the sodium salt) of the compounds of formula I in therapeutic applications is advantageous because of the rapid distribution of such salts in the body after administration. However, if insoluble salts of the compounds of the formula I are used in a special application, both

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For example, for use in depot preparations, if desired, such salts can be used in a conventional manner, for example with suitable organic amines.

Biologically acceptable metabolically labile ester derivatives which can be formed from compounds of Formula I include e.g. acyloxymethyl ester, e.g. lower alkanoyloxymethyl ester, such as acetoxymethyl, acetoxyethyl or pivaloyloxymethyl ester.

It can be seen that if R and R in the above formulas are different, the carbon atom to which they are attached may have a center of asymmetry. Compounds according to the invention in which R ^a and R are different can thus be diastereomers. The invention includes the individual diastereomers of such compounds and mixtures thereof.

The groups Y in formula I above can be derived from a large number of sulfur nucleophiles.

Examples of sulfur nucleophiles include thioureas including aliphatic, aromatic, araliphatic, alicyclically and heterocyclically substituted thioureas; Dithiocarbamates; aromatic, aliphatic and cyclic Thioamides, e.g., thioacetamide and thlosemicarbazld; Thiosulfates; Thiols; Thiophenols; Thio acids such as thiobenzoic acid or thiopicolinic acid; and dithio acids.

One class of sulfur nucleophiles comprises those compounds of the formula R .S (O) H, in which R is an aliphatic, for example lower alkyl, such as methyl, ethyl or n-propyl group; an alicyclic, for example lower cycloalkyl such as cyclohexyl or cyclopentyl group; an aromatic, for example Cg_ ₁₂ -mono- or bieyclic carbocyclic aryl such as phenyl or naphthyl group; is an araliphatic, e.g. phenyl-lower (e.g. Cj ^ J-alkyl such as benzyl group; or a heterocyclic group, and η is 0, 1 or 2. A preferred class of nucleophiles falling within the scope of the above formula

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2 2

fall, is that of the general formula R SH, wherein R is an aliphatic, e.g. lower alkyl such as methyl, ethyl or n-propyl or lower alkanoyl such as acetyl; araliphatic, e.g. lower alkyl such as methyl, ethyl or n-propyl or Lower alkanoyl such as acetyl; araliphatic, e.g., phenyl lower alkyl such as Benzyl or phenethyl or substituted phenyl lower alkyl; alicyclic, e.g. cycloalkyl such as cyclopentyl or cyclohexyl-; aromatic, e.g., phenyl, substituted phenyl or a heterocyclic group with at least one 5- or 6-membered ring with one or more heteroatoms selected from O, N and S means. Such heterocyclic

Groups R can be substituted and examples of suitable heterocyclic groups include thiadiazolyl, for example 5-methyl-1, j5,4-thiadiazol-2-yl; Diazolyl; Triazolyl, for example triazol-4-yl; Tetrazolyl, for example 1-methyl-tetrazol-5-yl, 1-ethyl-tetrazol-5-yl, i-phenyl-tetrazol-5-yl or i-carboxymethyl-tetrazol-5-yl; Thiazolyl; Thiatriazolyl; Oxazolyl; Oxadiazolyl, for example 2-phenyl-1,3,4-oxadiazol-5-yl; Pyridyl, for example N-methylpyrid-2-yl; Pyrimidyl; condensed heterocyclic ring systems such as benzimidazolyl, + benzoxazolyl, benzothiazolyl such as benzothiazol-2-yl, triazolpyridyl or purinyl; and substituted versions of such fused ring systems, for example nitrobenzothiazol-2-yl such as 5- or 6-nitrobenzothiazol-2-yl.

The group Y in the above formula I can also be derived from numerous oxygen nucleophiles. examples for Oxygen nucleophiles include water; Alcohols, e.g., alkanols such as methanol, ethanol, propanol and butanol; and lower alkane and -alkenoic acids.

The term "oxygen nucleophiles" thus includes compounds the following formula

R ⁵ OH

wherein the group R- ^{5 is} lower alkyl (eg methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl); Lower alkenyl (e.g. allyl); Lower alkynyl (e.g. propynyl); Lower cycloalkyl (for example cyclopropyl, cyclopentyl or cyclohexyl); Lower cycloalkyl-lower alkyl (e.g. cyclopropylmethyl), cyclopentylmethyl or cyclohexyl

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ethyl); Aryl (e.g. phenyl or naphthyl); Aryl lower alkyl (e.g. benzyl); a heterocyclic group (e.g. a heterocyclic group as defined for R such as N-methylpyrid-2-yl); heterocyclic lower alkyl (e.g. furfuryl); or any of these groups substituted by, for example one or more lower alkoxy (e.g. methoxy or ethoxy), lower alkylthio (e.g. methylthio or ethylthio), halogen (chlorine, Bromine, iodine or fluoro), lower alkyl (e.g. methyl or ethyl), nitro, hydroxy, acyloxy, carboxy, Carbalkoxy, lower alkylcarbonyl, lower alkylsulfonyl, lower alkoxysulfonyl, amino, lower alkylamino or Can be acylamino groups.

If the nucleophile is water, then jJ-hydroxymethylcephalosporin compounds are obtained. Such 3-hydroxymethyl compounds and their non-toxic derivatives can be antibacterial Have activity and it is worth noting that they can be metabolites of the compounds of general formula I, where Y is acetoxy. J-Hydroxymethylcephalosporins can acylated to form derivatives that are characterized by

4 are characterized as being the group J-CH ₀ .O.CO.R or

c ^ ii

3-CH _o .0.C0.AR ^J , in which A is 0, S or NH, R is an organic group and R- * is hydrogen or an organic group.

4 κ
The group R CO- or R- ^ A.CO- can be selected from a broad class of such groups which are described in the literature.

Ii be selected and have up to 20 carbon atoms. Around, if appropriate, R- * can thus each be a hydrocarbon group or such a group containing one or more substituent atoms or groups and can thus be selected from the following list, which is not exhaustive should be:

(i) ^c _n ^H 2n + i * ^where B is an integer from 1 to 7 #, for example 1 to 4. The group can be straight-chain or branched and, if desired, be interrupted by an oxygen or sulfur atom or an imino group or be substituted by

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Cyano, carboxy, lower alkoxycarbonate, hydroxy, carboxycarbonyl (HOOCCO.), Halogen (e.g. chlorine, bromine or iodine) or amino. Examples of such groups include methyl, Ethyl, propyl, isopropyl, η-butyl, t-butyl, sec-butyl and 2-chloroethyl.

(ii) CH ₂ 4, where η is an integer from 2 to 7.

The group can be straight or branched and if desired be interrupted by an oxygen or sulfur atom or an imino group. Examples of such groups include vinyl and propenyl.

(iii) R, where R is carbocyclic aryl (eg C ^^ - mono- or bicyclic carbocyclic aryl), heterocyclic aryl (eg comprising a 5- or 6-membered ring with at least one of the following atoms 0, N and S), lower cycloalkyl , substituted aryl and substituted cycloalkyl. Examples of this group include phenyl; substituted phenyl, for example hydroxyphenyl, chlorophenyl, fluorophenyl, tolyl, nitrophenyl, aminophenyl, methoxyphenyl or methylthiophenyl; Thien-2- and -3-yl; Pyridyl; Cyclohexyl; Cyclopentyl; Cyclopropyl; Sydnon; Naphthyl; and substituted naphthyl, for example 2-ethoxynaphthyl.
(iv) R (CHp ^ m ' ^{where R is as given} under (iii) above

m
Has meaning, and m represents an integer from 1 to 4.

