DE2639380A1 - 3-SQUARE CLAMP ON 1- (2-HYDROXYALKYL) -TETRAZOLE-5-YLTHIOMETHYL SQUARE CLAMP FOR -3-CEPHEM-4-CARBONIC ACIDS, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

^l '3-Z " ⁷ ' ~ (2-Hyaroxyalkyl) -tetrazol-5-ylthiomethyl7-3-cephem- ^/ f ~ carboxylic acids, process for their preparation and pharmaceuticals containing these compounds"

Priority: September 2, 1975, V.St.A., No. 609 333

The invention relates to the subject matter characterized in the claims.

The invention also includes the esters of the compounds of the general ! Formula I. Examples of these esters are simple alkyl and aryl esters as well as esters that are easily cleavable in the body, like the indanyl, pivaloyloxymethyl, acetoxymethyl, propionyl oxymethyl, glycyloxymethyl, phenylglycyloxymethyl and Thienyl glycyloxymethyl ester. If the radical A represents a carboxyl group, this group can be esterified in the same way, be. The invention includes all such esters.

7Ω98 10/1179

- ² - 263938Q

In the preferred compounds of the general formula I is η is an integer with a value from 2 to 5, compounds of the general formula I in which η has the value 2 and R is a group of the general formula

Il

X-CH-C-

represents. Particular preference is given to compounds of the general formula I in which η is 2 and R is a group of the general formula

ti

X-CH-C-t

X is a phenyl or hydroxyphenyl group and A is an amino or hydroxyl group.

Examples of the particularly preferred 7-acylamino radicals in the compounds of the general formula I are the cL -hydroxyphenylacetamido-, ei-aminophenylacetamido-, cat- -amino- ^ - hydroxyphenylacetamido-, trifluoromethylmercaptcacetamido-, methylmercaptoacetamido-, 2,2-trifluoroacetamido-trifluoroacetamido- , Cyanoacetamido,

c * - -Carboxyphenylacetamido-, & - -SuIf opheny! acetamido-, Me thy1sulfοnyIacetamido-,

J 709810/1

Cyanomethyl mercaptoacetamido,

o- -amino-4-carboxymethylaminophenylacetamido- and 2-aminomethylphenylacetamido group.

The 7-D-Mandelamido-3-, Zi- is especially "preferred (2-hydroxyethyl) tetrazole-5-ylthiomethyl / ^z -3 ~ cepheni- l- carboxylic acid.

Cephalosporin derivatives having a 7-acyl residue of those described above Kind are known. The substitution by substituted S-heterocyclothiomethyl radicals (-CHpSHet) in the 3-position of the cephem compounds are also known. Cephalosporin compounds with a heterocyclothiomethyl group substituted by a hydroxymethyl group in the 3-position are below inter alia in US Pat. No. 3,757,014, in which Het represents an oxadiazole group, and UL-OS 72.05 644, in which Het represents an oxadiazole group and HL-OS 72.07 368, in which Het a 2-oxopyrimidine group represents, and DT-OS 24 I5 402, although broadly defined in the Het, but only by a thiadiazole group is explained, and the DT-OSeη 24 42 302 and 24 42 702 described, in which Het means a thiadiazole group. In BE-PSs 819 540 and 819 541 are 3-hydroxymethylthiadiazolylthiomethylcephalosporins described. Finally, from BE-PS 819 591 are 3-hydroxymethyl- (oxadiazolyl- and -thiadiazolyl) -thiomethy! Cephalosporins known. In NL-OS 73.08 199, cephalosporins are generally described which are in the 7-position are substituted by a 3-halo-4-hydroxyphenylglycylacetamido group and which are a 3-heterocyclothiomethyl group (including a tetrazole group), in which the heterocyclic Remainder inter alia by a hydroxyalkyl · ^ st

70981 0/1179

is substituted. Only a hydroxymethyloxadiazolyl compound is specifically described. In NL-OS 69 16 151 are

