CH620215A5 - Process for the preparation of a syn-isomer or a mixture of syn- and anti-isomers of novel antibiotically active 7-beta-acylamidoceph-3-em-4-carboxylic acids - Google Patents

Description

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PATENT CLAIMS 1. Process for the preparation of a syn isomer or a mixture of syn and anti isomers, the proportion

H

l l

R.C.CONH 1-

I.

\ /

ORa in which

R furyl, thienyl or phenyl;

Ra Ci-C4-alkyl, C2-C4-alkenyl, Cz-Ca-alkynyl, C3-C7-

Cycloalkyl or phenyl;

Rs Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C7-

Cycloalkyl, benzyl or phenyl; and B> S or> S— »O

mean, and of their non-toxic salts, characterized in that a compound of the formula III present in the form of the syn isomer or a mixture of syn and anti isomers

H 1

Acyl.NH

0 ^ -

Ô00K (HD,

of the syn isomer is at least 90%, of antibiotic new 7β-acylamidoceph-3-em-4-carboxylic acids of the formula

4. The method according to claim 1, characterized in that the implementation of (III) with (IV) in a

20 temperature in the range of 0 to 25 0 C.

5. The method according to claim 1, characterized in that one carries out the reaction of (III) with (IV) in the presence of a tri-lower alkylamine.

6. The method according to claim 1, characterized in that a compound of formula I obtained is converted into a non-toxic salt.

7. The method according to claim 6, characterized in that a compound of formula I obtained by reaction with sodium 2-ethylhexenoate in its sodium salt

30 transferred.

8. The method according to claim 1, characterized in that one obtained a compound of formula I, wherein B> S, to the corresponding compound, wherein

B> S—> 0 means oxidized.

35 9. The method according to claim 1, characterized in that the syn isomer is obtained after separation of a mixture of the syn and anti isomers.

10. A process for the preparation of biologically compatible esters of compounds of the formula I, characterized in that a compound of the formula I is prepared and esterified by the process according to claim 1.

CH2O.CO.NH.R (i) a

C00H

CH20H

where acyl is the group R.C.CO.

II

N

vORa means and the dashed line indicates that the compound can be a Ceph-2-em or Ceph-3-em compound, optionally with intermediate protection of the 4-carboxyl group, with an isocyanate of the formula IV

Rs-NCO

(IV)

reacted and isomerized a ceph-2-em compound obtained to the corresponding ceph-3-em compound.

2. 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.

3. The method according to claim 1, characterized in that one carries out the reaction of (III) with (IV) at a temperature in the range from - 50 to +105 0 C.

45 The invention relates to a method according to claim 1.

The cephalosporin compounds referred to below are generally so 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.

Numerous cephalosporin compounds are known which have antibacterial activity. These compounds have A3 unsaturation and are substituted in the 3-position by an optionally substituted methyl group and in the 7-position by an acylamido group.

It has also been found that the antibiotic properties of a special ceph-3-em-4-carboxylic acid are mainly determined by the nature of the 7β-acylamido group and the nature of the substituent in the 3-position. Numerous researches have now been carried out to find combinations of these groups in order to obtain antibiotically active cephalosporin compounds with special properties. Ss cephalosporin antibiotics are used for the treatment of diseases which are caused by pathogenic bacteria in humans and animals. They are particularly used to treat diseases caused by

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Bacteria that are resistant to other antibiotics such as penicillins, as well as used to treat patients who are sensitive to penicillin. For many applications, there is a desire to have a cephalo-sporin antibiotic available which is effective against both gram-positive and gram-negative microorganisms. Great efforts have therefore been made to develop cephalosporin antibiotics with a broad spectrum of activity.

The use of a large number of commercially available or experimental cephalosporin antibiotics is limited in practice by their relatively high sensitivity to β-lactams, which are produced by numerous bacteria. Cephalosporin antibiotics with a broad spectrum of activity should therefore be endowed with considerable stability towards β-lactamases, including those which are produced by gram-negative microorganisms.

Another difficulty with the therapeutic use of cephalosporin antibiotics is that they are broken down in vivo, e.g. B. by enzymes present in the body, e.g. B. esterases, whereby they are inactivated.

It has now been found that the compounds of the formula I obtainable according to the invention have a special combination of the substituents in the 7β and 3 position,

which gives these compounds a broad spectrum of activity, combined with high ß-lactame stability and good stability in vivo.

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.

According to the suggestion by Ahmad and Spencer (Can. J. Chem. 1961, Vol. 39,9 1340), this configuration is shown as follows:

R.C.CO.NH- (Ia).

