CH637140A5 - Process for preparing novel cephalosporin derivatives - Google Patents

Description

The invention relates to a process for the preparation of cephalosporin compounds, namely a new class of cephalosporin compounds which have valuable antibiotic properties.

The present cephalosporin compounds are described with reference to "Cepham" according to J. Amer. Chem. Soc., 1962, 84,3400, the term “cephem” referring to the basic structure of cepham with a double bond. 20 Cephalosporin antibiotics are widely used in the treatment of diseases in humans and animals caused by pathogenic bacteria, and are particularly useful in the treatment of diseases caused by bacteria resistant to other antibiotics such as penicillin compounds, as well as in the treatment of penicillin-sensitive patients. In numerous cases, it has been desired to use a cephalosporinan tibiotic that is active against both gram-positive and gram-negative microorganisms, and extensive research has been directed to the development of various types of broad-spectrum cephalo-sporin antibiotics.

A particular interest is currently being directed to the development of broad spectrum cephalosporin antibiotics that are highly active against gram negative organisms. Existing commercially available β-lactam antibiotics tend to be sensitive to certain gram-negative organisms such as e.g. ß-lactamase-forming organisms, which are an increasingly common source of infection in humans 40, have a comparatively low activity. The practical therapeutic uses of aminoglycoside antibiotics such as gentamicin, which have an activity against Gram-negative organisms, tend to be restricted or difficult to administer due to the high toxicity of these antibiotics. It is well known that cephalosporin antibiotics are normally low in toxicity to humans, such that the development of broad-spectrum cephalosporin antibiotics with high activity against gram-negative organisms such as strains of Escherichia coli satisfies an essential need in chemotherapy.

The compounds obtainable according to the invention are 7β-acylamidoceph-3-em-4-carboxylic acid antibiotics and their non-toxic salts and esters, in which the acylamido part has the formula

25th

30th

35

R

R

\). (CH2) m.C. (CH9) Ti.C0.N.C0.NRCRd

2 n '

R

in which R is a phenyl, thienyl or furyl group selected from hydrogen, C 1 -C 4 -alkyl (for example methyl, tet; R'1 and R1 ', which may be the same or different, each ethyl, n-propyl, isopropyl or butyl), C2_4-alkenyl (e.g.

637 140

4th

Vinyl or allyl), C3_7-cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), phenyl, naphthyl, thienyl, furyl, carboxy, Co-j-alkoxycarbonyl (e.g. ethoxycarbonyl) and cyano, or Ra and Rb together with the carbon atom to which they are attached form a Ci_7-cycloalkylidene or cycloalkenylidene group (e.g. a cyclobutylidene, cyclopentylidene or cyclohexylidene group); Rc and Rd, which may be the same or different, are each hydrogen; -atom or an alkyl group or substituted alkyl group (for example a methyl, ethyl, propyl, isopropyl or tert-butyl group), or Rc and Rd together with the nitrogen atom to which they are attached mean my saturated or unsaturated heterocyclic Form a ring which contains 5 to 7 ring members and which may contain further heteroatoms such as N, O or S and which may be substituted by lower alkyl; Rc is water-5-carbon or C 1-4 alkyl (e.g., methyl, ethyl, n-propyl-isopropyl or butyl); and m and n each represent 0 or 1 such that the sum of m and n is 0 or 1.

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

R.C.CO.NH

H

H

COOH r €

(I)

c ^ d

.C. (CH0) .CO.N.CO.NR R 2 m • 2 n ■

wherein R, Ra, Rb, Rc, Rd, R "\ m and n are as defined above and Y represents the residue of an oxygen or sulfur nucleophile, and their non-toxic salts and F.ster.

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

be used to cause a variety of diseases

like B. to treat respiratory and urinary system infections.

These compounds show antibiotic activity with a broad spectrum of activity. The compounds have an activity against microorganisms which form β-lactamases

\ Ra

R '•' '

and have a very high stability to beta-Lacta mases, which are formed by a large number of Gram-negative organisms.

35 The new compounds were found to have good activity against numerous members of Enterobacteriaceae {e.g. B. strains of Escherichia coli, Klebsiella aerogenes and Proteus mirabilis). ';

The compounds in which at least one of the radicals Ra and 40 Rb has a different meaning than that of hydrogen, also showed activity against Pseudomonas organisms. Bj against strains of Pseudomonas aeruginosa.

defines that it is the syn-isomeric form with regard to the configuration of the group ~; '. • • •. • • •

R

c ^ d

0. (CH9V.C. (CIL) .CO.N. CO. NRCR

m z n. ; . • ■. - -

R

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

K.C.CO.NH-

N

R3

R

1

NSo- (CH2) m, ^ '(CH2) n * CÖ * ^ CO'NRCRd

637 140

referred to, this configuration based on the work of Ahmad and Spenser in Can. J. Chem., 1961, 39, 1340.

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 90% of the syn isomer. However, it is preferred that the compounds are syn isomers that are substantially free of the corresponding anti isomer.

