7-Acylamino-3-(1-(2-sulfamoylaminoethyl)-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids, a process for their preparation and compositions containing them

Description

[0001] This invention relates to cephalosporin compounds having antibacterial activity, processes for their preparation, pharmaceutical compositions containing them for use as antibacterial agents.

[0002] Cephalosporin derivatives having specific tetrazolylthiomethyl substituents at position 3 of the cephem nucleus are known. For example West German Offenlegungsschrift No. 2649545 discloses cephalosporin derivatives of general formula:

where W is hydrogen or a methoxy group and R¹ is

where X is thienyl, dihydrophenyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido or ureido; A is NH₂, OH, COOH, S0₃H or when X is a phenyl group a formyloxy group; Y is thienyl, tetrazolyl, sydnonyl, cyano or o-aminomethylphenyl; Z is a methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyridyl group; M is 0, 1 or 2 and N is 2, 3, 4 or 5.

[0003] The compounds of this invention differ from previously known cephalosporins in general and those of the above Offenlegungsschrift in particular principally because they have a 1-(2-sulfamoylaminoethyl)tetrazolyl-5-thiomethyl substituent at position 3 of the cephem nucleus.

[0004] According to the present invention there is provided a compound of formula (1):-

and esters thereof and pharmaceutically acceptable salts and amide derivatives thereof in which R represents:-

wherein:

X is thienyl, furyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido or ureido;

A is -NH₂, -OH, -COOH, -S0₃H, formyloxy or, when the a-C-hydrogen is absent, methoxyimino;

Y is cyano, sydnonyl, pyridonyl, thienyl, o-aminomethylphenyl, phenyl or tetrazolyl;

Z is methyl, trifluoromethyl, trifluoroethyl, pyridyl, or cyanomethyl; and m is zero to two.

[0005] Each of the three partial structures above represent subgeneric groups of compounds covered by this invention.

[0006] Representative 7-acylamino substituents of the compounds of formula (I) are listed below:

a-hydroxyphenylacetamido

a-aminophenylacetamido

a-amino-4-hydroxyphenylacetamido

trifluoromethylthioacetamido

2,2,2-trifluoroethylsulfinylacetamido

2,2,2-trifluoroethylthioacetamido

cyanoacetamido

a-carboxythienylacetamido

a-carboxyphenylacetamido

a-sulfophenylacetamido

methylsulfonylacetamido

cyanomethylthioacetamido

3-sydnonylacetamido

1-tetrazolylacetamido

2-thienylacetamido

a(Z)-(methoxyimino)-2-furanacetamido

4-pyridylthioacetamido

o-aminomethylphenylacetamido

[0007] It will be recognized that the 4-carboxylic acid group of the compounds of formula (I) and the group A when it is COOH or OH may be readily esterified by methods well-known to the art. Examples of esters of the carboxylic acid group include simple alkyl and aryl esters as well as esters which are cleaved within the body to the parent acid such as indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycyloxymethyl esters and others. Accordingly, by an ester of a compound of formula (I) we mean esters of one or more of these groups. All such ester derivatives are included within the scope of this invention.

[0008] Also covered in this invention are pharmaceutically acceptable salts and amide derivatives of the compounds of formula (I). By a pharmaceutically acceptable amide derivative we mean an amide derivative at an amino group contained in a 7-phenylglycylamino group, for example the furyl-, pyranyl-, oxolanyl- or oxiranyl- carbonyl amides (i.e., Belgian Patent No. 835,295). Examples of pharmaceutically acceptable salts of compounds of formula (I) are alkali metal salts such as the sodium or potassium salts, ammonium salts and organic amine salts such as those with procaine or dibenzylethylenediamine.

[0009] The compounds of the invention can exist in the form of solvates for example hydrates, glycolates and alcoholates. It will be understood that such forms are within the scope of invention.

[0010] Optical isomers are also possible such as with the mandeloyl or phenylglycyl substituents at position 7. The D-forms of these subgeneric groups are preferred.