II

N

^ OR1

The expression “non-toxic” as used here applies to those derivatives which are physiologically compatible at the dosage administered, namely salts which are biologically compatible.

- H I I

■ C. CONE

II

\ r /

H3

which may be in the form of the sodium or potassium salt, for example.

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

The reaction is preferably carried out in the presence of a tri-lower alkylamine, in particular a (Ci-GO-trialkylamine). The reaction can be carried out in the range from -50 to +105 ° C., expediently from 0 to 250 ° C.

It is advantageous to work in an essentially ester, 1-oxide and solvate, in particular hydrates.

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

Salts with inorganic bases, the alkali metal salts, s z. B. sodium and potassium salts, alkaline earth metal salts, e.g. B. calcium salts, and salts with organic bases, e.g. B. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethane-olamine, diethanolamine, triethanolamine and N-methyl-glucoseamine salts.

The salts can also be in the form of resinates which are formed, for example, with a polystyrene or cross-linked polystyrene / divinylbenzene copolymer resin having amino groups or quaternary ammonium groups.

If R in formula I is a furyl group, it can be a fur-2-yl or fur-3-yl group. If R is a thienyl group, it can be a thien-2-yl or thien-3-yl group. However, the preferred meaning of R is that of a fur-2-yl group.

Examples of the groups Ra in question are:

Methyl, ethyl, vinyl, allyl, propargyl and cyclopentyl. Rs and Ra can, if the definition permits, be the same or different. Examples include methyl, ethyl, vinyl, allyl and cyclopentyl.

Compounds of the formula I in which R is fur-2-yl and Ra is methyl are particularly preferred.

The compounds obtainable according to the invention, including the non-toxic salts of these compounds, are distinguished by their high antibacterial action against a large number of gram-positive and gram-negative organisms, which have a particularly high stability against β-lactamases and are characterized by various gram-negative organisms Organisms are formed, connected, from. These properties make the compounds suitable for the treatment of diseases caused by pathogenic bacteria in humans and animals.

Of the compounds of the formula I, owing to their broad spectrum of activity, their stability in the presence of human serum, their high stability against β-lactamases produced by a large number of microorganisms and their resistance to mammalian esterases, the syn isomer of (6R, 7R) -7- [2- (fur-2-yl) -2-methoxy-iminoacetamido] -3-N-methyl-carbamoyloxymethyl-ceph-3-em-4-carboxylic acid, according to formula II

inert organic solvents, e.g. B. in an N, N-di-6 # substituted amide, a halogenated hydrocarbon or an ether, e.g. B. by the method described in US Pat. No. 3,355,452.

The compounds of formula III serving as the starting material can, for. B. according to the methods described in GB-PS 1 121 308 and 6S of BE-PS 783 449.

Protective groups for the 4-carboxyl group are, in particular, those groups which are described in a later one

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Stage of the reaction sequence can be easily split off again and preferably have 1 to 20 carbon atoms. Examples of protected carboxyl groups are described in BE-PS 783 449. Preferred protected carboxyl groups are e.g. B. aryl-lower alkoxycarbonyl such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl, lower alkoxycarbonyl such as t-butoxycarbonyl, and halogen-lower alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl. The protective group can be split off by customary methods known from the literature, for example by acid or base-catalyzed hydrolysis or by enzymatically catalyzed hydrolysis.

The syn isomer of the compound of formula I can then be isolated in a conventional manner.

If a compound of the formula I in which B> S- »0 is obtained as the process product, this can be reduced to the corresponding compound in which B> S means. The reduction can be carried out in such a way that an acyloxysulfonium or alkyloxysulfonium salt prepared in situ, which, for. B. is obtained in the case of acetoxysulfonium salt by treating the sulfoxide with acetyl chloride, reduced. The reduction can be carried out with the aid of sodium dithionite or iodine ions, as described in solutions of potassium iodide in a water-miscible solvent, e.g. As acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide, are present, which is generally carried out at a temperature of -20 to + 50 ° C.

If a compound of formula I is obtained as a process product, wherein B is> S, this compound can be oxidized into the corresponding 1-oxide, i.e. H. a compound of formula I, wherein B> S- »0, are converted. Oxidation can be accomplished by treating with a suitable oxidizing agent. Suitable oxidizing agents are, for example, peracids, such as metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid, and t-butyl hypochlorite. It is convenient to work in the presence of a weak base such as pyridine.

Ceph-2-em compounds obtained can be isomerized to the corresponding ceph-3-em compounds by treatment with a base.