The term non-toxic salts and esters are to be understood as meaning those which are physiologically acceptable in the administration dose. It can be seen that when Ra or Rb is carboxy, salts and esters can be formed by reacting one or both of the carboxy groups present in such compounds of Formula I.

Non-toxic salts that can be formed from the compounds of general formula I include salts of inorganic bases such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts); Salts of organic bases (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine salts); and, if appropriate, acid addition salts, e.g. B. 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, e.g. B. with a polystyrene resin or cross-linked polystyrene-divinylbenzene copolymer resin containing amino or quaternary amino groups, or, if appropriate, contain sulfonic acid groups, or, if appropriate, with a resin containing carboxyl groups, e.g. B. a polyacrylic acid resin are formed. 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 is advantageous in therapeutic applications due to the rapid distribution of such salts in the body after administration. However, if insoluble salts of the compounds of formula I are desired in a specific application, for example for use in depot preparations, such salts can be formed in a conventional manner, for example with suitable organic amines.

Biologically acceptable, metabolically labile ester derivatives that can be formed from compounds of Formula I include e.g. B. acyloxymethyl ester, e.g. B. Lower alkanoyloxymethyl esters, such as acetoxymethyl, acetoxyethyl or pivaloyloxy methyl ester.

It can be seen that if Ra and Rh are different in the above formulas, the carbon atom to which they are attached can have an asymmetry center. Compounds obtainable according to the invention in which Ra and Rb are different can thus be diastereomers. The invention includes the preparation of 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, alicyclic and heterocyclic substituted thioureas; Dithiocarbamate; aromatic, aliphatic and cyclic thioamides, e.g. B. thioacetamide and thiosemicarbazide; Thiosulfates; Thiols; Thiophenols; Thioacids, e.g. B. thiobenzoic acid or thiopicolinic acid; and dithioic acids.

One class of sulfur nucleophiles includes those compounds of the formula R'.S (0) nH, wherein R1 is an aliphatic, e.g. B. lower alkyl, such as methyl, ethyl or n-propyl group; an alicyclic, e.g. Lower cycloalkyl such as cyclohexyl or cyclopentyl group; an aromatic, e.g. B. C () _ | 2-mono- or bicyclic carbocyclic aryl such as phenyl or naphthyl group; an araliphatic, e.g. B. phenyl-lower (e.g. C | _4) alkyl such as benzyl group; or is a heterocyclic group and n represents 0, 1 or 2. A preferred class of nucleophiles falling within the scope of the above formula is that of the general formula R2SH, where R2 is an aliphatic, e.g. B. lower alkyl such as methyl, ethyl or n-propyl or low alkanoyl such as acetyl; araliphatic, e.g. B. lower alkyl such as methyl, ethyl or n-propyl or lower alkanoyl such as aceto tyl; 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. B. phenyl, substituted phenyl or a heterocyclic group with at least one 5- or 6-membered ring with 15 one or more heteroatoms selected from O, N and S means. Such heterocyclic groups R2 may be substituted and examples of suitable heterocyclic groups include thiadiazolyl, e.g. B. 5-methyl-l, 3,4-thiadiazol-2-yl; Di-azolyl; triazolyl, e.g. Triazol-4-yl; tetrazolyl, e.g. B. 1-methyl-20 tetrazol-5-yl, l-ethyltetrazol-5-yl, l-phenyltetrazol-5-yl or 1-carboxymethyltetrazol-5-yl; Thiazolyl; Thiatriazolyl; Oxazolyl; Oxadiazolyl, e.g. B. 2-phenyl-l, 3,4-oxadiazol-5-yl; Pyridyl, e.g. B. N-methylpyrid-2-yl; Pyrimidyl; condensed heterocyclic ring systems such as benzimidazolyl, benzoxazolyl, benzothiazolyl 25 such as benzothiazol-2-yl, triazolpyridyl or purinyl; and substituted versions of such condensed ring systems, e.g. B. nitrobenzothiazol-2-yl such as 5- or 6-nitrobenzothiazol-2-yl.

The group Y in formula I above can also be derived from numerous oxygen nucleophiles. Examples of 30 oxygen nucleophiles include water; Alcohols, e.g. B. Alkanols such as methanol, ethanol, propanol and butanol; and lower riganic and alkanoic acids.

The term “oxygen nucleophiles” thus includes compounds of the following formula

35

RAW

wherein the R3 group is lower alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl); Lower alkenyl (e.g. 40 allyl); Lower alkynyl (e.g. propynyl); Lower cycloalkyl (e.g. cyclopropyl, cyclopentyl or cyclohexyl); Lower cycloalkyl-lower alkyl (e.g. cyclopropylmethyl), cyclopentylmethyl or cyclohexylethyl); Aryl (e.g. phenyl or naphthyl); Aryl-lower rigalkyl (e.g. benzyl); a heterocyclic group (e.g. a 45 heterocyclic group as defined for R2 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 ethyl 50thio), 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.