[0011] The compounds of the invention are most conveniently prepared by displacement of the acetoxy group of a known 7-acylamino-cephalosporanic acid of formula (II):-

where R¹ is hydrogen or a group R as defined with reference to formula (I) in which any amino, carboxy, sulfo or hydroxy groups are optionally protected, with 1-(2-sulfamoylaminoethyl)-1,4-dihydro-5H-tetrazole-5-thione of formula (III):-

and when R¹ is hydrogen, acylating the product with an acylating agent or active derivative of an acid ROH where R is as defined with reference to formula (I) thereafter removing any protecting groups and optionally thereafter converting the compound of formula (I) so obtained into an ester or a pharmaceutically acceptable salt or amide derivative.

[0012] The acylation step can be carried out by known methods. N-acylation procedures may be found in Cephalosporins and Penicillins, Flynn, Academic Press, 1972; U.S. Patent Nos. 2,721,196 and 3,953,424; Belgian Patent No. 832,725; German Patent Nos. 2,127,285 and 2,406,165.

[0013] Suitable protecting groups are known to the art (see "Protective Groups in Organic Chemistry", J.F.W. McOmie, Plenum Press, 1973, Chapters 2 and 3 for use of amino, carboxy, sulfo or hydroxyl protective groups).

[0014] For example, the t-butyl (for COOH) or t-butoxy-carbonyl (for NH₂) groups are easily removed by treatment with trifluoroacetic acid.

[0015] The tetrazole-5-thione (III) exists in tautomeric forms:-

and it is to be understood that formula (III) means both isomers.

[0016] The tetrazole-5-thione (III) is disclosed and claimed in our corresponding European Patent Application No. 0018669.

[0017] Certain compounds for formula (I) have shown antibacterial activity against both Gram positive and Gram negative bacteria with minimum inhibitory concentrations (MIC's) in vitro from 0.4 to 200 µg/ml. Test results for 7-D-(-)mandelamido-3-[1-(2-sulfamoylaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid, sodium salt, dihydrate (A) and 7-[α(Z)-(methoxyimino)-2-furanacetamido]-3-[1-(2-sulfamoylaminoethyl)tetrazolyl-5-ylthiomethyl]-3-cephem-4-carboxylic acid sodium salt (B) are:

[0018] Compound A gave an ED₅₀ in mice of 0.26 against E. coli as well as 0.195 mg/kg against Kleb. pneumo. (s.c.).

[0019] Pharmaceutical compositions having antibacterial activity which comprise a pharmaceutical carrier containing an active quanitity of a compound of formula (I) or a pharmaceutically acceptable salt or amide derivative thereof which is easily cleaved within the body, as well as their use in combating bacterial infections by administering such a composition to an infected animal, or human host in a non-toxic amount sufficient to combat such infections are also within this invention. The administration, which, of course, should be of a non-toxic quantity of a compound of formula (1) may be oral or by parenteral injection for example subcutaneous, intramuscular or intravenous. The injection of suitably prepared sterile solutions or suspensions containing an effective non-toxic amount of the new cephalosporin compound is the preferred route of administration.

[0020] The compounds of the invention used in this way are preferably formulated and administered in the same manner as other prior art cephalosporins such as cephazolin or cephalothin. The dosage regimen preferably comprises administration, preferably by injection, of an active but non-toxic quantity of a compound of formula (I) selected from the dosage unit range of from about 250 mg to 60C mg with the total daily dosage regimen being from about 750 mg to 6 g. The precise dosages are dependant upon the age and weight of the subject and on the susceptibility of the infection being treated in each individual. These can be determined by those skilled in the art based on the data disclosed herein compared with that available to the art attained with the known cephalosporins outlined herebefore.

[0021] The following Examples 2 to 5 illustrate compounds and compositions df the invention. Example 1 illustrates the preparation of an intermediate for preparing the compounds. Temperatures are in degrees Centigrade (°C) unless otherwise stated.

EXAMPLE 1

[0022] To a solution of 20.4 g. (0.20 mol) of N-(2-aminoethyl)acetamide in 200 mi. of 95% ethanol was added 27.9 ml. (0.20 mol) of triethylamine and 12.0 ml. (0.20 mol) of carbon disulfide. The exothermic reaction reached reflux and then cooled to ambient temperature over a 1.5 hour period. Methyl iodide (28.4 g.; 0.20 mol) was added which again produced an exothermic reaction. After 1.75 hours the reaction mixture was evaporated to dryness and the solid residue was dissolved in 200 ml. of water. The aqueous solution was extracted twice with 250 ml. portions of ethyl acetate. The extracts were combined, shaken with sodium thiosulfate, dried (MgS0₄) and evaporated to dryness to give methyl 2-acetamidoethyldithiocarbamate.