The process products can then in their non-toxic derivatives, for. B. salts or esters are transferred.

The preferred sodium salt is obtained, for example, by reaction with sodium 2-ethylhexenoate.

The conversion into physiologically compatible esters can be carried out using conventional esterification agents.

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 from 0.1% upwards, preferably in amounts from 10 to 60%, depending on the route of administration. When the compositions comprise unit dosages, each unit preferably contains 50 to 1500 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. B. other cephalosporins, penicillins or tetracyclines.

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

All temperatures are given in ° C. The melting points in Examples 1 to 6 were determined on a Kofler bench. The melting points in Examples 7 and 8 were determined in open capillaries on a Mettler device and take the form (My), where x is the rate of heating in ° C. per minute and y is the switch-on temperature. Rotations were measured in the temperature range from 18 to 24 ° C. Ultraviolet spectra were measured in a pH 6 phosphate buffer. The structures were also confirmed by infrared spectroscopy and nuclear magnetic resonance spectroscopy.

example 1

(6R, 7R) -7- [2- (fur-2-yl) -2-methoxyimino-acetamido] -3-N-phenyl-carbamoyloxymethyl-ceph-3-em-4-carboxylic acid (syn-isomer)

A solution of 1.00 g of the syn isomer of (6R, 7R) -7- [2-Fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethyl-ceph-3-em-4-carboxylic acid in 20 ml of N, N-dimethylformamide (purified by filtering through basic aluminum oxide) was cooled to 5 ° C. and treated with 0.73 ml of triethylamine and 2.85 ml of phenyl isocyanate. The mixture was stirred at 5 ° C. for 1 hour and then the ice bath was removed and stirring was continued at 20 ° C. for 1.5 hours. The solution was partitioned between 100 ml of 3 percent aqueous sodium carbonate solution and 100 ml of ethyl acetate. The layers were separated and the aqueous solution was washed with 3 × 100 ml of ethyl acetate and then covered with 100 ml of ethyl ether and acidified to pH 1.8 with concentrated hydrochloric acid.

The layers were separated and the aqueous layer was extracted with 4 X 100 ml more ethyl acetate. The combined organic extracts were washed with 5 X 100 ml water and 100 ml saturated sodium chloride solution and dried (MgSO-i) and the solvent was removed in vacuo to give a yellow foam which was triturated with 50 ml ether, giving 905 mg of the title compound was obtained, [cc] d + 27 ° (c 1, DMSO) X PH6 max 255 nm (e 23 500) and 270 nm (e 19 500).

Example 2

Sodium (6R, 7R) -7- [2- (fur-2-yI) -2-methoxy-iminoacetamido] -3-N-methylcarbamoyloxy-methylceph-3-em-4-carboxylate (syn-isomer)

By treating 1.525 g of the syn isomer of (R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylic acid in 60 ml of N, N-dimethylformamide with 1.12 ml of triethylamine and 2.0 ml of methyl isocyanate, as in Example 1, gave 0.803 g of the syn isomer (6R, 7R) -7- [2- (fur-2-yl) -2- methoxyimino-acetamido] -3-N-methylcarbamoyloxymethylceph-3-em-4-carboxylic acid. A portion of 0.726 g thereof was dissolved in 2 ml acetone and a solution of 1.6 mmol sodium DL-2-ethylhexanoate in 1.6 ml acetone was added and the solution was cooled overnight. The product was filtered off, washed with chilled acetone and dried in vacuo to give 282 mg of the title compound.

[a] D + 59 ° (C 1, H20); X PH6 max 274 nm (s 17 600).

Example 3

(6R, 7R) -3- (N-ethylcarbamoyloxymethyl) -7- [2- (fur-2-yI) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

By reacting 1.54 g of the syn isomer (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethyl-ceph-3-em-4-carboxylic acid in 60 ml of NsN-dimethylformamide with 2.0 ml of ethyl isocyanate and 1.12 ml of triethylamine, as in

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55

60

65

Example 1 gave 622 mg of the title compound, [<x] d + 68 ° (C 1, DMSO); X PH6 max 273 nm (e 16 350).

Example 4

(6R, 7R) -3- (N-t-Butylcarbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

By reacting 2.00 g of the syn isomer of (6R, 7R) -7- [2-fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylic acid in 60 ml of N , N-dimethylformamide with 5.20 g of t-butyl isocyanate and 2.92 ml of triethylamine, as in Example 1, gave 1.58 g of the title compound, [<x] d + 77 ° (c 1, DMSO); XP ^ max275 nm (e 16 400).