55 If water is the nucleophile, 3-hydroxymethyl-cephalosporin compounds are obtained. Such 3-hydroxymethyl compounds and their non-toxic derivatives can have antibacterial activity and it is worth noting that they can be metabolites of the compounds of general formula I 60, where Y is acetoxy. 3-Hydroxymethylcephalosporins can be acylated to form derivatives which are characterized by having the group 3-CH2.O.CO.R4 or 3-CH2.O.CO.AR5, wherein AO, S orNH, R4 is one is organic group and R5 is hydrogen or an organic group.

The group R4CO- or R5A.CO- can be selected from a broad class of such groups, which are described in the literature, and can have up to 20 carbon atoms. R4

637 140

io

15

and, if appropriate, R3 can thus each be a hydrocarbon group or such a group which contains one or more substituent atoms or groups and can thus be selected from the following list, which is not intended to be exhaustive:

(i) CnH2 "-M, where n is an integer from 1 to 7, e.g. B. 1 to 4 means. The group can be straight-chain or branched and, if desired, can be interrupted by an oxygen or sulfur atom or an imino group or can be substituted by cyano, carboxy, lower alkoxycarbonate, hydroxy, carboxycarbonyl (HOOC.CO.), halogen (e.g. chlorine, Bromine or iodine) or amino. Examples of such groups include methyl,

Ethyl, propyl, isopropyl, n-butyl, t-butyl, sec-butyl and 2-chloroethyl.

(ii) C "H2" _1, where n is an integer from 2 to 7. The group can be straight-chain or branched and, if desired, can be interrupted by an oxygen or sulfur atom or an imino group. Examples of such groups include vinyl and propenyl.

(iii) R6, in which R6 carbocyclic aryl (for example C6_ | 2-mono- or 20 bicyclic carbocyclic aryl), heterocyclic aryl (for example comprising a 5- or 6-membered ring with at least one of the following atoms O, N, and S), Is lower cycloalkyl, substituted aryl and substituted cycloalkyl. Examples of this group include phenyl; substituted phenyl, e.g. B. Hydroxyphenyl. Chlorophenyl, fluorophenyl, tolyl, nitrophenyl, aminophenyl, methoxyphenyl or methylthiophenyl; Thien-2- and -3-yl; Pyridyl; Cyclohexyl; Cyclopentyl; Cyclopropyl; Sydnon;

H

25th

Naphthyl; and substituted naphthyl, e.g. B. 2-ethoxynaphthyl.

(iv) Rf '(CH2) m, wherein R "is the one given in (iii) above

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 R6 groups indicated under (iii) e.g. B. Low cycloalkyl-Q-j-alkyl and carbocyclic or heterocyclic aryl-Cj_4-alkyl such as benzyl and the suitable substituted benzyl groups.

3-position substituents of the above type thus include lower alkanoyloxymethyl groups such as acetoxymethyl and isobutyryloxymethyl, lower alkenoyloxymethyl groups such as crotonyloxymethyl; Aroyloxymethyl groups such as benzoyl oxymethyl; Carbamoyloxymethyl, N- (lower alkyl) carbamoyloxymethyl such as N-methylcarbamoyloxymethyl, and N- (haloalkyl) carbamoyloxymethyl such as N- (2-chloroethyl) carbamoyloxymethyl.

The term "low", as used herein to identify aliphatic groups, indicates that this group can contain up to 6 carbon atoms, unless stated otherwise. The term "low" as used to identify cycloaliphatic groups indicates that the group can contain 3 to 7 (e.g. 5 to 7) carbon atoms.

One class of the new cephalosporin antibiotics includes compounds of the general formula

H

R.C.CO.NH

II

N "j

\? O

O.C.CO.NH

t

Rf

- - <H, C0.NRgRh I

■ W

(II)

COOH

wherein R is as defined above; Rj and Rf, which may be the same or different, each represent a hydrogen atom or a methyl group, or RJ and Rf together with the carbon atom to which they are attached form a cyclopentylidene group; Rg and Rh, which may 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 -CH2SRW, where Rw is selected from pyridyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl and substituted (e.g. lower alkyl, carboxyme

45

50

thyl- or phenyl-substituted) versions of these groups such as N-methylpyrid-2-yl, l-methyltetrazol-5-yl, l-phenyltetrazol-5-yl; l-carboxymethyltetrazol-5-yl; 5-methyl-l, 3,4-thiadiazol-2-yl and 5-phenyl-l, 3,4-oxadiazol-2-yl, and their non-toxic salts and esters.

The compounds obtainable according to the invention are u. a. those described in British Patent 1399 086.

The invention thus relates to a process for the preparation of an antibiotic compound of the general formula I, which is as defined above, or a non-toxic salt thereof, which is characterized in that a compound of the formula:

H

h2n_

(f

H

I.