[0023] To a solution of 38.4 g. (0.198 mol) of methyl 2-acetamidoethyldithiocarbamate in 100 ml. of 95% ethanol was added a solution of 13.5 g. (0.208 mol) of sodium azide in 100 ml. of water. The reaction mixture was refluxed for 24 hours then cooled and concentrated under reduced pressure to about half volume. The solution was cooled to 15° and 50 ml. of 6N sulfuric acid was added. The acidic solution was filtered and the filtrate was concentrated to about 100 ml. and chilled at 5°C. to induce crystallization of 1-(2-acetamidoethyl)tetrazole-5-thiol which was collected by filtration, mp 139-139,5⁰C. Additional amounts of the product were obtained by continuous extraction of the filtrate with ethyl acetate.

[0024] A solution of 9.3 g. (0.050 mol) of 2,4-dinitrofluorobenzene in 50 mi. of acetone was added to a solution of 9.35 g. (0.050 mol) of 1-(2-acetamidoethyl)tetrazole-5-thiol and 6.85 ml. (0.050 mol) of triethylamine in 100 mi. of acetone and the reaction mixture was stirred for 1 hour. The solid material was collected by filtration and recrystallized from acetonitrile to give 1-(2-acetamidoethyi)-5-(2,4-dinitrophenylthio)tetrazole, mp 197-198°C..

[0025] A mixture of 6.5 g. (0.02 mol) of 1-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, 100 ml. of 12N hydrochloric acid and 100 ml. of 95% ethanol was refluxed for 4.5 hours. The mixture was evaporated to dryness to give a gummy residue which crystallized upon addition of ethanol to give 1-(2-aminoethyl)-5-(2,4-dinitrophenylthio)tetrazole hydrochloride, mp 217-219°C. (d).

[0026] Triethylamine (1.0 g., 0.01 mol) was added to a suspension of 1.73 g. (0.005 mol) of the above tetrazole hydrochloride in 50 ml. of dry tetrahydrofuran. The suspension was cooled to 0°C. At that . temperature 0.885 g. (0.005 mol) of N-tert-butylsulfamoyl chloride in 40 ml. of dry tetrahydrofuran was added. After 30 minutes of stirring, the triethylamine hydrochloride was separated by filtration. The filtrate was evaporated to dryness. The residue was suspended in water, a little dilute hydrochloric acid was added and the suspension was extracted with ethyl acetate. The extract was dried over MgS0₄ and stripped in vacuo to give the desired 1-(2-N-tert-butylsulfamidoethyl)-5-(2,4-dinitrophenylthio)-tetrazole as a yellow solid. This reaction was repeated using 51.9 g. of the tetrazole hydrochloride.

[0027] The tert-butyl compound (51.5 g.) was added to 500 mi. of trifluoroacetic acid and 250 ml. of m-dimethoxybenzene. The mixture was stirred at room temperature for 3 hours then stripped of the trifluoroacetic acid in vacuo. The dimethoxybenzene solution was diluted with 1.5 I. of ether to give a yellow precipitate. The solid was chromatographed on silica using 50:50 acetone/chloroform as eluant. The product-containing eluate was stripped. The residue was triturated with 100 ml. of ethanol to give a product which after recrystallization from ethanol gave 1-(2-sulfamoylaminoethyl)-5-(2,4-dinitro- phenylthio)tetrazole, mp 123-125°C. as the hemihydrate.

[0028] The sulfamoylamino intermediate (25.55 g., 0.065 mol) was suspended in 300 ml. of dry methanol and treated with 17 ml. of 25% sodium methoxide in methanol at room temperature with stirring. The methanol was stripped off in vacuo and the residue dissolved in 300 ml. of water. After filtering, the aqueous solution (pH 9.0) was extracted with ethyl acetate and then adjusted to pH 7.5 with dilute hydrochloric acid and again extracted with ethyl acetate.

[0029] The aqueous layer was taken to pH 1.5 with dilute hydrochloric acid and extracted with ethyl acetate. This extract was dried (MgS0₄) and stripped in vacuo to give a yellow powder, 1-(2-sulfamoylaminoethyl)-1,4-dihydro-5H-tetrazole-5-thione.

