CH621790A5 - Process for the preparation of a syn-isomer or of a mixture of syn- and anti-isomers of novel antibiotically active 7beta-acylamidocephem-4-carboxylic acids - Google Patents

Description

The present invention relates to a process for the preparation of a syn isomer or a mixture of syn and anti isomers, in which the proportion of the syn isomer is at least 75%, of antibiotic new 7β-acyla-mido-cephem-4- carboxylic acids, of which the syn isomer has the formula I,

CO.

COOK

wherein R is a hydrogen atom or an organic group; Ra is a hydrogen atom or an acyl group; B> S or> S- »0; and Y is a quaternary ammonio radical, which is the radical of a tertiary aliphatic, araliphatic, aromatic or cyclic amine or a heterocyclic amine having more than one hetero atom, where at least one hetero atom consists of the nitrogen atom, and the dashed line between the second -, 3- and 4-position indicates that the compound can be a Ceph-2-em or Ceph-3-em compound, as well as their non-toxic salts.

The 7β-acylamido-ceph-3-em-4-carboxylic acids obtainable according to the invention are antibiotics from the cephalosporin series. In the cephalosporin series, these antibiotics may contain various 3-position substituents, including unsubstituted methyl groups and methyl groups substituted with a variety of substituents as described in the literature.

The new compounds obtainable according to the invention are distinguished by the fact that the 7-acylamido group of the cephalosporin antibiotic is an a-hydroxyiminoacylamido or a-acyloxyiminoacylamido group, the compounds being syn isomers or mixtures in which the syn isomeric form is at least 75% represents.

As mentioned, the compounds obtainable according to the invention have the syn (cis) isomeric form with regard to the configuration of the ORa group with regard to the carboxamido group. The isomeric mixtures preferably contain at least 90% of the syn isomer and not more than 10% of the anti isomer.

According to the suggestion by Ahmad and Spencer (Can. J. Chem. 1961, Vol. 39, 9.1340), these configurations are represented as follows:

R • C • CO • NH—

il syn configuration

R • C • CO • NH—

N anti configuration

RaO

The term "non-toxic" as used herein includes those salts which are physiologically acceptable at the dosage administered.

Salts that can be prepared from the compounds obtainable according to the invention include:

(a) salts with inorganic bases, such as alkali metal salts,

e.g. B. sodium and potassium salts, alkaline earth metal salts, e.g. B. Calcium salts and salts with organic bases, e.g. B. procaine, phen-ylethylbenzylamine and dibenzylethylenediamine salts and

(b) acid addition salts, e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, Phoss

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phosphoric acid, p-toluenesulfonic acid and methanesulfonic acid.

The salts can also be in the form of resinates, e.g. with a polystyrene resin containing amino groups, quaternary amino groups or sulfonic acid groups or with a resin containing carboxyl groups, e.g. Polyacrylic acid resin. If desired, the resin may be cross-linked, i.e. it can be a styrene / divinyl benzene copolymer which contains the appropriate groups. In addition, the derivatives can be in the form of a chelate with a heavy metal, such as iron or copper.

The compounds obtainable according to the invention, including the non-toxic derivatives of these compounds, are characterized by their high antibacterial activity against a large number of gram-positive and gram-negative organisms, which is associated with a particularly high stability against β-lactamases, which is caused by various gram-negative organisms Organisms are formed.

The stability to β-lactamases can be assessed in comparison to cephaloridine, which by definition can be assigned a value of 1 with regard to the particular organism.

The cephalosporin compounds referred to below are generally named with respect to the cepham (J. Amer. Chem. Soc. 84 [1962] 3400). The term "cephem" refers to the basic structure of cepham, which is provided with a double bond. The penicillin compounds referred to below are generally described with respect to the Penam (J.

Amer. Chem. Soc. 75 [1953] 3293).

The compounds of formula I are prepared using the method defined in the characterizing part of claim 1.