_N

(III)

-ch2y

COOR

wherein Y is as defined above and R7 is hydrogen or an aliphatic or araliphatic alcohol or a carboxyl blocking group, e.g. B. the rest of an ester-forming ester-forming phenol, silanol or stannanol (this

637 140

Alcohol, this phenol, this silanol or stannanol preferably containing 1 to 20 carbon atoms) or a symmetrical or mixed anhydride group derived from a suitable acid; or a salt, e.g. B. an acid addition salt such as a hydrochloride. Hydrobromide, sulfate, nitrate, phosphate, methanesulfonate or tosylate, or an N-silylated derivative thereof with the syn isomer or with a mixture of the syn and anti isomer of an acid of the formula

R.C. COOH

N

\

f f

0. (CHo) .C. (CH-) .CO.N.CO. v 2'm I 2. n kb

(IV)

NR ° Rd wherein R, Ra, R1 ', Rc, Rd, R °, m and n are as previously defined, or condensed with an acylating agent corresponding thereto, after which any carboxyl blocking group which may be present is cleaved and finally the desired compound of formula I or a non-toxic salt thereof, if necessary after separation of the isomers, wins.

The carboxylic acids obtained can be converted into non-toxic esters, for example by methods known from the prior art. Thus, e.g. B. Biologically acceptable esters can be prepared using conventional esterification agents. 1-oxides can be treated by treating the corresponding cephalosporin sulfides with a suitable oxidizing agent, e.g. B. with a peracid such as metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid or with t-butyl hypochlorite,

this latter reagent being suitably used in the presence of a weak base such as pyridine.

Acylating agents that can be used in the preparation of the compounds of Formula I include acid halides, especially acid chlorides or bromides. Such acylating agents can be prepared by combining an acid (IV) or a salt thereof with a halogenating agent, e.g. B. phosphorus pentachloride, thionyl chloride or oxalyl chloride. Treatment of the sodium, potassium or triethylammonium salt of the acid (IV) with oxalyl chloride is advantageous in that isomerization is minimal under these conditions.

Acylations using acid halides can be carried out in aqueous and non-aqueous reaction media, suitably at temperatures from -50 to + 50 ° C, preferably -20 to + 30 ° C, if desired in the presence of an acid-binding agent. 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 dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes such as low 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which are used in the Bind the acylation reaction released hydrogen halide.

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

25th

40

The acylation can with other amide-forming derivatives such as acids of formula IV, such as. A symmetrical anhydride or a mixed anhydride (e.g. pivalic acid 20 or formed with a halogen formate such as a lower alkyl halogen formate). The mixed or symmetrical anhydride can be formed in situ. So z. B. A mixed anhydride can be formed using N-ethoxycar-bonyl-2-ethoxy-l, 2-dihydroquinoline.

It can be seen that in processes for the preparation of compounds of the formula I in which Ra or Rb denotes a carboxy group, it is in many cases necessary to remove the carboxy group, for example by substitution with a carboxyl-blocking group, e.g. B. a group, as defined above in connection with R7, is required. Compounds with a 3 substituent

-CHiY

35 wherein Y represents a hydroxy group can be prepared according to the methods described in British Patents 1121308,1399086 and 1474519.

The carbamoylation of the 3-hydroxymethyl compounds can be carried out by conventional methods. For example, a 3-hydroxymethylcephalosporin can be reacted with an isocyanate of the formula Rk.NCO (where Rk represents an unstable substituent group or an alkyl group) to give a compound which is in the 3-position a substituent of the formula -CH20. CONHRk contains (where Rk has the meaning given above). If Rk is an unstable substituent, this substituent can, if desired, be subsequently cleaved off, for example by hydrolysis, to give a 3-carbamoyloxymethyl group. Unstable groups Rk that are easily cleaved 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 Rk groups can generally be cleaved by acid or base catalyzed hydrolysis (e.g. by 55 base catalyzed hydrolysis using sodium bicarbonate).

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

If a compound of formula I is obtained as a mixture of isomers, the syn-isomer can be obtained, for example, by f> 5 conventional methods, such as crystallization or chromatography.

The acids corresponding to formula IV and the corresponding acid halides and anhydrides are new.

50

637 140

8th

For use as starting materials for the preparation and the corresponding anti-isomers, which preferably contain at least 90% of the compounds of the general formula I, syn-isomers are used.

Compounds of the general formula IV and those der- The acids (IV) can by etherification of an acid of the speaking acid halides and anhydrides in their syn formula

Isomeric form or in the form of mixtures of the syn isomers 5

R. C. C00H 'n

N.

OH

(VIII)

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

R

t

R

i c ^ d

T '. (CH0) .C. (CH0) .CO.N.CO.NR R Z in «* À ri

R

(Vlla)

(wherein R \ Rb, Rc, Rd, Rc, m and n are as defined above and T 'is halogen such as chlorine, bromine or iodine, or sulfonate such as tosylate). The separation of the isomers can be carried out either before or after such etherification. The etherification reaction is preferably carried out in the presence of a base, e.g. B. of potassium t-butoxide or sodium hydride and preferably in an organic solvent such as. B. dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane, or an N, N-substituted amide such as dimethylformamide. Under these conditions, the configuration of the oximino group remains essentially unchanged by the etherification reaction. This process is particularly important in manufacturing

30th

of acids (IV) where both Ra and Rb are hydrogen.

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

Another process for the preparation of acids of the general formula (IV) is that of reacting a gly-oxyacid of the formula

35

R.CI-COOH

(IX)

(wherein R is as defined above) with a compound of the formula

R

HoN.0. (CH) o (î;. (CH0) .CO. '2 m n -

Rb

2 n

R

Ä.