Cephalosporins described which have a 3-heterocyclothiomethyl group, including a tetrazole group which is substituted by a hydroxyalkyl radical. In the DT-OS 24-15 7 ~ acyl-3-heterocyclothiomethylcephalosporins are described, which are substituted in the heterocyclic radical by a hydroxyalkyl radical. Examples are 7-thienylacetamido and 7-Tetrazolylacetamido-3- (2-hydroxyethyl) thiadiazolylthiomethyl cephalosporins called. US Pat. No. 3,819,623 describes 7-heterocyclo- and 7-heterocyclothioacetamidocephalosporins, which is a heterocyclothiomethyl radical in the 3-position, including a tetrazole residue, included, among others is substituted by a hydroxyalkyl radical. The only example is 7- (tetrazol-1-ylacetamido) -3- (1-hydroxypropyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid described. From BE-PS 823 861 finally the 7- / 2- (2-aminothiazol-4-yl) -acetamidü / -3- / 1- (2-hydroxyethyl) -tetrazol-5-yl / -thioiaethyl-3- cephem-4 ~ carboxylic acid known.

The compounds of general formula I can be prepared by acylating a 7-amino-3- / 1- (2-hydroxyalkyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid of the general formula II

COOK*

<CH ₂ ) _n = OH

_J 70981 0/1179

in which η is an integer with a value from 2 to 10 and

p
R represents a hydrogen atom or a carboxyl protective group, can be prepared with the appropriate acylating agent and, if appropriate, subsequent cleavage of the protective groups.

The carboxyl group of the acylating agent can be activated by conventional methods, for example by conversion into the mixed anhydride, acid chloride, acid imidazolide or an activated ester. Furthermore, the condensation can be carried out with a dehydrating agent, such as dicyclohexylcarbodiimide, provided that the carboxyl group in the 4-position of the cephem compound is replaced by an easily removable protective group, such as a benzhydryl, tert-butyl, trichloroethyl, benzyl, benzyloxymethyl , p-methoxybenzyl or p-nitrobenzyl ester group. If the radical A is an amino group, the oil- amino group of the acylating agent is preferably initially protected with an easily cleavable protective group, such as a tert-butoxycarbonyl, trichloroethoxycarbonyl or benzyloxycarbonyl group, the enamine formed with methyl acetoacetate or similar groups used for peptide synthesis will.

The compounds of the general formula II are also a subject the invention.

The compounds of general formula I can also be obtained by acylating 7-Aniinocephalosporanäure with a corresponding protected acylating agent and subsequent substitution

709 810/1179

the 3-acetoxy group by the corresponding hydroxyalkyltetrazolthiol and subsequent splitting off of the protective group (s). The hydroxyalkyltetrazolthiols "of the general formula III

(III)

in which η is an integer with a value of 2 to 10 also the subject of the invention. They are valuable intermediates for the preparation of the compounds of the general formula I.

The protective groups can be split off in a manner known per se, for example with trifluoroacetic acid in the case of the tert. Butyl or tert-butoxycarbonyl group. The resulting salt with the trifluoroacetic acid is then through. Treat with a basic Ion exchange resin, for example a polystyrene-amine ion exchange resin (Amberlite IR-4-5) or by alkalizing an aqueous solution of the salt, converted into the corresponding zwitterionic product or the free acid.

The acylating agents used in the process according to the invention are either known or are produced in a manner known per se.

The 7-amino-3-hydroxyalkyltetrazolylthiomethylcephalosporins used according to the process of the general formula II are obtained by reacting 7-aminocephalosporanic acid with a hydroxy

709810/1 179

alkyltetrazolthiol of the general formula III produced.

ι ■. ■ ■ ■

The hydroxyalkyltetrazolthiols of the general formula III are prepared by reacting an N-acetoxyalkyldithiocarbamate, such as 2-Acetoxyäthyldithiocarbamic acid methyl ester - manufactured by Acetylation of the corresponding N-hydroxyalkyldithiocarbamate with an azide such as sodium azide. The N-hydroxyalkyldithiocarbamates are made by reacting a hydroxyalkylamine, such as ethanolamine, with carbon disulfide and an alkyl halide, such as methyl iodide, in the presence of a base such as triethylamine, manufactured.

Certain compounds of the invention can be salts with bases, for example alkali or alkaline earth metal salts, such as sodium, Form potassium or calcium salts, or ammonium salts. When the radical A is an amino group, the compounds can either exist as a zwitterion or as a salt with an acid or a base. These salts are produced by customary methods.