For the preparation of compounds of formula I in which Y represents one of the radicals indicated, the starting materials are tertiary aliphatic, aromatic, aliphatic and cyclic amines, including trialkylamines, e.g. Triethylamine, pyridine bases such as pyridine and alkylpyridines; as well as heterocyclic amines with more than one heteroatom, where at least one heteroatom is nitrogen, such as pyrimidines, purines, pyridazines, pyrazines, pyrazoles, imidazoles, triazoles and thiazoles.

A preferred group of these compounds corresponds to the formula:

I (Rd) n where n is zero or an integer from 1 to 5, and Rd, where the groups Rd, if n is an integer from 2 to 5, are the same or different, an aliphatic group, e.g. a lower alkyl group such as methyl, ethyl, n-propyl or isopropyl; an aryl group, e.g. Phenyl; an aliphatic group, e.g. a phenyl-lower alkyl group such as benzyl or phenylethyl; an alkoxymethyl group, e.g. Methoxymethyl, ethoxymethyl, n-propoxymethyl or isopropoxymethyl; an acyloxymethyl group, e.g. an alkanoyloxymethyl group such as acetoxymethyl, formyl; a carbamoyl group; an acyloxy group, e.g. an alkanoyloxy group such as acetoxy; an esterified carboxyl group; an alkoxy group, e.g. Methoxy, ethoxy, n-propoxy or isopropoxy; an aryloxy group, e.g. Phenoxy; an aralkoxy group, e.g. Benzyloxy; an alkylthio group, e.g. Methylthio or ethylthio; an arylthio group; an aralkylthio group; a cyano group;

621790

a hydroxy group, an N-mono-lower alkylcarbamoyl group, e.g. B. N-methylcarbamoyl or N-ethylcarbamoyl; an N, N-di-lower alkylcarbamoyl group, e.g. N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl; an N- (hydroxy-lower alkyl) carbamoyl group, e.g. N- (hydroxymethyl) carbamoyl or N- (hydroxyethyl) carbamoyl; or a carbamoyl-deralkyl group, e.g. B. is a carbamoylmethyl or carbamoyl-ethyl.

Ceph-2-em compounds of the formula I obtained can then be isomerized in a conventional manner to the corresponding ceph-3-em compounds. Sulfoxides obtained, i.e. Compounds of the formulas I, Ia and Ib, in which B> S-> 0, can be reduced to the corresponding, particularly preferred, compounds in which B> S.

This can be done, for example, by reducing the corresponding acyloxysulfonium or alkyloxysulfonium salt, which can be used in situ e.g. can be made with acetyl chloride in the case of an acetoxysulfonium salt by doing the reduction e.g. by sodium dithionite or by iodine ions, such as in a solution of potassium iodide in a water-miscible solvent, e.g. Acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide is carried out. The reaction can take place at a temperature of -20 to + 50 ° C.

Alternatively, the reduction of the 1-sulfinyl group by phosphorus trichloride or phosphorus tribromide in solvents such as methylene chloride, dimethylformamide or tetrahydrofuran can be accomplished, preferably at a temperature of from -20 to + 50 ° C.

The salts of the compounds obtained can be prepared by customary methods. For example, the base salts are advantageously prepared by reacting the acids obtained with sodium or potassium 2-hexenoate.

In the process products, the group Ra, if it is an acyl group, can be selected from a large number of possible groups. Thus the group Ra can be a carboxylic acyl group, Rc CO, which has 1 to 20 carbon atoms. In particular, the group Rc can be an aliphatic, cycloaliphatic or aromatic group or it can be an organic group which is connected to the carbonyl group via an oxygen atom, a sulfur atom or an imino group. Such an aliphatic, cycloaliphatic or aromatic group can be substituted by halogen atoms, e.g. F, Cl, Br or J, amino groups, nitro groups, alkyl groups with 1 to 6 carbon atoms or alkoxy groups with 1 to 6 carbon atoms.