Examples of this group include methyl, ethyl or butyl substituted by the various specific R groups indicated under (iii), for example lower cycloalkyl-Cj u alkyl and carbocyclic or heterocyclic aryl-CL-alkyl such as benzyl and the appropriate substituted benzyl groups.

^ -Position substituents of the above type include thus lower alkanoyloxymethyl groups such as acetoxymethyl and isobutyryloxymethyl, lower alkenoyloxymethyl groups such as Crotonyloxymethyl; Aroyloxymethyl groups such as benzoyloxymethyl; Carbamoyloxymethyl, N- (lower alkyl) carbamoyloxymethyl such as N-methylcarbamoyloxymethyl, and N- (haloalkyl) -carbamoyloxymethyl such as N- (2-chloroethyl) carbamoyloxymethyl.

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The term "low" as it is used in the present case to denote aliphatic groups, unless otherwise indicated, indicates that this group has up to 6 carbon may contain atoms. The term "low" as used to denote cycloaliphatic groups indicates that the group can contain 3 to 7 (e.g. 5 to 7) carbon atoms.

One class of the cephalosporin antibiotics according to the invention comprises compounds of the general formula

R. C. CO. NH -τ =

N _R y JN JV (II)

OCCO.NH.CO.NR ^ * ¹

t COOH

R ^f

[wherein R is as defined above; R ** and R, which may be the same or different, each represent a hydrogen atom or a methyl group, or R ^J and R together with the carbon atom to which they are attached form a cyclopentylidene group; R ^g and R, which can be the same or different, each represent a hydrogen atom or a methyl group; and W is selected from: i) acetoxymethyl,
ii) carbamoyloxymethyl,
iii) N-methylcarbamoyloxymethyl and

iv) the group -CHpSR ^w , in which R ^{w is} selected from pyridyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl and substituted (eg lower alkyl, carboxymethyl or phenyl-substituted) versions of these groups such as N-methylpyrid-2 -yl, 1-methyltetrazol-5-yl, 1-phenyltetrazol-5-yl; i-carboxymethyltetrazol-5-yl; 5-methyl-1,3,4-thiadiazol-2-yl and 5-phenyl-1,3,4-oxadiazol-2-yl] and their non-toxic derivatives.

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The compounds of the invention can be prepared by any suitable method, for example by techniques similar to those described in British Patent specification 1 399 086 are analogous, getting produced.

Thus, another object of the invention relates to a method for producing an antibiotic compound of the general formula I, which is as defined above, or a non-toxic derivative thereof, which is characterized is that you either (A) a compound of formula

H H

(III)

[wherein Y is as defined above; B> S or> S - »0 (α- or ß-); R 'denotes hydrogen or a carboxyl' blocking group, e.g. the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol ( this alcohol, phenol, silanol or stannanol preferably containing 1 to 20 carbon atoms) or a symmetrical or mixed anhydride group derived from a suitable acid; and the dashed line connecting the 2, 3 and 4 positions indicates that the compound is a Ceph-2-em or Ceph-3-em compound] or a salt, for example an acid addition salt such as a hydrochloride, hydrobromide, sulfate , Nitrate, phosphate, methanesulfonate or tosylate odex 'an N-silylated derivative thereof with an acid of the formula
RCCOOH

N?

0. (CH ₉ ) .C (CH ₉ ) .CO.N.CO.NR ^C R ^d

R ^b

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^a RR ^c RR ^e

(wherein R, R ^a , R, R ^c , R, R ^e , m and η are as defined above) or condensed with an acylating agent corresponding to the same, or
(B) a compound of the formula

R.C.CO.NH

ti

O. (CH ₂ ) _m .C. (CH ₂ ) _n .CO.N.CO.NR R

K-

(where B, R, R ^a , R, R ^c , R, R ^e , the dashed line, R ^, m and η are as defined above; and Y ^{1 is} an exchangeable residue of a nucleophile, e.g. an acetoxy, dichloroacetoxy or hydroxy group or a halogen atom such as chlorine, bromine or iodine) with an oxygen or sulfur nucleophile, or
(C) a compound of the formula

R.C.CO.NH

Il

OH

COOR '

(VI)

• 7

(wherein B, R, R, Y and the dashed line are as defined above) with a compound of the formula

T. (CH ₂ ) _m .C. (CH ₂ ) _n .CO.N CONrV

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(in which R ^a , R, R ^c , R, R ^e , m and η are as defined above and T is chlorine, bromine or iodine or a sulfonyloxy group, for example a mesyloxy or tosyloxy group), preferably in the presence of a base, in particular one non-nucleophilic base, after which, if necessary and / or if desired, one of the following reactions (D) is carried out in any suitable order:

i) Conversion of an A isomer into the desired ^ isomer, ii) reduction of a compound in which B> S- * O means to a

To form compound in which B> S means, iii) deacylation of a 3-acyloxymethyl compound to give a 3-

To form hydroxymethyl compound, iv) acylation of a 3-hydroxymethyl compound to form a J-

To form acyloxymethyl compound, v) carbamoylation of a 3-hydroxymethyl compound to form a unsubstituted or substituted 5-carbamoyloxymethyl compound to form and

vi) removal of carboxy1-blocking groups, and finally (E) the desired compound of the formula I or a non-toxic derivative thereof, if necessary after separation of isomers wins.

Non-toxic derivatives of the compounds of the formula I can be used in any suitable manner, for example according to the prior art Technique known methods. Thus, for example, salts of bases can be obtained by reacting the cephalosporic acid with Sodium 2-ethylhexanoate or potassium 2-ethylhexanoate are formed. Biologically acceptable ester derivatives can be prepared using conventional esterifying agents. 1-oxides can by treating the corresponding cephalosporin sulfide with a suitable oxidizing agent, for example with a peracid such as Metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid or with t-butyl hypochlorite, where this latter reagent is suitably used in the presence of a weak base such as pyridine.

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Acylating agents involved in the preparation of the compounds of the formula I can be used include acid halides, in particular acid chlorides or bromides. Such acylating agents can be prepared by taking an acid (IV) or reacting a salt thereof with a halogenating agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride. A treatment of the sodium, potassium or triethylammonium salt of the acid (IV) with oxalyl chloride is advantageous insofar as isomerization is minimal under these conditions is.

Acylations employing Säurehalogenlden can in aqueous and non-aqueous reaction media, conveniently at temperatures of -50 to +50 ⁰ C, preferably -20 to +50 ⁰ C, gewUnsentenfalls in the presence of an acid-binding agent, performed. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile or mixtures of two or more such solvents. Suitable acid-binding agents include tertiary amines (e.g. triethylamine or di-methylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide), which bind the hydrogen halide released during the acylation reaction.

The acids of the formula IV can be used as such as acylating agents in the preparation of compounds of the formula I. will. Acylations using acids (EV) are, if desired, carried out in the presence of a condensing agent such as a carbodiimide such as Ν, Ν'-dicyclohexylcarbodiimide. The acylation reactions of this type are, if desired, carried out in an anhydrous reaction medium, e.g. methylene chloride, dimethylformamide or acetonitrile.

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The acylation can be carried out with other amide-forming derivatives such as acids of the formula IV, such as, for example, a symmetrical anhydride or a mixed anhydride (e.g. with pivalic acid or formed with a haloformate such as a lower alkyl haloformate). The mixed or symmetrical anhydride can be formed in situ . For example, a mixed anhydride can be formed using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

It can be seen that in processes for the production of

away

bonds of the formula I in which R or R is a carboxy group, in many cases it is necessary to block the carboxy group, for example by substitution with a carboxyl group Group, e.g., a group as defined above in connection with R '.