CO «NRCRd

(X)

(wherein Ra, Rb, Rc, Rd, Rc, m and n are as defined above). If necessary, the reaction of IX with X can be followed by a separation of the syn and anti isomers.

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

Carboxyl-blocking groups R7 which are used in the preparation of compounds of the formula I or in the preparation of required starting materials are preferably groups which can easily be split off during a suitable stage in the reaction sequence, advantageously during the last stage. However, in some cases it may be appropriate to use biologically acceptable, metabolically labile carboxyl blocking groups such as acyloxymethyl groups (e.g. acetoxymethyl, acetoxyethyl and pivaloyloxymethyl) and to retain them in the final product to provide a biologically acceptable ester derivative of a compound of the Form Formula I.

Suitable carboxyl blocking groups are well known in the art, with a list of representative carboxyl blocking groups in the British patent

50

1399 086 is included. Preferred carboxyl blocking groups include aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-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, an acidic, basic or enzymatically catalyzed hydrolysis and reductive method can be used in many cases.

The new antibiotic compounds, e.g. B. The compounds of formula I and their non-toxic salts and esters can be formulated for administration in any suitable manner in analogy to other antibiotics, i.e. H. in the form of pharmaceutical compositions containing such an antibiotic compound and which are suitable for use in human or veterinary medicine. Such compositions can be prepared for use in a conventional manner using any required pharmaceutical carrier or excipient.

The new antibiotic compounds can be used for injection

60

9

637 140

don are formulated and can be presented in the form of a unit dose in ampoules or in containers containing multiple doses with an added protective agent or preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reprocessing with a suitable carrier, e.g. B. sterile, distilled water for injection, before use.

The antibiotic compounds can also be formulated in a form suitable for absorption by the gastrointestinal tract, e.g. B. in the form of tablets or capsules. The antibiotic compounds can also be formulated as suppositories, e.g. B. conventional suppository bases such as cocoa butter or any other glyceride.

The veterinary compositions may e.g. B. be formulated as intramammary preparations in bases or bases with either a long duration of action or rapid release.

The compositions may contain 0.1% or more, e.g. B. 0.1 to 99%, preferably 10 to 60%, contain active material depending on the method of administration. If the compositions contain dosage units, each preferably contains 50 to 1500 mg of the active ingredient. The dosage used to treat an adult is preferably 500 to 5000 mg / day depending on the route of administration and the frequency of administration, although higher daily doses may be required to treat some infections.

The antibiotic compounds of the formula I can be administered in combination with other therapeutic agents such as antibiotics, for example penicillins or other cephalosporins.

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

Preparation 1 1-bromocyclopentane carbonyl chloride

Boil 6.4 g of l-bromocyclopentane carboxylic acid with 6 ml of thionyl chloride at reflux for 40 min. Removal of the thionyl chloride and distillation gave the acid chloride, 5.6 g, bp. 85-87 ° C / 17 mm, y ™ * 1780 cm "'(COC1), x (CDC13) approx. 7.2- 8.4 (cyclopentyl).

Preparation 2 1-bromo-l-ureidocarbonylcyclopentane

3.5 g of 1-bromocyclopentanecarbonyl chloride were stirred with 3.15 g of urea at 80 ° C. for 30 minutes. The mixture was cooled and 30 ml of water were added, and the pH was then brought to 7. The solid was filtered off and crystallized twice from ethanol to give 0.7 g of acylurea, F = 189-191 ° C, Ymax (Nujol) 3420.3300.3220, (NH, NH,), 1702, 1690 and 1585 cm'1 (CONH, CONH2), x (DMSO dfi) -approx. 0.2 (NH), - about 2.4 and - about 2.6 (NH2), about 7.3-8.5 (cyclopentyl).

Manufacturing 3

syn-triethylammonium triphenylmethoxyiminofur-2-ylacetate

5.05 g (6.9 ml) of triethylamine was added to a stirred suspension of 3.10 g of syn-hydroxyiminofur-2-yl-acetic acid in 30 ml of methylene chloride. The solid quickly dissolved and then the triethylamine salt partially separated. A solution of 6.15 g of chlorotriphenylmethane in 30 ml of dry was added

15

Add methylene chloride to a slurry and stir the mixture to dryness under reduced pressure 1 h before evaporation. The remaining solid was stirred with 100 ml of water for 1 h, filtered off and dried and then stirred with 50 ml of 5 ether. The title salt was filtered off and dried (8.95 g) .x (DMSO df); 60 MHz) 2.34 and 3.48 (syn-2-furyl protons) 2.63 (m, Ph protons) 6.95 (q, J 7 Hz; N-CH -.- CH,) and 8 , 80 (t, J 7 Hz; N-CH2CH3).