Examples of groups Ra include alkanoyl, alkenoyl and alkinoyl groups with up to 7 carbon atoms, e.g. the acetyl group, the propionyl group, the butyryl group, the acrylyl group or the crotonyl group, substituted groups of this type, e.g. halogenated groups (F, Cl, Br or J) or amino derivatives or substituted amino derivatives of such groups, e.g. the chloroacetyl group, the dichloroacetyl group or the β-aminopropionyl group, alkoxycarbonyl groups with up to 7 carbon atoms, e.g. the ethoxycarbonyl group or the tertiary butoxycarbonyl group, substituted alkoxycarbonyl groups, e.g. the 2,2,2-trichloroethoxycarbonyl group, alkylthiocarbonyl groups with up to 7 carbon atoms and substituted derivatives of these groups, aralkyloxycarbonyl groups, e.g. the benzhydryloxycarbonyl group or the benzyloxycarbonyl group, aroyl groups with 7 to 13 carbon atoms, e.g. the benzoyl group and substituted e.g. nitrated derivatives of such groups, e.g. the nitrobenzoyl group and substituted or unsubstituted carbamoyl or thiocarbamoyl groups, i.e. Compounds in which the group Ra of the formula

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621790

(Rb) 2N • CO- or (Rb2N • CS-

corresponds, where Rb may be the same or different and a hydrogen atom or a substituent, such as an alkyl group having 1 to 7 carbon atoms, e.g. An ethyl group or a methyl group or a substituted e.g. halogenated alkyl group with 1 to 7 carbon atoms, e.g. represents a chloroethyl group or the group Ru, where Ru has the meaning given below.

The group R in the above formulas can be selected from the following not necessarily complete list:

(I) hydrogen,

(II) Ru, wherein Ru represents an aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl group or a non-aromatic or mesoionic group. Examples of these groups include: the phenyl group, the naphthyl group, substituted phenyl or naphthyl groups such as e.g. by halogen atoms, e.g. Chlorine or bromine atoms, hydroxy groups, lower alkyl groups, e.g. Methyl groups, nitro groups, amino groups, lower alkylamino groups, e.g. Methylamino groups, di-lower alkylamino groups, e.g. Dimethylamino groups, lower alkanoyl groups, e.g. B. acetyl groups, lower alkanoylamido groups, lower alkoxy groups, e.g. B. methoxy or ethoxy groups, or lower alkylthio groups, e.g. Methylthio groups are substituted; or 5- or 6-membered heterocyclic groups containing at least one heteroatom such as S, N or O, e.g. Thien-2-yl, thien-3-yl, furyl, pyridyl, 3- or 4-isoxazolyl, substituted 3- or 4-isoxazolyl groups, e.g. the 3-aryl-5-methylisoxazol-4-yl group, the aryl group being a phenyl group or a halophenyl group; the cyclohexyl group, the cyclopentyl group, the sydnone group or a cyclohexadienyl group.

(III) R "(CH2) mQn (CH2) p, where m is zero or an integer from 1 to 4, n is zero or 1, p is an integer from 1 to 4 and QS, O or NR1, where R1 is hydrogen or an organic group, for example an alkyl group such as the methyl group or an aryl group such as the phenyl group, examples of these groups being methyl, ethyl or butyl groups which are substituted by the various groups Ru mentioned above under (II) Benzyl groups and the corresponding substituted benzyl groups.

(VI) CnHan-3, wherein n represents 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 the group NR11, in which Rn represents a hydrogen atom or an organic group, e.g. an alkyl group such as a methyl group or an aryl group such as a phenyl group; or the group may be substituted by a cyano group, a carboxy group, an alkoxycarbonyl group, a hydroxy group or a carboxycarbonyl group (HOOC.CO.) or by a halogen atom. Examples of such groups include hexyl, heptyl, butylthiomethyl, cyanomethyl or trihalomethyl groups.