[0030] A mixture of 4.49 g. of 7-(D-(-)-mandelamido)cephalosporanic acid, sodium salt hydrate in 10 ml. of water with 1.92 g. of 1-(2-sulfamoylaminoethyl)-1,4-dihydro-5H-tetrazole-5-thione and 0.84 g. of sodium bicarbonate in 10 ml. of water was heated at 65° for four hours while keeping the pH at 7.4-7.6. The cooled reaction mixture was extracted with ethyl acetate. The aqueous layer was applied to an XAD-4 column (a nonionic resin which is a crosslinked copolymer of styrenedivinylbenzene) and eluted first with water and then 50% aqueous methanol. The methanol was stripped in vacuo from the pooled product-containing fractions. The remaining aqueous solution was treated with dilute hydrochloric acid to a pH of 1.5 and then extracted with ethyl acetate. After drying (MgS0₄) the extracts, the ethyl acetate was removed in vacuo to give a residue which was dissolved in dry methanol and adjusted to pH of 7.0 with 12.5% sodium methoxide in methanol. Diluting with ether gave a white solid. This material was dissolved in water and eluted with water through a Bio-Gel P-2 column (a copolymerized acrylamide-N,N-methylene-bis-acrylamide porous beads available from Bio-Rad.). The product-containing eluate was lyophilized to give 7-[D-(-)-mandel- amido]-3-[1-(2-sulfamoylaminoethyl)tetrazole-5-ylthiomethyl]-3-cephem-4-carboxylic acid, sodium salt hemihydrate. Analysis Calculated for C₁₉H₂₁NaN₆H₇S₃. 1/2 H₂0:C, 37.93; H, 3.69; N, 18.63. Found: C, 37.63; H, 3.85; N, 18.66.

EXAMPLE 2

[0031] A mixture of 2.15 g. (0.0096 mol) of 7-[a(Z)-methoxyimino)-2-furanacetamido]cephalosporanic acid sodium salt in a solution of 0.78 g. (0.0096 mol) of sodium bicarbonate in 100 ml. of water with 4.05 g. (0.0091 mol) of 1-(2-sulfamoylaminoethyl)-1,4-dihydro-5H-tetrazole-5-thione was heated at 65°C. for 6 hours during which time the pH was maintained at a pH of 7.6-7.8 with dilute sodium bicarbonate. After cooling, the reaction mixture (pH 7.0) was extracted with ethyl acetate. The aqueous layers were taken to pH of 1.5 with dilute hydrochloric acid and reextracted with ethyl acetate. After drying, the latter extract was stripped off in vacuo to give a yellow solid which was purified with XAD-4 and Bio-Gel P columns as described in Example 1 to give a lyophilized product, 7-[a(Z)-(methoxyimino) - 2 - furanacetamido] - 3 - [1 - (2 - sulfamoylaminoethyl)tetrazole - 5 - ylthiomethyl]-3-cephem-4-carboxylic acid hydrate. Analysis calculated for C₁₈H₂₀N₂NaO₈S₃-1 H₂0: C, 34.45; H, 3.53; N, 20.09. Found: C, 35.47; H, 3.31; N, 20.68.

EXAMPLE 3

[0032] A mixture of 5.22 g. (10.0 mmol) of 7-(D-a-t-butoxycarbonylamino-4-hydroxyphenylacetamido)-cephalosporanic acid and an excess (15.0 mmol) of 1-(2-sulfamoylaminoethyl)-1,4-dihydro-5H-tetrazole-5-thione in 75 ml. of pH 6.4 phosphate buffer solution is treated with sufficient sodium bicarbonate to give a pH of 6.4. The mixture is heated at 70° for 3 hours, cooled, acidified with dilute hydrochloric acid to pH 2 and extracted with ethyl acetate. Removal of the ethyl acetate in vacuo gives the t-boc derivative of the desired compound. This derivative is stirred at 25°C. with 25 ml. of 1,3-dimethoxybenzene for 2 hours. The mixture is evaporated to dryness in vacuo, ethyl acetate is added to the residue and the precipitated salt is collected. This is dissolved in water and treated with Amberlite IR-45 weakly basic ion-exchange resin. The solution is lyophilized to give 7-(D-a-amino-4 - hydroxyphenylacetamido) - 3 - [1 - (2 - sulfamoylaminoethyl)tetrazole - 5 - yithiomethyl] - 3 - cephem - 4 - carboxylic acid. Similar treatment of the t-boc derivatives of the 7-DL-(a-aminophenylacetamido)cephalosporanic acid gives the corresponding 7-DL-(a-aminophenylacetamido)-3-[1-(2-sulfamoytaminoethyl)tetrazote-5-ylthiomethyl]-3-cephem-4-carboxylic acid.