The above reaction (C) is generally carried out under basic conditions which serve to deprotonate to effect the hydroxyimino group of the compound of formula VI, for example in the presence of a base selected from organic Bases such as tertiary amines, e.g., triethylamine, 1,5-diazabicyclo- [4,3 # 0] -non-5-ene and 1,5-diazabicyclo- [5,4,0] -undec-5-ene and inorganic bases such as metal hydrides, e.g. alkali metal and alkaline earth metal hydrides (e.g. sodium hydride, lithium hydride and calcium hydride), metal alkyls such as alkali metal lower alkylene (e.g. butyl lithium) and metal amine salts such as lithium amine salts (e.g. lithium diisopropylamide and lithium di (trimethylsilyl) amide). Alternatively, in the method according to the invention base used is a quaternary ammonium salt, for example a bis-tetraalkyl (e.g. η-butyl) ammonium salt of the compound of Formula VI (when R 'is hydrogen) used as the starting material.

The reaction of the compounds of formula VI and VII is convenient in an aprotic solvent, selected for example from halogenated hydrocarbons, e.g. dichloromethane, Ethers, e.g. tetrahydrofuran, dioxane and diethylene glycol dimethyl ether (diglyme), amides, e.g. dimethylformamide, dimethyl acetamide

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and hexamethylphosphoramide, sulfoxides, e.g., dimethyl sulfoxide and sulfones, e.g., suIfolan.

The reaction of the compounds of the formulas VI and VII is preferably carried out at a temperature of from -15 to +50.degree. C., advantageously from 0 to + 55.degree.

According to a particularly preferred embodiment of reaction (C) the compounds of the formulas VI and VII are reacted at room temperature in the presence of triethylamine in a dimethylformamide solvent.

Any conversions of the 3-position substituents that occur in The preparation of special compounds of the formula I may be necessary, for example, by methods described in the literature.

Thus, for example, compounds of the formula I in which Y is an ether or thioether group can be prepared, as described in British Patents 1,241,656, 1,241,657, 1,277,415 and 1,279,402. Compounds in which Y means the remainder of a nucleophile can also be obtained by reacting a 3-acetoxymethylcephalosporin compound with a nucleophile, for example a sulfur-linking or inorganic one Nucleophiles, as described in British Patent 1,012,945 is described, or a sulfur-linking nucleophile, as described in British patents 1,059,562, 1,101,423 and 1 206 505 is described. Compounds in which Y represents the residue of a nucleophile can also be prepared by reacting a 3-halomethylcephalosporin with any of the in the nucleophiles mentioned above, such a process being described in British Patent 1,241,657, or by reaction a 3-halomethylcephalosporin sulfoxide with any of the nucleophiles described in the above references, such a method in British Patent 1,326,531. The content of the above

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cited British patents are hereby incorporated by reference.

Compounds with a 3-substituent

-CH ₂ Y

where Y is a hydroxyl group, according to the British patents 1,121,508, 1,399,086 and 1,474 methods described are produced.

The carbamoylation of the 3-hydroxymethyl compounds can after conventional methods. For example, a 3-hydroxymethylcephalosporin with an isocyanate of the formula

k k

R .NCO (where R is a labile substituent group or an alkyl group) can be reacted to form a compound give rise to a substituent of the formula in the 3-position

If U

-CHgO.CONHR contains (where R "has the meaning given above owns). If R is a labile substituent, this substituent can, if desired, subsequently, for example by hydrolysis, cleaved to form a 3-carbamoyloxymethyl group to surrender. Labile groups R that are easily cleavable by subsequent treatment include chlorosulfonyl and bromosulfonyl; halogenated lower alkanoyl groups such as dichloroacetyl and trichloroacetyl; and halogenated lower alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. These labile R groups can generally be replaced by acidic or base-catalyzed hydrolysis (e.g. by base-catalyzed hydrolysis using sodium bicarbonate) will.

A Ceph-2-em reaction product can also be oxidized to. to give the corresponding Ceph-3-em-i-oxide, for example by reaction with a peracid as mentioned above. The sulfoxide obtained can then, if desired, as above described, be reduced to give the corresponding Ceph-3-em-sulfide.

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If a compound is obtained in which B> S- »O, this can be converted into the corresponding sulfide, for example by reducing the corresponding acyloxysulfonium or alkyloxysulfonium salt, prepared in situ by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt, where the reduction is carried out, for example, with sodium dithionite or with iodide ions, such as in a potassium iodide solution in a water-miscible solvent, for example acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction may be carried out at a temperature of -20 to +50 ⁰ C.

If a compound of the formula I is obtained as a mixture of isomers, the syn isomer can be obtained, for example, by conventional methods such as crystallization or chromatography.

The acids corresponding to formula IV and those corresponding to them Acid halides and anhydrides are new.

For use as starting materials for the preparation of the compounds of the general formula I according to the invention, preference is given to compounds of the general formula IV and the acid halides and anhydrides corresponding to them in their syn isomer form or in the form of mixtures of the syn isomers and the corresponding anti isomers, which contain at least 90 % of the syn isomer is used.

The acids (fV) can be etherified by an acid of the formula

R. C. COOH (VIII)

Il

OH

(wherein R has the meaning given above) by reaction with a compound of the general formula

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R ^e

cd T \ (CH ₂ ) _m .C. (CH ₂ ) _n .CO.N.CO.NRR

(Vila)

(wherein R ^a , R, R ^c , R, R ^e , m and η are as defined above and T ^{1 is} halogen such as chlorine, bromine or iodine, or sulfonate such as tosylate). The isomers can be separated either before or after such an etherification. The etherification reaction is preferably carried out in the presence of a base, for example potassium t-butoxide or sodium hydride, and preferably in an organic solvent such as dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane, or a Ν, Ν-disubstituted amide such as dimethylformamide. Under these conditions the configuration of the oximino group remains essentially unchanged by the etherification reaction. This process is particularly useful in the production of acids (IV)
are fabric.

Acids (IV) are suitable in which both R ^a and R water

The separation of the isomers can be carried out at any suitable stage in the sequence of reactions.

Another process for the preparation of acids of the general formula (iv) is that of a reaction of a glyoxylic acid the formula

R.CO.COOH (IX)

(wherein R is as defined above) with a compound of Formula 1

R ^a

.CO. Λ. CO.NR ^C R ^d (X)

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(wherein R ^a , R, R ^c , R, R ^e , m and η are as defined above). The reaction of IX with X can, if necessary, be followed by a separation of the syn and anti isomers.

The acids of the formula IV can be converted into the corresponding acid halides and anhydrides by conventional methods.

Carboxyl-blocking groups R, which are used in the preparation of compounds of the formula I or in the preparation of required starting materials, are preferably groups which are readily available during a suitable stage In the reaction sequence, expediently during the last Stage, can be split off. However, it can be in some In some cases it may be useful to use biologically acceptable, metabolically labile carboxyl-blocking groups such as acyloxymethyl groups (e.g. acetoxymethyl, acetoxyethyl and pivaloyloxymethyl) and retain them in the final product to produce a biologically acceptable ester derivative of a compound of the Formula I to form.

Suitable carboxyl blocking groups are well known in the art, with a list of representative ones Carboxyl blocking groups in British Patent 1,399,086 is included. Preferred carboxyl blocking Groups include aryl-lower alkoxycarbonyl groups such as jD-methoxybenzyloxycarbonyl, jg-nitrobenzyloxycarbonyl and Diphenylmethoxycarbonyl; Lower alkoxycarbonyl groups such as t-butoxycarbonyl; and haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group can then be removed by any suitable method described in the literature. For example are an acidic, basic or enzymatically catalyzed hydrolysis and reductive methods can be used in many cases.