Due to another asymmetric center at the ck carbon atom in the 7-acetamido group of the compounds of the general Formula I, in which R represents the group X-CH-G-, the compounds can exist as epimers. Depending on whether a racemic or a side chain acid split into the enantiomers is used as acylating agent, either the epimeric - Get mixtures or the epimers. The enantiomeric side chain acids can be obtained from the racemates by cleavage,

70 98 10/1179

- ⁸ - 263938Q

for example by fractional crystallization of a salt prepared with an optically active acid or base will. The invention includes all isomers and their mixtures.

The compounds of general formula I are antibiotics with action against gram-positive and gram-negative germs. The minimum inhibitory concentration (MIC) is in the range from 0.2 to> / μg / ml in in vitro tests. The MICs are given below Values given for 7-D-mandelamido-3-Z ^: K2-hydroxyeth7l) tetrazol-5-ylthiomethyl7-3 ~ cephem-4-carboxylic acid.

Test germ MIC , / µg / ml

S. aureus HH 127 0.8, 1.6

S. aureus SK 23590 0.2, 0.2

S. villaluz SK 7O39O 12.5, 25

Strep, faecalis HH 34358 25, 25

E. coli SK 12140 0.8, 0.4

E. coli HH 33779 0.8, 0.8

Glue, pneumo. SK 4200 0.8, 0.4

Glue, pneumo. SK 1200 0.4, 0.2

Salmonella ATGC 12176 0.2, 0.4

Shigella HH 117 0.2, 0.1

Pseudo, airy. HH 63> 200,> 200

Serratia marc. ATCC I388O 25, 25

Proteus morgani 179 0.8, 0.4

Entero. aerog. ATCC 13048 3.1, 1.6

Entero. cloacae HH 31254 0.4, 0.4

709810/1179

Experiments on the infected mouse resulted in subcutaneous administration of 7-D-mandelamido-3-zi- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid an ED of 0.39 mg / kg against E. coli 12140 and 3.9 mg / kg against Kleb, pneumo. 4200.

The compounds of the invention can be in the form of customary dosage forms administered orally or parenterally, preferably parenterally.

The examples illustrate the invention.

example 1

7-D-Mandelamido-3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl 7-3-cephem-4-carboxylic acid

A solution of 30.54 g (0.50 mol) of ethanolamine in 500 ml of ethanol and 30 ml of V / water is mixed with 60.6 g (0.60 mol) of triethylamine. The mixture is ^{cooled to 15 °} C. and 45.0 g (0.6 mol) of carbon disulfide are added while stirring. Then, the mixture was cooled to 5 to 10 ⁰ C and treated with 80.0 g (0.56 mol) of methyl iodide and stirred for 30 minutes. The reaction mixture is then evaporated, 350 ml of water are added to the residue and the mixture is extracted with hexane. The aqueous phase is cooled in an ice bath and acidified to pH 2.0 with concentrated phosphoric acid. Sodium phosphate is added and the mixture is extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated to dryness. It goes

The methyl 2-hydroxyethyldithiocarbamate remains.

ι
A solution of 150.0 g (0.99 mol) of methyl 2-hydroxyethyldithiocarbamic acid in 1 liter of methylene chloride is admixed with 79.0 g (1.0 mol) of pyridine. The mixture is cooled in an ice bath and 102.0 g (1.0 mol) of acetic anhydride are slowly added. The reaction mixture is then stirred for 12 hours at 25 ° C. and then extracted with 1N hydrochloric acid until the extracts react acidic. The aqueous extracts are combined and extracted with methylene chloride. The methylene chloride extract is washed with dilute aqueous sodium carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and treated with activated charcoal. After evaporation under reduced pressure, the 2-acetoxyethyldithiocarbamic acid methyl ester remains.

A solution of 80.0 g (0.415 mol) of 2-acetoxyethyldithiocarbamic acid methyl ester in 600 ml of acetonitrile, 30.1 g (0.4-6 mol) of sodium azide are added and the mixture is refluxed for 4 × 1/2 hours. At the same time, acetonitrile is distilled off and the volume is kept constant by adding fresh acetonitrile. Then the reaction mixture is cooled to room temperature, filtered and evaporated to dryness. The residue is with 250 ml of water are added and the aqueous mixture is treated with diethyl ether extracted. The layers are separated and the aqueous phase is cooled in an ice bath and washed with concentrated phosphoric acid acidified to pH 3.0. The solution is then extracted with ethyl acetate. The organic phases will

709810/1179

combined, dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated to dryness. The 1- (2-acetoxyethyl) tetrazole-5-thiol remains.