(V) CnH2n-i where n is an integer from 2 to 7. The group may be straight or branched and may be interrupted by an oxygen or sulfur atom or the group NR11, where R11 is a hydrogen atom or an organic group, e.g. represents an alkyl group such as the methyl group or an aryl group such as the phenyl group. An example of such a group is the vinyl group or the propenyl group.

(VI) CnH2n-3, wherein n represents an integer from 2 to 7. An example of such a group is the ethynyl group.

(VII) Various organic groups connected via carbon atoms, including cyano groups, amido groups and lower alkoxycarbonyl groups.

Of course, the process according to the invention can also be applied to cephalosporanic acid derivatives which have any acyl group in the 7-position, in particular a precursor of the group

R-C-CO-

N

^ Ndr3

wear, be applied.

The syn and anti isomers can be different by suitable methods, e.g. by their ultraviolet spectra, by thin-layer chromatography or paper chromatography processes or by their nuclear magnetic resonance spectra. For example, in solution in DMSO-d6 the amide NH doublets of the compounds of the formula I appear in the syn isomers at a lower field than is the case with the anti isomers. These factors can be used to monitor reactions.

The antibacterial compounds obtainable according to the invention can be formulated in any way into a form suitable for administration in human as well as in veterinary medicine by working in an analogous manner to other antibiotics.

The preparations can contain the active ingredient in amounts of 0.1% upwards, preferably in amounts of 10 to 60% depending on the route of administration. When the compositions comprise unit dosages, each unit preferably contains 50 to 500 mg of the active ingredient. The dosage for treating adults is preferably in the range of 100 to 3000 mg, e.g. B. 1500 mg daily, depending on the route and frequency of administration.

The compounds obtainable according to the invention can be used in combination with other therapeutic agents such as antibiotics, e.g. other cephalosporins, penicillins or tetracyclines.

The following examples are intended to further illustrate the present invention.

example 1

N- [7ß- (2-Hydroxyimino-2-phenylacetamido) -ceph-3-em-3-yl-methyl] - (4-carbamoylpyridinium) -4-carboxylate (syn isomer)

A solution of 500 mg of 3-acetoxymethyl-7ß- (2-hydroxyi-mino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomer) and 500 mg of isoenicotinamide in 10 ml of water was stirred for 1.5 Heated to 70 ° C for hours. The solution was then diluted with water, filtered to remove the bulk of a dark insoluble material and passed over an ion exchange column (Bio-rad AG-1-X8 in the acetate form). The eluate was examined by electrophoresis at pH 1.9, and it was found that two components were present, both of which migrated towards the cathode. The faster moving component corresponded to isonicotinamide while the slower one had mobility similar to that of cephaloridine and which also gave the expected purple color with iodine platinum reagent. Evaporation of the eluate under reduced pressure at 35 ° C gave a residue which was triturated with acetone and filtered. The solid was washed with acetone and dried to give 140 mg (25%) of the title compound. The material was homogeneous on electrophoresis at a pH of 1.9 and migrated towards the cathode.

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[cc] D -44 ° (c 0.72, DMSO);

UV spectrum: Àmax. (EtOH) 251 nm (e 13,000).

IR spectrum: Vmax. (Nujol) 3330, 3150 (NH and OH), 1771 (β-lactam), 1680 and 1560 (CONH) and 1606 cm'1 (CO2-).

NMR spectrum: x (DMSO-de) u. a. 0.37.1.50 (two doublets (branches of a quartet), J 7 Hz; p-disubstituted pyridine ring), 1.15 and 1.76 (two broad singlets; CONH2), 2.3-2.7 (Multiplet; aromatic protons), 4.26 (multiplet; C-7 H and C-3 CH2), 4.8 (multiplet; C-6 H and C-3 CH2), 6.40 and 6.88 (two Doublets (branches of a quartet), J 18 Hz; C-2 CH2).