809822/0980

The antibiotic compounds according to the invention, for example the compounds of the formula I and their non-toxic Derivatives can be formulated for administration in any suitable manner analogous to other antibiotics and the invention therefore also encompasses pharmaceutical compositions containing an antibiotic compound according to the invention and which are suitable for use in human or veterinary medicine. Such compositions can for use in conventional form with the aid of any required pharmaceutical carrier or excipient getting produced.

The antibiotic compounds of the invention can be formulated for injection and can be in the form of a Unit dose in ampoules or in containers, the multiple doses with an added protective agent or preservative included. The compositions can take such forms as suspensions, solutions or emulsions Accept in oily or aqueous vehicles and can formulatory agents such as suspending, stabilizing and / or Contain dispersants.Alternatively, the active ingredient can be in powder form for reprocessing with a suitable Carrier, e.g. sterile, distilled water for injection ^ available before use.

The antibiotic compounds can also be formulated in a form that is suitable for absorption through the gastrointestinal tract is suitable, e.g. in the form of tablets or capsules. The antibiotic compounds can also be used as suppositories can be formulated, e.g. conventional suppository raw materials such as cocoa butter or any other glyceride.

The compositions for veterinary medicine can be used, for example, as intramammary preparations in bases or bases with either long duration of action or quicker release.

809822/0980

The compositions can be 0.1 # and more, for example 0.1 to 99 # »preferably 10 to 60 pounds, depending on active material the method of administration. If the compositions contain dosage units, each preferably contains 50 to 1500 mg of the active ingredient. The dosage used for treating an adult is preferably 500 to 5000 mg / day depending on the route of administration and the frequency of administration, although higher daily when treating some infections Doses may be required.

The antibiotic compounds according to the invention can in combination with other therapeutic agents such as antibiotics, for example penicillins or others Cephalosporins.

The following examples illustrate the invention. The structures of the products were determined by NMR and IR spectroscopy secured.

Manufacturing 1

1-bromocyclopentanecarbonyl-chlorld

6.4 g of 1-bromocyclopentanecarboxylic acid were refluxed with 6 ml of thionyl chloride for 40 minutes. The removal of the Thlonylchlorids and distillation gave the acid chloride, 5.6 g, b.p. 85-87 ^O C / _I7mm. ^^ 1780 cm " ¹ (COCl), - f (CDCl,) approx. 7 * 2 - 8.4 (cyclopentyl).

Manufacturing 2

1-bromo-1-ureidocarbonylcyclopentane

3.5 g of 1-bromocyclopentanecarbonyl were stirred with 3.15 g of urea for 30 minutes at 80.degree. The mixture was cooled and added to 30 ml of water and then bringing the pH to a value of 7. The mixture was filtered from the Peststoff and crystallized twice from ethanol to give 0.7 g acylurea received, P = 189-191 ⁰ C. , 0 (NuJoI) 3420, 33OO, 3220 (NH, NH ₂ ), 1702, 1690 and 1585 cm "" (CONH, CONH ₂ ), τ (DMSO

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approx. 0.2 (NH), - approx. 2.4 and - approx. 2.6 (NH ₂ ), approx. 7 * 5 - 8.5 (cyclopentyl).

Manufacturing 3
^ y_n-Triäthylammonium-trlphen ylmethoxylminofur-2-ylacetat were added 5.05 g (6.9 ml) of triethylamine to a stirred suspension of 3.10 g of syn -Hydroxyitr.inofur-2-yl-acetic acid in 30 ml of methylene chloride. The solid rapidly dissolved and then some of the triethylamine salt separated. A solution of 6.15 g of chlorotriphenylmethane in 30 ml of dry methylene chloride was added to the slurry and the mixture was stirred under reduced pressure for 1 hour before evaporating to dryness. The remaining solid was stirred with 100 ml of water for 1 hour, filtered off and dried and then stirred with 50 ml of ether. The title salt was filtered off and dried (8.95 g) .r (DMS0 d _g ; 60 MHz) 2.34 and 3.48 ( syn- 2-furyl protons) 2.63 (m, Ph protons) 6.95 (q, J 7 Hz; N-CH ₀ -CH,) and 8.80 (t, J 7 Hz; N-CH ₀ CH,).

d J ei YY

Manufacturing 4 Sodium salt of the £ yj} - (6R, 7R) -3-carbamoyloxymethyl-7- (hydroxy-

iminofur-2-ylacetamido) -ceph-3-em-4-carboxylic acid

A solution was cooled 5.0 g of syn -Triäthylammonium-triphenylmethoxy-iminofur-2-yl acetate in 30 ml of dry methylene chloride containing one drop of dimethylformamide, treated at -5 to -1O ⁰ C and treated with 0.86 ml oxalyl chloride. The mixture was stirred for 0.75 hours when the temperature was allowed to rise to 0 ^° C. The mixture was evaporated under reduced pressure, finally under high vacuum, below ⁰ ° C. The remaining solid was treated with about 80 ml of dry ether, filtered off as quickly as possible and the filtrate was evaporated to dryness under reduced pressure. The residual foam was treated with dry petroleum ether (b.p. 40 to 6O ⁰ C.) And then to dryness, finally under high vacuum, evaporated to give 4.8 g of a crystalline mass of the acid chloride r: u result.

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The 4.8 g of acid chloride were dissolved in 40 ml of dry methylene chloride and added dropwise with stirring over 20 minutes to a solution of 5.15 g of diphenylmethyl- (6R, 7R) -7-amino-3-carbamoyloxymethylceph-J-em- ^ carboxylate in a mixture of 60 ml of dry methylene chloride and 5 ml of 1,2-epoxypropane at -5 ° C. The mixture was allowed to ^{warm to 0} ° C. over 20 minutes and to room temperature over a further 30 minutes. The mixture was shaken with dilute sodium bicarbonate solution and the organic phase separated and filtered off from a small amount of amorphous material. The methylene chloride solution was washed successively with dilute hydrochloric acid, water, dilute sodium bicarbonate solution and water. The solution was dried and evaporated to dryness under reduced pressure. The residue was treated with dry ether (ca 50 ml) and the crystalline ester collected (6.29 g). A sample recrystallized from benzene gave the syn -diphenylmethyl- (6R, 7R) -J-carbamoyloxymethyl-Y- (triphenylmethoxyiminofur-2-yl-acetamido) -ceph-3-em-4-carboxylate. F = 178 ° C (dec.); T (DMSO dg; 100 MHz) values include -0.05 (d J 8 Hz; -CONH), 3.97 (d, d J 4 and 8 Hz / C- 7 H) 2.27 and 3.40 (svn-2-furyl and NHg), 3.06 (s, -CHPh ₃ ), 2.69 (phenyl protons) 4.67 (d, J 4 Hz; C-6 H), 5.15 and 5.38 (AB quartet; J 13 Hz; -CH ₂ O) and 6.39 (broad s, C-2 Hg).

4.0 g of the above ester were placed in an 8 ml ice bath Anisole was stirred and 25 ml of trifluoroacetic acid were added. The dark brown solution was stirred at an ice bath temperature for 1/2 hour. and then diluted with about 50 ml of ice-cold water. the The mixture was evaporated to a small amount under high vacuum and the residue was dissolved in ethyl acetate and washed with a Shaken excess sodium bicarbonate solution. The alkaline extract was washed two more times with ethyl acetate and then acidified to pH 2 with hydrochloric acid under a layer of ethyl acetate. The organic layer was separated, combined with two other extracts, dried and evaporated to dryness under reduced pressure. The remaining foam was treated with ether and then filtered off and washed with ether,

to give 1.817 g of the title compound.