EXAMPLE 4

[0033] A mixture of an excess (12.2 mmol) of 1-(2-sulfamidoethyl)1,4-dihydro-5H-tetrazole-5-thione, 20.3 mmol of sodium bicarbonate and 8.1 mmol of 7-trifluoromethylthioacetamidocephalosporanic acid in 50 ml. of water is stirred at 70° for 5 hours. The reaction mixture is cooled and applied to an XAD-2 column and eluted with water and then methanol. The product-containing effluent is evaporated to dryness to give a residue which is dissolved in a small amount of water and lyophilized to give 7-trifluoromethylthioacetamido-3-[1-(2-sulfamoylaminoethyl)tetrazole-5-ylthiomethyl]-3-cephem-4-carboxylic acid sodium salt. Substituting 7-(2-thienylacetamido)-cephalosporanic acid gives 7 - (2 - thienylacetamido) - 3 - [1 - (2 - sulfamylaminoethyl)tetrazole - 5 - ylthiomethyl) - 3 - cephem - 4-carboxylic acid sodium salt.

[0034] Stoichiometric quantities of cephalosporanic acids having the individual 7-acylamino substituent listed hereabove may be substituted in Examples 1-3 with variations which will be obvious to those skilled in this art.

EXAMPLE 5

[0035] An injectable pharmaceutical composition is formed by adding sterile saline solution (2 ml.) to 500 mg. of the product of Example 1. This material is injected parenterally four times daily to a human patient infected with susceptible bacteria. Other compounds of this invention may be similarly used.

Claims

1. A compound of formula (1):-

and esters thereof and pharmaceutically acceptable salts and amide derivatives thereof where R is

where:

X is thienyl, furyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido or ureido;

A is NH₂, OH, COOH, S0₃H, formyloxyl or methoxyimino, the a-carbon hydrogen then being absent.

Y is cyano, sydnonyl, pyridonyl, thienyl, o-aminomethylphenyl, phenyl or tetrazolyl;

Z is methyl, trifluoromethyl, trifluoroethyl, pyridyl, or cyanomethyl;

m is zero to two.

2. The D-form of a compound as claimed in Claim 1 which has optical isomers.

3. A compound of formula (I) as claimed in Claim 1 or Claim 2 and pharmaceutically acceptable salts and amide derivatives thereof and esters thereof which are cleaved in the body.

4. 7 - [a(Z) - (Methoxyimino) - 2 - furanacetamido] - 3 - [1 - (2 - sulfamoylaminoethyl)tetrazole - 5 - ylthiomethyl] - 3 - cephem - 4 - carboxylic acid.

5. A process for preparing a compound as claimed in claim 1 characterized in that a compound of the formula (II):-

where Ac is acetyl, R¹ is hydrogen or a group R as defined with reference to formula (I) in which any amino, carboxy, sulfo or hydroxy groups are optionally protected is reacted with the compound of formula (III):-

and when R¹ is hydrogen acylating the product with an acylating agent or activated derivative of formula ROH where R is as defined with reference to formula (I) thereafter removing any protecting groups and optionally thereafter converting the compound of formula (I) so obtained into an ester, or a pharmaceutically acceptable salt or amide derivative.

6. A pharmaceutical composition comprising a compound as claimed in claim 3 or claim 4 and a pharmaceutically acceptable carrier.

Revendications

1. Composés caractérisés par la formule générale (I):

ainsi que leurs esters et sels et dérivés amidiques pharmaceutiquement acceptables, dans laquelle R représente

où:

X représente un radical thiényle, furyle, phényle ou phényle monosubstitué par un groupe hydroxy, hydroxyméthyle, formamido ou uréido;

A représente un groupe NH₂, OH, COOH, SO₃H, formyloxy, ou méthoxyimino, l'hydrogène sur l'atome de carbone en a étant alors absent;

Y représente un radical cyano, sydnonyle, pyridonyle, thiényle, o-aminométhylphényle, phényle our tétrazolyle;

Z représente un groupe méthyle, trifluorométhyle, trifluoroéthyle, pyridyle ou cyanométhyle;

m varie de 0 à 2.