Example 2

N- [7ß- (2-Hydroxyimino-2-phenylacetamido) -ceph-3-em-

3-yl-methyl] -pyridinium-4-carboxylate (syn isomer)

A solution of 5.0 g of 3-acetoxymethyl-7ß- (2-hydroxyi-mino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer and 4 ml of pyridine in 100 ml of water was added for 3 hours heated under a nitrogen atmosphere to 70 ° C. The reaction mixture was then cooled and passed over an ion exchange column (AG-1-X8 resin acetate form), eluting with water, and 100 ml fractions were collected and those used in electrophoresis containing the desired product were combined and freeze-dried to give 0.75 g (14%) of N- [7β- (2 ~ hydroxyi-mino-2-phenylacetamido) -ceph-3-em-3-yl-methyl] - pyridium-4-carboxylate

5 621790

(syn isomer), [cx] d -49.5 ° (c0.83, DMSO);

UV spectrum: Xmax. (pH 6 phosphate buffer) 255 nm (e 20 500). IR spectrum: Vmax. (Nujol) 1770 (β-lactam), 1660 and 1550 cm-1 (CONH).

5 NMR spectrum: t (DMSO-dô) u. a. 0.46.1.36 and 1.80 (pyridine ring protons), 2.3-2.7 (multipatt; aromatic protons)

1 »Example 3

N- [7β- (2-Hydroxyimino-2- (fur-2-yl) acetamido) ceph-3-em-3-ylmethyl] -4'-carbamoylpyridinium-4-carboxylate (syn isomer)

A solution of 2.5 g of 3-acetoxymethyl-7β- [2-hydroxyi-is-mino- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid and 2.5 g of isonikotinamide in water was heated to 65-70 ° C for 3 hours under nitrogen. The cooled mixture was passed down through a column of AGLX8 resin (acetate form) and eluted with water. Fractions were pooled on the basis of the electrophoretograms and freeze-dried to a white powder which was washed well with acetone and dried to give 0.834 g (29%) of the title compound; [cx] d - 610 (c 0.84, DMSO)

25 UV spectrum:> .max. (pH 6 buffer) 267.5 nm (e 19 500) IR spectrum: Vmax. (Nujol) 3340 (NH), 1772 (ß-lactam), 1680 and 1560 (CONH), 1608 cm "1 (CO2-)

NMR spectrum: r (d6-DMSO) the values include 0.40, 1.26, 1.50 and 1.75 (multiplets, aromatic protons), 1.26 and 30 1.75 (broad singlets; CONH2), 4.26 (multiplet; C-7H), 4.28 and 4.77 (C-3 CH2), 4.88 (d, J 5 Hz, C-6 H).

B

Claims (3)

621790 2. The method according to claim 1, characterized in that an isomerized A2 isomer of the formula I isomerized to the corresponding A3 isomer. 2nd Claims 1. Process for the preparation of the syn isomer or a mixture of syn and anti isomers, in which the proportion of the syn isomer is at least 75%, of compounds of the formula I. R.C.CO.NH COOK wherein R represents a hydrogen atom or an organic group; Ra is a hydrogen atom or an acyl group; B> S or> S-> 0; and Y is a quaternary ammonio radical, which is the radical of a tertiary aliphatic, aliphatic, aromatic or cyclic amine or a heterocyclic amine with more than one hetero atom, at least one hetero atom consisting of the nitrogen atom, and the dashed line between the second -, 3- and 4-position indicates that the compound can be a Ceph-2-em or Ceph-3-em compound, as well as their non-toxic salts, characterized in that the syn isomer or a Mixture of syn and anti isomers in which the proportion of the syn isomer is at least 75%, corresponding compounds of which the syn isomer has the formula II R.C.CO.NH (II) COOH wherein Y 'is a removable group, optionally with intermediate protection of the 4-carboxyl group, reacted with an amine defined under Y and optionally converting the compound obtained into a non-toxic salt. 3. The method according to claim 1, characterized in that a compound of the formula I obtained in which B> S-> 0 is reduced to the corresponding compound in which B> S is reduced.