809822/0 980

0.50 g of acid was stirred with 10 ml of acetone and 0.15 ml of water was added to obtain a clear solution. A solution of 0.215 g of 2-ethylhexanoate in 6 ml of acetone was added and the flaky precipitate was stirred for 1/2 hour. The solid was filtered off and washed with acetone, giving 0.343 g of the title salt. X (D "0; 100 MHz) values include 2.32, 3.13 and 3.35 (.sy2} -2-furyl protons) 4.14 (d, J 4 Hz; C-7 H), 4.76 (d, J 4 Hz; C-6-H) and 6.29 and 6.61 (AB-quartet J 17 Hz; C-2-H ₂ ).

example 1

(6R _J 7R) -3-Acetoxymethyl-7- [Z-2- (fur-2- yl) -2- (2-ureidocarbonylprop-2-yloxyirnino) -acetamide] -ceph - ^ - em-4 -carboxylic acid Man added 1.65 g of 2-bromo-2-methylpropionylurea to a stirred solution of 1.13 g of the sodium salt of (6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) -2- hydroxyiminoacetamido] -ceph-3-em-4-carboxylic acid and 0.73 ml of triethylamine in 30 ml of dimethylformamide. The mixture was stirred for 48 hours, then 100 ml of ethyl acetate were added and the solution was washed three times with 30 ml of 2N hydrochloric acid and extracted three times with sodium hydrogen carbonate solution. The aqueous extract was acidified with 2N hydrochloric acid and extracted three times with 30 ml of ethyl acetate. The extract was _{dried over Na 2} SO ^ and evaporated. The residue was dissolved in a little acetone and added dropwise to 150 ml of stirred-light petroleum to give 0.87 g of title compound (b.p. 40 to 6O ⁰ C.); [a] ^ ⁵ + 84 ° (c 1, DMSO), χ _e "(EtOH) 275 nm (ς 15 700), ^ _max (Nujol) 3700-2100 (bound OH), 3420, 3300, 3280 (NH, NH ₂ ), 1784 (β-lactam), 1735 (acetate), 1710 (CO ₂ H), 1565 cm " ¹ (CONH, CONHCONH ₂ ), -i (DMSO d _β ) comprised 0.1 (CONH), 0 , 68, 2.25 and 2.7 (CONHCONH ₂ ), 2.18, 3.21, 3.38 (a-furyl), 4.78 (6 H), 4.09 (7 H), 4, 98, 5.3 (3 -CH ₂ ), 6.28, 6.5 (2 -CH ₂ ), 7.92 (OCOCH ₅ ), 8.55 (CMe ₂ ).

Example 2

(6r, 7R) -3-Carbamoyloxymethyl-7- [Z-2- (fur-2-yl) -2-ureldocarbonylprop-2-yloxyimino) -acetamido] -ceph-3-em-4-carboxylic acid , This acid was from 2-bromo-2-methylpropiony! urea and *

809822/0980

the sodium salt of (6R, 7R) -3-carbamoyloxyriethyl-7- [Z-2- (fur-2-yl) -2-hydroxyiminoace taraldo] -cephO-em ^ -carboxylic acid prepared by the method described in Example 1. Yield 52 % i _{Λ max} (EtOH) 274 nm (£ 15,300), & _max (NuJoI) 3420, 3300, 3100 (-NH-, NH ₂ ), 3700-2100 (bound OH), 1782 cm " ¹ (CO ₂ H, -OCONH ₂ ), χ (DMSO dg) 2.2, 2.62 (NHCONHg), 1.62 (CONHCO), 8.5 (C (Me) ₂ ), 3.19 x 3.3. 2.1 (fur-2-yl), 4.1 (7 H), 4.72 (6 H), 6.29, 6.49 (2 CH _2), 5.02, 5.32 (CH 3 ₃ ), 3.4 (OCONH ₂ ).

Example 3

(6R, 7R) -3-acetoxymethyl-7-fZ-2- (fur-2-yl) - »2- (1-ureidocarbonylcyclopent-i-yloxlmlno) -acetamido1-ceph-3-em-4-carboxylic acid This acid was made from 1-bromo-1-ureidocarbonylcyclopentane and the sodium salt of (6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) -2-hydroxyiminoacetamido] -ceph-3-em-4 -carboxylic acid prepared analogously to Example 2, [a] ^ ² + 95 ° (c 0.55, ⁰ MS ⁰ ) * χ max (EtOH) 275 mn (t 16 500), ^ _max (NuJoI) 3 * 20, 3300 (NH, NH ₃ ), 3700-2100 (bound OH), 1788 (β-lactam), 1735 (acetate), 1710, 169O, 1565, 1550 cm " ¹ (CONH, CONHCONH ₂ ), r (DMSO dg) 7 , 92 (OAc), 4.95, 5.28 (dd J 13) (3 -CH ₂ ), 6.23, 6.49 (dd, J 18) (2 -CH ₂ ), 4.71 (d , J = 5) (6 H), 4.09 (dd J - 5, 8) (7 H), 0.02 (d, J = 8) (CONH), 2.11, 3.19, 3, 32 (puryl), 7.9-8.3 (cyclopentyl), 0.65 (CONHCO), 2.17, 2.64 (CONH ₂ ). Yield; 85 %.

Example 4

(6R.7R) -3-acetoxymethyl-7- ^ Z-2- (fur-2-yl) -2-r2- (3-methyl ureidocarbonyl) prop-2-yloxyimino1-acetamido \ -ceph-3-em-4- carboxylic acid

This acid was obtained from 1- (2-bromo-2-methylpropionyl) -3-methyl-

urea and the sodium salt of (6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) -2-hydroxyiminoacetamido] -ceph-3-em-4-carboxylic acid prepared according to the method described in Example 1.

809822/0980

[α] ²² + 84.6 ° (c 0.65, DMSO), A _ (EtOH) 274 nm (ίΐ6,900), (Nujol) 3340 (NH), 3700-2100 (bound OH), 1790

(ß-lactam), 1740 (OCOCH,), 17ΟΟ (CO ₂ H), 169Ο, 1540 cm "(-CONIi-, -CONHCONH-), τ (DMSO dg), 2.25, 3.2, 3, 35 (Fur-2-yl), 8.51, 8.52 (C (Me) ₂ ), 0.5 (-CONHCO), 1.75 (CONHMe), 7.28 (CONHMe), 4.1 ( 7 H), 4.75 (6 H), 6.28, 6.50 (2 CH ₂ ), 4.97, 5.29 (3 CH ₂ ), 7.9 (OCOCH). Yield: 76 %. '

Example 5

(6R, 7R) -3-acetoxymethyl-7-rE-2- (thien-2-yl) -2- (2-ureidocarbonylprop-2-yloxyimino) -acetamidoI-ceph-3-em-4-carboxylic acid

This acid was prepared from 2-bromo-2-methylpropionylurea and the sodium salt dihydrate of (6R, 7R) -3-acetoxymethyl-7- [E-2-hydroxyimino-2- (thien-2-yl) -acetamido] -ceph-3 -em-4-carboxylic acid prepared by the method described in Example 1. bound [cc] ^{2, 3} + 100 ° (c 0.75, DMSO), _Ajnax (EtOH) 263.5 nm _(fc 8OO 13), (NuJoI) 3420, 328O (NH, NH _0), 3700-2000 ( OH),

egg

1782 (ß-lactam), 17ΟΟ (-COgH), 156Ο (-CONH, CONHCONH ₂ ), 1735 cm " ¹ (OCOCH,), t (DMS0 d ₆ ) -0.01 (CONH), 4.0 (7 H), 4.7 (6H), 6.22, 6.43 (2 -CH ₂ ), 0.55 (-CONHCO-), 4.91, 5.22 (3 CH ₂ ), 7.95 (OCOCH ₃ ), 2.22, 2.68, 2.8 (thien-2-yl), 8.45 (C (Me) ₂ ), 2.2, 2.6 (-CONH ₂ ). Yield: 83 %.