2. Forme D du composé suivant la revendication 1, caractérisée en ce qu'elle présente des isomères optiques.

3. Composés de formule (I) suivant la revendication 1 ou 2 ainsi que leurs sels et dérivés amidiques et esters pharmaceutiquement acceptables qui sont scindés dans le corps.

4. Acide 7 - [α(Z) - (méthoxyimino) - 2 - furanacétamido - 3 - 1 - (2 - sulfamoylaminoéthyl)-tétrazole - 5 - ylthiométhyl] - 3 - céphème - 4 - carboxylique.

5. Procédé de préparation d'un composé suivant la revendication 1 caractérisé en ce que: on fait réagir un composé de formule (II)

dans laquelle R¹ représente un atome d'hydrogène ou un groupe R tel que défini dans la formule (I) dans laquelle tous groupes amino, carboxy, sulfo ou hydroxy sont éventuellement protégés, avec un composé de formule III:

et lorsque R¹ représente un atome d'hydrogène, on acyle le produit au moyen d'un agent acylant ou d'un dérivé activé de formule ROH où R est tel que défini dans la formule (I), on élimine ensuite tous groupements protecteurs et on transforme ensuite éventuellement le composé de formule (I) ainsi obtenu en un ester ou sel ou dérivé amidique pharmaceutiquement acceptable.

6. Composition pharmaceutique caractérisée en ce qu'elle contient un composé suivant la revendication 3 ou 4 en association avec un véhicule pharmaceutiquement acceptable.

Ansprüche

Patentansprüche für folgende(n) Vertragsstaat(en) : (5) EPÜ in Verbindung mit Regel 51 (4)

1. Verbindungen der Formel (1)

ihre Ester, pharmazeutisch verträgliche Salze und Amidderivate, wobei R die Reste

bedeutet, in denen

X eine Thienyl- oder Furylgruppe oder einen gegebenenfalls mit einer Hydroxy-, Hydroxymethyl-, Formamido- oder Ureidogruppe einfach substituierte Phenylgruppe ist;

A NH₂, OH, COOH, S0₃H, eine Formyloxyl- oder Methoxyiminogruppe ist, wobei das α-Kohlenstoffatom kein Wasserstoffatom aufweist;

Y eine Cyano-, Sydnonyl-, Pyridonyl-, Thienyl-, o-Aminomethylphenyl-, Phenyl- oder Tetrazolylgruppe ist;

Z eine Methyl-, Trifluormethyl-, Trifluoräthyl-, Pyridyl- oder Cyanomethylgruppe ist;

m den Wert 0 bis 2 hat.

2. Die D-Form einer Verbindung nach Anspruch 1, die optische Isomere aufweist.

3. Eine Verbindung der Formel 1 nach Anspruch 1 oder 2, ihre pharmazeutisch verträglichen Salze, Amidderivate und Ester, die im Körper gespalten werden.

4. 7 - [a(Z) - (Methoxyimino) - 2 - furanacetamido] - 3 - [1 - (2 - sulfamoylaminoäthyl) - tetrazol - 5 - ylthiomethyl] - 3 - cephem - 4 - carbonsäure.

5. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß eine Verbindung der Formel II

in der R¹ ein Wasserstoffatom ist oder den Rest R bedeutet, wie er im Anspruch 1 definiert ist, wobei etwaige Amino-, Carboxy-, Sulfo- oder Hydroxygruppen gegebenenfalls geschützt sind, mit einer Verbindung der allgemeinen Formel III

umgesetzt wird und falls R¹ ein Wasserstoffatom ist, die Verbindung mit einem Acylierungsmittel oder einem aktivierten Derivat der Formel ROH, wobei R die in Anspruch 1 angegebene Bedeutung hat, acyliert wird, anschließend die Schutzgruppen entfernt werden und gegebenenfalls die so erhaltene Verbindung der Formel I in einen Ester, ein pharmazeutisch verträgliches Salz oder ein Amidderivat umgewandelt wird.

6. Arzneimittel, enthaltend eine Verbindung nach Anspruch 3 oder 4 und einen pharmazeutisch verträglichen Träger.