10 Example a) Methyl-Z-2-hydroxyimino-2-phenylacetate 4.0 g of Z-2- (hydroxyimino) -2-phenylacetic acid in 50 ml of ether were methylated by adding a small excess of diazomethane in ether. The excess diazomethane was destroyed by acetic acid and the solution was washed with saturated sodium bicarbonate solution, dried over Na2SO4 and evaporated to leave the ester. 4.16 g, Ymax (CHBrV) 3600 (OH), 3300 (bound OH), 1722 cm "1 (-CO.R), x (DMSO d6) -2.0 (-OH), 6.08 (- CH,), 2.47 "(phenyl).

b) Methyl-Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) -

acetate

25 Sodium hydride (80% dispersion in oil, 0.44 g) was added to a solution of 2.6 g of methyl-Z-2-hydroxyimino-2-phenylacetate in 10 ml of benzene and 8 ml of dimethylformamide and the mixture was stirred 30 min. 3.0 g of 2-bromo-2-methylpropionylurea were added and the mixture was stirred for 20 h. 50 ml of 30 water were added and the solution was extracted four times with 25 ml of ethyl acetate. The extracts were washed with water, dried over Na2S04 and evaporated. The residue was purified by chromatography on silica gel in light petroleum (bp 40-60 ° C) and ethyl acetate (1: 1 vol / vol) to give the ester as a white solid, 3.3 g; ymax (Nujol) 3400.3270.3240.3140, (-NH; -NH-.); 1748.1728.1703 cm "1 (-CO, R, -CONHCONHi), x (DMSO d6) 2.3-2.5 (phenyl), 6.0 (methyl), 8.42 (C (Me), ), 0.9 (CONHCO), 2.0-2.8 (CONH2).

40

c) Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyiminoacetic acid. 6.6 ml of N-aqueous sodium hydroxide solution were added dropwise.

solution to a stirred suspension of 1.0 g of methyl-Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) acetate in 25 ml of Metha-45 noi at 0 ° C. The mixture was stirred at 25 ° C. for 18 h, 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 dried 50 over Na2SO4 and evaporated and the residue was washed with 10 ml carbon tetrachloride, leaving the acid, 170 mg,> .max (EtOH) 252 nm (e 11800), Ymax (Nujol) 3600-2100 (bound OH ), 3430.3280 (NH, NH,), 1720 (-C02H), 1652.1613.1580 cm- "1 (-CONHCONH-.), T 55 (DMSO dfl) 2.47 (phenyl), 8.47 (C (Me),), 2.0 (CONHCO), 2.2-2.8 (-CONH2).

d) Diphenylmethyl- (6R, 7R) -3- (l-methyltetrazol-5-ylthiomethyl) -7- [Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) -

® acetamido] -ceph-3-em-4-carboxylate

A solution of 460 mg of Z-2-phenyl-2- (2-ureidocar-bonylprop-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 65 (6R, 7R) -3- (l-methyltetrazol-5-ylthiomethyl) -7-aminoceph-3-em-4-carboxylate in 10 ml methylene chloride and 3 ml dimethylformamide and stirred the mixture for 20 h. The solution was filtered off, the filtrate was evaporated and the residue was dissolved in 50 ml

637 140

10th

Ethyl acetate. The filtered solution was washed twice with 15 ml of 2N hydrochloric acid and twice with 15 ml of saturated sodium bicarbonate solution, dried over Na, SO, and evaporated. The residue was purified on silica gel plates in a mixture of light petroleum and ethyl acetate (1: 1 vol / vol) 5 to give the ester, 580 mg, ymax (Nujol) 3400, 3280 (NH, NH,), 1788 (β-lactam) , 1720.1710 (-C02R), 1685, 1670 cm1 (-CÓNHCONIL, -CONH-), x (DMSO d6) 0.60 (-CONHCO-), 8.59 (-C (M ~ e), -) , 2.0-2.9 (phenyl), -0.06 (-CONH-), 3.87 (7 H), 4.62 (6 H), 5.9, 6.5 (2-CHr) , 5.59, 5.79 w (3-CH, -), 6.09 (-N-Me), 3.0 (-CHPh2).

e) (6R, 7R) -3- (l-methyltetrazol-5-ylthiomethyl) -7- [Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) acetamido] -ceph-3-em- 4-carboxylic acid

15

580 mg of diphenylmethyl- (6R, 7R) -3- (l-methylte-trazol-5-ylthiomethyl) -7- [Z-2-phenyl-2- (2-ureidocarbonylprop-2-yloxyimino) acetamido] - were stirred ceph-3-em-4-carboxyIat 10 min with 6 ml trifluoroacetic acid and 4 ml anisole. The solution was poured into 60 20 ml of saturated sodium bicarbonate 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, 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 (bp 40-60 ° C) to give the acid as a yellow powder, 180 mg, Xmax (EtOH) 257 , 5 nm (e 15100), Ymax (Nujol) 3400.3280 (NH, NH2), 3700-2100 (bound OH), 1782 (ß-lactam), 1700 (-CO, H), 1685.1675.1560cm " 1 (-CONH-, 30

-CONH,), x (DMSÒ dfi) 2.42 (phenyl), 8.5 (-C (Me) 2-), 0.6 (-CONHCO-), 2.0-2.8 (-CONH, ), 0.0 (-CONH-), 4.01 (7 H), 4.75 (6 H), 6.21 (2-CH2-), 5.62 (3-CH, -), 6, 0 (N-CH3).