Example 6

(6R, 7R) -2-acetoxymethyl-7- [7.-2- (fur-2-yl) -2-ureldocarbonyl methoxyiminoacetamido Ί-ceph-3-em-4-carboxylic acid

This acid was prepared from iodoacetylurea and the sodium salt of (6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) -2-hydroxyiminoacetamido] -ceph-3-em-4-carboxylic acid according to the Method described in Example 1 prepared. ^ _mav . (EtOH) 274 nm («17,300), max ( ^Nu J ^o1 ) 3420, 3260 (-NH-, -NH ₂ ), 3700-2100 (bound OH), 1780 (β-lactam), 1720 (-CO ₃ H, acetate), 1700, 1570, 1545 cm " ¹ (CONH, CONH ₂ ), T (DMSO dg) 2.11, 3.3, 3.18 (furyl), 5.28 (-0-CH ₂ ) , 0.09 (-CONHCO-), 2.5 (CONH ₂ ), 0.11 (CONH), 4.1 (7H), 4.78 (6H), 6.29, 6.51 (2nd -CH ₂ ), 4.95, 5.28 (3 -CH ₂ ), 7.93 (CH ₃ CO-). Yield: 34 *.

809822/0 980

Example 7

a) 1- (2-Bromo-2-methylproplonyl) -3,3-diniethylurea

8.9 g of 2-bromo-2-methylpropionyl bromide in 20 ml of methylene chloride were added dropwise at ⁰ ° C. to a stirred suspension of 3.4 g of 1,1-dimethylurea in 25 ml of methylene chloride and 16 ml of triethylamine. The mixture was stirred for 4 hours at 22 ° C. and the solvent was evaporated. The residue was stirred with 40 ml of saturated sodium hydrogen carbonate solution and extracted three times with 20 ml of ethyl acetate. The ethyl acetate solution was dried and evaporated. The residue was stirred with 50 ml of light petroleum (boiling point 40-60 ° C.) and the remaining solid was filtered off, suspended in sodium hydrogen carbonate solution and extracted twice in 20 ml of ethyl acetate. The ethyl acetate solution was dried and evaporated, the urea remaining in the form of a pale brown solid, 1.4 g, F = 98-100 ° C,) _max (NuJoI) 3400, 3370 (NH), 1742, 1685 cm " ¹ (- CONH.CON-), r (DMSO dg) 8.05 (-C (Me) ₂ ), 7.01 (-N (Me) ₂ ), 1.6 (-CONHCO-).

b) (6R, 7R) -3-acetoxymethyl-7-fZ-2- ^t .2- (3.3-dlmethylureldocarbonyl) -prop-2-yloxyimino 1-2- (fur-2-yl) -acetamido 1 -ceph ^ -em ^ -carboxylic acid

This compound was prepared from i- (2-bromo-2-methylpropionyl) -3,3-dimethylurea and the sodium salt of (6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) - 2-hydroxyiminoacetamido] -ceph-3-em-4-carboxylic acid prepared by the method described in Example 1. _Xmax (EtOH) 275 nm (ei6 500), ^ _max (Nujol) 3260 (NH), 3700-2100 (bound OH), 1788 (β-lactam), 1735 (acetate), 1720 (-CO ₂ H), 1670 , 1540 cm " ¹ (-CONH), ^ (DMSO dg) 7.09 (N (Me) ₂ ), 0.97 (-CO] WCO-), 8.5 (C (Me) ₂ ), 2, 06, 3.28, 3.16 (furyl), 0.18 (CONH), 4.01 (7H), 4.71 (6H), 6.25, 6.46 (2-CH ₂ -) , 4.97, 5.29 (3-CH ₂ -), 7.98 (CH ₅ CO). Yield: 59 #.

Example 8

a) methyl Z-2-hydroxylmino-2-phenyl acetate 4.0 g of Z-2- (hydroxyimino) -2-phenylesslgsäure were methylated in 50 ml of ether by adding a small excess of diazomethane in ether. The excess of diazomethane was reduced by Esslg-

809822/0980

acid destroyed and the solution washed with saturated sodium hydrogen carbonate solution, _{dried over Na 2} SOn and evaporated, the ester remaining. 4.16 g, O _e "(CHBr,) 36OO (OH), 3300

λ ms. x j

(OH attached), 1722 cm "(-CO ₂ R), t (DMSO dg) -2.0 (-0H), 6.08 (-CH ₃ ), 2.47 (phenyl).

b) methyl Z-2-phenyl-2- (2-ureldocarbonylprop-2-yloxyimino) acetate

Sodium hydride (80 # dispersion in oil, 0.44 g) was added to a solution of 2.6 g of methyl Z-2-hydroxyimino-2-phenyl acetate in 10 ml of benzene and 8 ml of dimethylformamide, and the mixture was stirred for 30 minutes. 3.0 g of 2-bromo-2-methylpropionylurea were added and the mixture was stirred for 20 hours. 50 ml of water were added and the solution was extracted four times with 25 ml of ethyl acetate. The extracts were washed with water, over Na ₂ SO ^. dried and evaporated. The residue was purified by chromatography on silica gel in light petroleum - and ethyl acetate (1: 1 v / v) to give to give a white solid the ester in the form, 3.3 g; o _max (NuJoI (bp 40 60 ⁰ C). ) 3 ² K) O, 3270, 3240, 31 ^ 0 (-NH; -NH ₃ ), 17W, 1728, 1703 cm " ¹ (-CO ₂ R, -CONHCONH ₂ ), r (DMSO dg) 2,3 - 2.5 (phenyl), 6.0 (methyl), 8.42 (C (Me) ₂ ), 0.9 (CONHCO), 2.0-2.8 (CONH ₂ ).

c) Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyiminoacetic acid

6.6 ml of N-aqueous sodium hydroxide solution were added dropwise to a stirred suspension of 1.0 g of methyl Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyiniino) acetate in 25 ml of methanol at ⁰ ° C. The mixture was stirred for 18 hours at 25 ° C., the pH was adjusted to 7 and the methanol was evaporated off. The residue was dissolved in sodium hydrogen carbonate solution and the solution was washed with ethyl acetate, acidified with 2N hydrochloric acid and extracted three times in 15 ml of ethyl acetate. The extracts were over Na ₃ SOj. dried and evaporated and the residue was washed with 10 ml of carbon tetrachloride, the acid remaining, 170 mg, v _maY (EtOH) 252 nm (a 11 800) _{,;} v} (NuJoI) 3600-2100 (bound

'Πΐίχλ JiICLJv 4

OH), 3 ^ 30, 328O (NH, NH ₂ ), 1720 (-CO ₂ H), 1652, 1613, 1580 cm " ¹ (-CONHCONH ₂ ), T (DMSO dg) 2.47 (phenyl), 8 , 47 (C (Me) ₂ ), 2.0 (CONHCO), 2.2-2.8 (-CONH ₂ ).

809822/0980

d) pipheny! methyl- (6R, 7R) -3- (1-methyltetrazol-5-yl-thlomethy1) -7- [Z-2-phenyl-2- (2-ureldocarbonylprop-2-yloxyimino) -acetamido] - ceph-3-em-4-carboxylate

A solution of 460 mg of Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) acetic acid in 6 ml of methylene chloride and 2 ml of dimethylformamide was slowly added to a stirred solution of 370 mg of dicyclohexylcarbodiimide and 790 mg of diphenylmethyl- (6R , 7R) -3- (1-methyltetrazol-5-ylthiomethyl) -7-aminoceph-3-em-4-carboxylate in 10 ml of methylene chloride and 3 ml of dimethylformamide and the mixture was stirred for 20 hours. The solution was filtered off and evaporated the Plltrat and dissolved the residue in 30 ml of ethyl acetate. The filtered solution was washed twice with 15 ml of 2N hydrochloric acid and twice with 15 ml of saturated sodium hydrogen carbonate solution _{, dried over Na 2} SO ₁ and evaporated. The residue was purified on silica gel plates in a mixture of light petroleum and ethyl acetate (1: 1 vol / vol) to give the ester, 58O mg, a "(NuJoI) 3 ² K) O, 328O (NH, NH ₀ ),

UlcLX. ^ C.