Example 5

(6R, 7R) -3- (N-allylcarbamoyloxymethyl) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

By treating 2.00 g of the syn isomer of (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethyl-ceph-3-em-4-carboxylic acid in 100 ml of N, N-dimethylformamide with 2.0 ml of triethylamine and 4.42 g of allyl isocyanate, as in Example 1, gave 1.63 g of the title compound, [a] D + 32 ° (c 1.1, DMSO); XPH6max 274 nm (e 13 100).

Example 6

(6R, 7R) -7- [2- (fur-2-yl) -2-methoxyimino-acetamido] -3-N-methylcarbamoyloxymethyl-ceph-3-em-4-carboxylic acid (syn isomer)

A suspension of 1.00 g of the syn isomer of (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethyl-ceph-3-em-4-carboxylic acid in 50 ml of dry methylene chloride were mixed with 0.871 g of tri-n-butyltin oxide and stirred at 210 under nitrogen for 30 minutes, during which the suspension dissolved. 0.60 g (10.50 mmol) of methyl isocyanate was added and the mixture was stirred for a further 3 hours. 30 ml of ethyl acetate and 30 ml of water were added and the methylene chloride was removed in vacuo. The volume of the ethyl acetate was brought to about 30 ml and the pH of the solution was adjusted to 8.5 with aqueous sodium bicarbonate solution. The aqueous solution was washed with 3 × 30 ml of ethyl acetate, then covered with 30 ml of ethyl acetate and adjusted to pH 1.9 with hydrochloric acid. The phases were separated and the aqueous phase was extracted with a further 3 × 50 ml of ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution and dried (magnesium sulfate) and the solvent was removed in vacuo,

whereby 0.962 g of the title carboxylic acid was obtained as an almost white foam; [cx] d + 47 ° (c 0.57, DMSO); Xmax 273 nm (e 15 450).

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Example 7

(6R, 7R) -3-N-cyclohexylcarbamoyloxymethyl-7- [2-methoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

A suspension of 1.00 g of the syn isomer of (6R, 7R) -3-hydroxymethyl-7- [2-methoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid in 50 ml of dry benzene, 0.870 g of tri-n-butyltin oxide was added under nitrogen, and a solution was obtained after stirring for 30 minutes. 1.318 g of cyclohexyl isocyanate was added and stirring was continued for 3 1/2 hours after which the reaction was essentially complete.

By adding 50 ml of water to the reaction mixture, a precipitation of dicyclohexylurea was obtained (which was filtered off). The benzene layer was separated, stirred and 50 ml of 0.1 M hydrochloric acid was added to give a white gelatinous precipitate which was filtered off.

The precipitate was dissolved in aqueous sodium bicarbonate solution and extracted with 50 ml of ethyl acetate. The aqueous phase was acidified with 2 M hydrochloric acid and extracted with 2 × 80 ml of ethyl acetate. The organic layer was washed with 2 × 150 ml of water, dried over magnesium sulfate and evaporated in vacuo, giving 396 mg of

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Title compound obtained as an almost white solid, F (Mso) = 162 °, [oc] d'5 + 38.0 °, (c 1.0 dioxane), Xmax (pH6 phosphate buffer) 274 nm (e 16 930).

Example 8

(6R, 7R) -3-N-n-butylcarbamoyloxymethyl-7- [2-methyloxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

A suspension of 2.00 g of the syn isomer of (6R, 7R) -3-hydroxymethyl-7- [2-methoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid in dry benzene (under nitrogen) was treated with 1.74 g of tri-n-butyltin oxide and a solution was obtained after stirring for 1 hour. 2.08 g of n-butyl isocyanate was added and stirring was continued for 4 hours. 100 ml of water was added to the reaction mixture, and the stirred separated benzene layer was treated with 100 ml of 0.1 M hydrochloric acid to give a gelatin-like precipitate, which was filtered off and dissolved in 100 ml of saturated aqueous sodium bicarbonate solution. After washing the aqueous solution with 2 × 100 ml of ethyl acetate, the aqueous phase was acidified with 2 m hydrochloric acid under a layer of 100 ml of ethyl acetate. The organic phase was separated and the aqueous layer was extracted again with 100 ml of ethyl acetate. The combined organic extracts were washed with 2 × 100 ml of water, dried over magnesium sulfate and evaporated in vacuo to give 1.124 g of the title compound as a pale yellow solid of mp (M80) = 149.6 ° C.; [a] D ° '5 + 42.6 ° (c 1.03, DMSO), Àmax (pH 6 phosphate buffer 274 nm) (e 16 960).

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B