The following connections can also be made using the same procedure: 35

(6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) -2- (2-ureidocar-bonyl-prop-2-yloxyimino) -acetamido] -ceph-3-em- 4-carbon acid; [a] ^ + 84 ° (c 1, DMSO),), max (EtOH) 275 nm (e 15700),

Ymax (Nujol) 3700-2100 (bound OH), 3420.3300.3280, (NH, NH2), 1784 (β-lactam), 1735 (acetate), 1710 (CO, H), 1565 40 cm "1 (CONH , CONHCONH2), x (DMSO d6) included Ö, 1 (CONH), 0.68.2.25 and 2.7 (CONHCONH,), 2.18.3.21.3.38 (a-furyl), 4 , 78 (6 H), 4.09 (7H), 4.98.5.3 (3 -CH2), 6.28.6.5 (2 -CH,), 7.92 (OCOCH,), 8 , 55 (CMe2);

(6R, 7R) -3-carbamoyloxymethyl-7- [Z-2- (fur-2-yl) -2-ureido-carbonylprop-2-yloxyimino) -acetamido] -ceph-3-em-4-carboxylic acid ; Amax (EtOH) 274 nm (e 15300), Ymax (Nujol) 3420.3300, 3100 (-NH-, -NH2), 3700-2100 (bound OH), 1782 cm "1

45

(CO, H, -OCONH,), x (DMSO d6), 2.2 2.62 (NHCONH,), 1.62 (CONHCO), 8.5 (C (Me),), 3.19.3 , 3.2.1 (Fur-2-yl), 4.1 (7H), 4.72 (6H), 6.29.6.49 (2CH,), 5.02.5.32 (3 CH2), 3.4 (OCONH2);

(6R, 7R) -3-acetoxymethyl-7- [Z-2- (fur-2-yl) -2- (l-ureidocar-bonylcyclopent-l-yloximino) -acetamido] -ceph-3-em-4- carboxylic acid; [a] £ + 95 ° (c0.55, DMSO), Xmax (EtOH) 275 nm (e 16500), Ymax (Nujol) 3420.3300 (NH, NH2), 3700-2100 (bound OH), 1788 (ß -Lactam), 1735, (acetate), 1710, 1690, 1565, 1550 cm "1 (CONH, CONH CONH,), x (DMSO d6) 7.92 (OAc), 4.95.5.28 (dd J13 ) (3-CH,), 6.23.6.49 (dd, J18) (2-CH,), 4.71 (d, J = 5) (6H), 4.09 (dd J = 5 , 8) (7H), 0.02 (d, J = 8) (CONH), 2,11,3,19,3,32 (furyl), 7,9-8,3 (cyclopentyl), 0,65 (CONHCO), 2.17, 2.64 (CONH2);

(6R, 7R) -3-acetoxymethyl-7- {Z-2- (fur-2-yl) -2- [2- (3-methyl-ureidocarbonyl) prop-2-yloxyimino] acetamido} -ceph- 3-em-4-carboxylic acid; [a] d + 84.6 ° (c0.65, DMSO), Amax (EtOH) 274 nm (e 16900), Ymax (Nujol) 3340 (NH), 3700-2100 (bound OH), 1790 (β-lactam ), 1740 (OCOCH,), 1700 (CO, H), 1690, 1540 cm "1 (-CONH-, -CONHCONH-), x (DMSO d6), 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 (6H), 6.28.6.50 (2 CH2), 4.97, 5.29 (3 CH2), 7.9 (OCOCH3);

(6R, 7R) -3-acetoxymethyl-7- [E-2- (thien-2-yl) -2- (2-ureidocar-bonylprop-2-yloxyimmo) -acetamido] -ceph-3-em-4- carboxylic acid; [a] o + 100 ° (c0.75, DMSO), Xmax (EtOH) 263.5 nm (e 13800), Ymax (Nujol) 3420.3280 (NH, NH2), 3700-2000 (bound OH), 1782 (β-lactam), 1700 (-C02H), 1560 (-CONH, CONH-CONH,), 1735 cm "1 (OCOCH,), x (DMSOd6) -0.01 (CONH), 4.0 (7H ), 4.7 (6H), 6.22.6.43 (2 -CH2), 0.55 (-CONHCO-), 4.91.5.22 (3CH,), 7.95 (OCOCH ,), 2,22,2,68,2,8 (Thien-2-yl), 8.45 (C (Me) 2), 2.2, 2.6 (-CONH2);

(6R, 7R) -2-acetoxymethyl-7- [Z-2- (fur-2-yl) -2-ureidocarbonylmethoxyiminoacetamido] -ceph-3-em-4-carboxylic acid; km; a (EtOH) 274nm (e 17300), Ymax (Nujol) 3420.3260 (-NH-, -NH2), 3700-2100 (bound OH), 1780 (ß-lactam), 1720 (-C02H, acetate) , 1700.1570.1545 cm "1 (CONH, CONH,) x (DMSO d6) 2.11,3,3,3,18 (furyl), 5.28 (-0-ÇH,), 0.09 ( -CÓNHCO-), 2.5 (CONH2), 0.11 (CONH), 4.1 (7 H), 4.78 (6 H), 6.29.6.51 (2-CH2), 4, 95, 5.28 (3 -CH,), 7.93 (CH3CO);