1788 (ß-lactam), 1720, 1710 (-CO ₀ R), 1685, 1670 cm (-CONHCONH ₂ , -CONH-), χ (DMSO dg) 0.60 (-CONHCO-), 8.59 (- C (Me) ₃ -), 2.0-2.9 (phenyl), -0.06 (-CONH-), 3.87 (7 H), 4.62 (6 H), 5.9, 6 , 5 (2-CH ₂ -), 5.59, 5.79 (3-CH ₂ -), 6.09 (-N-Me), 3.0 (-CHPh ₃ ).

e) (6R, 7R) -3- (i-methyltetrazol-5-yl-methyl) -7-rZ-2-phenyl-2- (2-ureidocarbonylprop-2-yloxylmino) -acetamido] -ceph-3-em-4 -carboxylic acid

58O mg of diphenylmethyl- (6R, 7R) -3- (1-methyltetrazol-5-ylthiomethyl) -7- [Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) -acetamido] -ceph- were stirred 3-em-4-carboxylate 10 min. With 6 ml trifluoroacetic acid and 4 ml anisole. The solution was poured into 60 ml of saturated sodium hydrogen carbonate solution and washed three times with 15 ml of ethyl acetate. The aqueous layer was acidified and extracted three times with 15 ml of ethyl acetate, and the extracts were dried and evaporated. The remaining gummy substance was dissolved in a little acetone and the solution was slowly added to 100 ml of vigorously stirred light petroleum (boiling point 40-60 ° C.), the acid being obtained in the form of a yellow powder, 180 mg,> _max (EtOH) 257 , 5 nm (e15 100), * _max (NuJoI)

809822/0980

3400, 3280 (NH, NH ₂ ), 3700 - 2100 (bound OH), 1782 (ß-lactam), 17OO (-CO ₂ H), 1685, 1675, 1560 cm " ¹ (-CONH-, -CONH ₂ ) , t (DMS0 dg) 2.42 (phenyl), 8.5 (-C (Me) ₂ -), 0.6 (-CONHCO-), 2.0-2.8 (-CONH ₂ ), 0, 0 (-CONH-), 4.01 (7 H), 4.75 (6 H), 6.21 (2-CH ₂ -), 5.62 (3-CH ₂ -), 6.0 (N -CH ₃ ).

Example 9

a) 1- (2-Bromo-2-methylpropionyl) -1,3-dimethylurea This compound was prepared analogously to the i- (2-bromo-2-methylpropionyl) -3,3-dimethylurea in the example "Yes. From 2-bromine -2-methylpropionyl bromide and 1,3-dimethylurea were obtained in 38% yield as a yellow oil, $ _β

. Max

(Nujol) 333Ο (NH), 173Ο, 17ΟΟ cm (CON. CON), τ (DMSO dg) 6.44 (NMe) 7.13 (d, J 5; NHMe), 7.95

b) (6R, 7R) -3-acetoxymethyl-7- [Z-2- ^ 1,3-dlmethylureldocarbonylprop-2-yloxyimino3 -2- (fur-2-yl) -acetamido] -ceph-3-em-4 -carboxylic acid

This compound was prepared from 1- (2-bromo-2-methylpropionyl) -1,3-dimethylurea and the sodium salt of (6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) - 2-hydroxyiminoacetamido] -ceph-3-em-4-carboxylic acid prepared by the method described in Example 1. Yield: 73 % ,, _mQv (EtOH) 274 nm ( ε ^ 2 500), ο _mav (Nujol) 33ΟΟ (NH), 3700-2100 (bound OH), 1789 (ß-lactam), 1730 (CO ₂ H) , 1685, 1535 (CONH), t (DMSO dg) 0.18 (CONH), 2.11,

3.28 3.31 (furyl), 4.11 (7 H) 4.77 (6 H), 4.97, 6.29 (3-CH _2),

6.29, 6.49 (2-CH ₂ ), 6.75 (NMe), 7.28 (NHMe), 7.93 (OAc), 8.41 (CMe ₂ ).

Pharmaceutical compositions according to the invention can be formulated analogously to the following examples.

Example A.

(a) Dry powder for injection

The sterile sodium salt of (6R, 7R) -3-acetoxy-methyl-7- [Z-2- (fur-2-yl) -2- (1-ureidocarbonylcyclopent-1-yloximino) -acetamido] -ceph-3- em-4-carboxylic acid is filled in glass vials, whereby

809822/0 980

the claimed content of each container 500 mg and 1.0 g of cephalosporin. The purging is carried out aseptically under a nitrogen atmosphere. Dfe vials will be closed using rubber stoppers or stoppers held in place by aluminum locking rings, wherein a gas exchange or the penetration of microorganisms is prevented. It is possible to make the product by dissolving it in water for injection or in any suitable sterile vehicle immediately prior to administration.

(b) Intramammary injection (for lactating or lactating

Cow)

Percentage composition (w / w)

Sodium salt of the cephalosporin used in (a): 8.33

Carrier, added to: 100.00

Carrier: Tween 60 3.00

White beeswax 6.00

Peanut oil 91.00

The three carrier components are ^{heated together to 130 °} C. for 1 hour and then cooled to room temperature with stirring. The sterile, finely powdered antibiotic is aseptically added to this carrier and the product is refined with a high speed mixer. The preparation is aseptically filled into sterile containers such as breakable aluminum tubes or plastic syringes. The filling weight is 3.0 g, each container containing 250 mg of cephalosporic acid in the form of the sodium salt. The product is intended for administration into the mammary gland through the teat canal.

809822/0980

Claims (9)

Dr. F. Zumstein Sr. - Dr. E. Assmar.n - Dr. R. Koeninsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. Γ. KCngseisen - Dr. F. Zumstein jun. PATENTANWÄLTE ΘΟΟΟ Munich 2 ■ BrauhausstraOe 4 · Telephone Semmel No. 22 53.41 ■ Telegram Zumpat ■ Telex 529979 Ceph 234/237 GLAXO LABORATORIES LIMITED, Greenford, Middlesex / England New cephalosporin derivatives, processes for their production and pharmaceutical compositions containing them. Claims 1 .J Antibiotic compounds of the general formula (I) ,, a COOH _p e ι K (CH ₉ ) .C- (CH) · CO-N-CCNR ⁰ R ⁰ 'b
H [wherein R represents a phenyl, thienyl or furyl group, R ^a and R, which are identical or different, are selected from hydrogen, C ₁ η alkyl, C ^ u -alkenyl, C, cycloalkyl, phenyl, naphthyl , Thienyl, furyl, carboxy, C ₂ _, - alkoxycarbonyl and cyano, or R ^a and R together with the carbon atom to which they are attached form a C 1 -C cycloalkylidene or cycloalkenylidene group, R ^c and R which may be the same or different, in each case a hydrogen atom or a substituting group, for example an alkyl group or substituted alkyl group, or R ^c and R together with the nitrogen atom to which they are bonded represent a saturated one 809822/0980 ORIGINAL INSPECTED Form heterocyclic ring, which contains 5-7 ring members, and which can contain further heteroatoms and through Lower alkyl may be substituted; R is hydrogen or Cj_ji-alkyl means, m and η each represent 0 or 1 such that the sum of m and η is 0 or 1 and Y is selected under: (i) a group of the formula -S (O) _n R ¹ wherein R is lower alkyl, lower cycloalkyl, phenyl-lower alkyl, Cg .. ^ - mono- or bicyclic carbocyclic aryl or a denotes a heterocyclic group and η is 0, 1 or 2, (ii) a group of the formula -OR ⁵ wherein R ^ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, Lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, heterocyclic, heterocyclic Lower alkyl or any of the above groups substituted by one or more lower alkoxy, lower alkylthio, halogen, Lower alkyl, nitro, hydroxy, acyloxy, carboxy, lower alkoxycarbonyl, lower alkylcarbonyl, lower alkylsulfonyl, lower alkoxysulfonyl, Amino, lower alkylamino and acylamino means (iii) a group of the formula -O.CO.R ⁴ wherein R is selected from C ₁ "-alkyl, which can be interrupted by an oxygen or sulfur atom or by an imino group or can be substituted by cyano, carboxy, lower alkoxycarbonyl, hydroxy, carboxycarbonyl, halogen or amino; C ₂ _ ₇ alkenyl, which may be interrupted by an oxygen or sulfur atom or by an imino group; Lower cycloalkyl; carbocyclic! or heterocyclic! Aryl, which can be substituted by hydroxy, halogen, nitro, amino, lower alkyl or lower alkylthio; Lower cycloalkyl-C 1-4 alkyl; and carbocyclic or heterocyclic! ArylC 1-4 alkyl; and 809822/0980 (iv) a group of the formula -O.CO.AR ⁵ where R- ^{5 is} hydrogen or a group as defined above for R and A>0,> S or> NH] and their non-toxic derivatives. 2.) Compound according to claim 1, characterized in that it is a syn isomer which is essentially free of the anti isomer. 3 ·) Compounds according to claim 1, wherein Y is a group -SR ² 2
denotes in which R is a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidyl, benzimidazolyl, benzoxazolyl, benzothiazolyl or triazolopyridyl group . 4.) Compounds according to claim 1, wherein Y is an acetoxy or Means carbamoyloxy group. 5.) Compounds according to claim 1 of the general formula R. C.CO.NH N COOH OCCO.NH.CO.NR ^g R ^h (5 Q η ρ ο ο / Π q f) f) [wherein R is as defined in claim 1; R ^J and R, which can be the same or different, each represent a hydrogen atom or 1 f represents a methyl group, or R ^J and R together with the carbon atom to which they are attached form a cyclopentylidene group; R ^g and R, which can be identical or different, each represent a hydrogen atom or a methyl group, and W is selected from (i) acetoxymethyl (ii) carbamoyloxymethyl and (iii) N-methylcarbamoyloxymethyl, and (iv) a group of the formula wherein R ^{w is} a pyridyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl or oxadiazolyl group] and their non-toxic derivatives. 6.) Compounds according to claim 5 * wherein W is a group of the formula -CH ₂ SR ^W means in which R ^{w is} i-methyltetrazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 1-carboxymethyltetrazol-5-yl. 7.) A connection selected under
(6R, 7R) -3-acetoxymethyl- 7- [2- (fur-2-yl) -2- (2-ureido-carbonylprop-2-yloxyimino) -acetamido] -ceph - ^ - em-4-carboxylic acid ( syn -isomeres), (6R, 7R) -3-Carbamoyloxymethy1-7- [2- (fur-2-yl) -2- (2-ureidocarbonylprop-2-yloxyimino) -acetamido] -ceph-3-em-4-carboxylic acid ( syn- isomer), (6R, 7R) -3-acetoxymethyl-7- [2- (fur-2-yl) -2- (1-ureidocarbonylcyclopent-1-yloximino) -acetamido] -ceph-5-em-4-carboxylic acid ( syn- Isomer), (6R, 7R) -3-acetoxymethyl-7- ^ 2- (fur-2-yl) -2- [2- (3-methylureidocarbonyl) -prop-2-yloxyimino] -acetamido ^ -ceph-3-em- 4-carboxylic acid ( syn -isomer), (6R, 7R) O-acetoxymethyl ^ - [2- (thien-2-yl) -2- (2-ureidocarbonylprop-2-yloxyimino) -acetamido] -ceph - ^ - em ^ -carboxylic acid 809822/0980 -5-. 275322Q ( syn -isomeres), (6R, 7R) -5-acetoxymethyl-7- [2- (fur-2-yl) -2-ureidocarbonylmethoxyiminoacetamidol-ceph - ^ - em - ^ - carboxylic acid ( syn -Isomeres), (6R, 7R) -3- acetoxymethyl-7- [2-t2- (3,3-dimethylureidocarbonyi) -prop-2-yloxyimino ) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid ( syn -Isomeres ), (6R, 7R) -> (i-Methyltetrazol-5-ylthiomethyl) -7- [2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) -acetamido] -ceph ^ -em ^ - carboxylic acid ( syn -Isomeres ); and (6R, 7R) -3-acetoxymethyl-7- [2- ^ 1,3-dimethylureidocarbonylprop-2-yloxyiminoj-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid ( syn Isomer). 8.) Process for the preparation of an antibiotic compound of the formula I according to claim 1 or a non-toxic derivative thereof, characterized in that either (A) is a compound of the formula (wherein Y is as defined in claim 1; B> S or> S- »0 (α- or ß-) means; R 'is hydrogen or a carboxyl blocking Group represents; and the dashed line that represents the 2-, 3- and 4-position connects, indicating that the connection a Ceph-2-em or Ceph-5-em compound) or a salt or an N-silylated derivative thereof with an acid the formula R.C.COOH NR ^a "e R ^d (IV) 809822/0980 (wherein R, R ^a , R, R ^c , R, R ^e , m and η are as defined in claim 1) or condensed with an acylating agent corresponding to the same,
or (B) a compound of the formula CH ₂ Y ' R ^e l I COOR _d \>. (CHJ .C. (CH_) .CO.NCO.NR ^ R ^{2 m} 'b ² (wherein B, R, R ^a , R ^b , R ^c , R ^d , R ^e , the dashed line, R ⁷ , m and η are as defined in claim 1; and Y represents an exchangeable residue of a nucleophile) with an oxygen or Converts sulfur nucleophiles; or (C) a compound of the formula RC ₍ .CO.NH
N
^% 0H COOR ^y (wherein B, R, R, Y and the dashed line are as defined in claim 1) with a compound of the formula T. (CH ₂ ) _m .C. (CH ₂ ) _n .C0.NC0NR ^C R ^d (VII) 809822/0980 (wherein R ^a , R, R ^c , R, R ^e , m and η are as defined in claim 1 «and T is chlorine, bromine or iodine, or a sulfonyloxy group), after which, if necessary and / or desired, any of the Perform the following reactions (D) in any suitable order: (i) Conversion of a ^ -isomer to the desired / N ^ -isomer. (ii) Reduction of a compound in which B> S -> 0 means to one To form a compound in which B ^ S is (iii) deacylation of a 3-acyloxymethyl compound to give a 5-hydroxymethyl compound to form, (iv) acylation of a 3-hydroxymethyl compound to form a To form 3-acyloxymethyl compound, (v) Carbamoylation of a 3-hydroxymethyl compound to give a unsubstituted or substituted 5-carbamoyloxymethyl compound to form, and (vi) removing carboxy1 blocking groups; and finally (E) the desired compound of formula I or a non-toxic derivative thereof, if necessary after Separation of the isomers wins. 9.) Pharmaceutical composition, characterized in that it contains an antibiotic compound according to claim 1 in a form suitable for use in human or veterinary medicine. 809822/09 8 0