(6R, 7R) -3-acetoxymethyl-7- [Z-2- {2- (3,3-dimethylureidocar bonyl) prop-2-yloxyimino} -2-fur-2-yl) acetamido] ceph -3-em-4-carboxylic acid; Xmax (EtOH) 275 nm (e 16500), Ymax (Nujol) 3260 (NH), 3700-2100 (bound OH), 1788 (β-lactam), 1735 (acetate), 1720 (-C02H), 1670.1540 cm "1 (-CONH), x (DMSO d6) 7.09 (N (Me) 2), 0.97 (-CONHCO-), 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, -), 4.97, 5 , 29 (-3-CH, -), 7.98 (CH3CO).

m

Claims (9)

637 140 PATENT CLAIMS 1 c d 0. (CO .C. (CHj .CO.N.CO.NR R Z in i, 2 n R ° in which R denotes a phenyl, thienyl or furyl group, Ra and Rb, which may be the same or different, are selected from hydrogen, C1-4-alkyl, C2_4-alkenyl, C3_7-cycloalkyl, phenyl, naphthyl, thienyl, furyl, Carboxy, C2-5 alkoxycarbonyl and cyano, or Ra and Rb together with the carbon atom to which they are attached form a C3_7-cycloalkylidene or cycloalkenylidene group, Rc and Rd, which may be the same or different, each represent a hydrogen atom or represent an alkyl group or substituted alkyl group, or Rc and Rd together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which contains 5-7 ring members and which can contain further hetero atoms and are substituted by lower alkyl can be; Rc is hydrogen or Q_4-alkyl, m and n are each 0 or 1, such that the sum of m and n is 0 or 1, and Y is selected from: (i) a group of the formula -S (0) nR ' where R1 is lower alkyl, lower cycloalkyl, phenyl-lower alkyl, Q, _, 2-mono- or bicyclic carbocyclic aryl or a heterocyclic group and n is 0, 1 or 2, (ii) a group of the formula -OR3 wherein R3 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 alkoxy sulfonyl, amino , Lower alkylamino and acylamino means (iii) a group of the formula 30th -O.CO.R4 wherein R4 is selected from C [_7-alkyl, which may be interrupted by an oxygen or sulfur atom or by an imino group, or may be substituted by cyano, carboxy, lower alkoxycarbonyl, hydroxy, carboxycarbonyl, halogen or amino; C2_7 alkenyl which can 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, _4-alkyl; and carbocyclic or heterocyclic aryl-C, _4-alkyl; and (iv) a group of the formula 45 -O.CO-A R5 in which R3 is hydrogen or a group as defined above for R4 and A> 0,> S or> NH, and their non-toxic salts, characterized in that a compound of the formula: (III) COOR wherein Y has the above meaning and R7 represents hydrogen or a silylated derivative thereof with the syn isomer or with a carboxyl blocking group, or a salt or an N mixture of the syn and anti isomer of an acid of the formula: 1. Process for the preparation of the syn isomer or a syn isomer of antibiotic compounds of the formula: Mixing of the syn and anti isomers with at least 75% of the (I) R 2. The method according to claim 1, characterized in that one produces a syn isomer which is essentially free of the anti isomer. 3. The method according to claim 1, characterized in that compounds of the formula I are prepared in which Y is a group -SR2 means in which R2 a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolyl - And Purinylgruppe means. 3rd 637 140 R.C. COOH II N R (IV) R 0. (CH2) m-Ç. (CH?) ^. CO.N.CO.NRcRd R wherein R, Ra, Rb, Rc, Rd, Rc, m and n are as defined above, or condensed with an acylating agent corresponding thereto and removing the carboxyl blocking group if the compound obtained bears one. 4. The method according to claim 1, characterized in that compounds of formula I are prepared in which Y is an acetoxy or carbamoyloxy group. 5. The method according to claim 1, characterized in that the carboxylic acids of the formula I obtained are converted into corresponding salts by reaction with a non-toxic base. 6. The method according to claim 1, characterized in that a 3-acyloxymethyl compound obtained is deacylated to form the corresponding 3-hydroxymethyl compound. 7. The method according to claim 1, characterized in that acylated 3-hydroxymethyl compound obtained to form a corresponding 3-acyloxymethyl compound. 8. The method according to claim 1, characterized in that carbamoylated a 3-hydroxymethyl compound obtained to form a corresponding, unsubstituted or substituted 3-carbamoyloxymethyl compound. 9. A process for the preparation of non-toxic esters of the carboxylic acids of the formula I, in which the symbols have the meanings given in claim 1, characterized in that a carboxylic acid of the formula I is prepared by the process according to claim 1 and these are then esterified. R.C.GO.NH- ii N