A solution of 60.0 g (0.32 mol) of 1- (2-acetoxyethyl) tetrazole-5-thiol in 250 ml of water is slowly mixed with 230 ml of trifluoroacetic acid. The mixture is refluxed for 4 hours and then cooled to room temperature. The trifluoroacetic acid is distilled off and the remaining aqueous solution is treated with sodium phosphate and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated to dryness. The residue is dissolved in toluene and again evaporated to dryness several times in order to separate off residual trifluoroacetic acid. The residue is then recrystallized from a mixture of ethyl acetate and hexane. It is 1- (2-hydroxyethyl) tetrazole-5-thiol from P. 138 received to 140 ⁰ C.

A suspension of 2.19 g (0.015 mol) of 1- (2-hydroxyethyl) tetrazole-5-thiol in water, which is kept at a pH of 7.0 by adding solid sodium bicarbonate, is added 4.38 g of the methanolate adduct of 7-D-mandelamidocephalosporanic acid were added. The pH is then adjusted to 6.3 and the mixture is ^{heated to 65 to 70 °} C. for 5 hours. The reaction mixture is then cooled to room temperature, diluted with 50 ml of water and extracted with diethyl ether. The solution is then adjusted to pH 2.0 with concentrated phosphoric acid and extracted several times with ethyl acetate. The unite

7098 10/1179

th ethyl acetate extracts are dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated to dryness. The residue is treated with a mixture of hexane and diethyl ether digested and chromatographed on Kjeselgel. As running medium is a mixture of 0.0 to 1.0% ethyl acetate in acetic acid is used. The eluate is evaporated and the residue from a mixture recrystallized from acetonitrile, ethyl acetate and diethyl ether.

S ^H 20 * 6 ° 6 ^S 2 ' 0.25 ¹ C ₄ H 10 ° ο, ί 5 H ₂ O C. H N ber. : 46 , 19th 55 16, 16 found : 46 , 32 4, 59 15, 92

Example 2

7- (D-cc-aminophenylacetamido) -3- / 1- (2-hydroxyethyl) tetrazol-5-ylthioraethyl 7-3-cephem-4-carboxylic acid

A solution of 7.58 g (0.015 mol) of 7- (D- ^ -tert-butoxycarbonylaminophenylacetamido) -cephalosporanic acid, 1.46 g (0.01 mol) of 1- (2-hydroxyethyl) -tetrazol-5-thiol and 2.52 g (0.03 mol) of sodium bicarbonate in 125 ml of water is ^{stirred at 60 °} C. for 5 hours. The pH value is adjusted to 7.0 to 7 »2 by adding sodium bicarbonate. The reaction mixture is then cooled and extracted with ethyl acetate. The aqueous phase is adjusted to a pH of 2.5 with 3N hydrochloric acid and the acidic solution is extracted again with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and evaporated to dryness. .The residue is treated with 5 percent aqueous

709810/1179

2639350

ger sodium carbonate solution added up to a pH of 7.1. The sodium salt of 7- (D - <* - tert-butoxycarbonylaminophenylacetamido) -3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid is used obtain.

By acidifying the aqueous solution of the sodium salt is the get free acid. About 1 g of the free acid are at 25 ° C with 25 ml of trifluoroacetic acid and 25 ml of 1,3-dimethoxybenzene Stirred for 2 1/4 hours. Thereafter, the reaction mixture is evaporated to dryness, the residue is treated with diethyl ether and the resulting precipitate was filtered off, washed with diethyl ether and stirred in acetonitrile for 2 hours. After that the crystals filtered off and dried under reduced pressure. The title compound is obtained.

Example 3

According to Example 2, the N-tert-butoxy carbonyl derivatives of 7- (oL-amino-4-hydroxyphenylacetamido) -cephalosporanic acid, 7- ( C1-amino-4-formamidophenylacetamido) -cephalosporanic acid, 7- (oc-amino -3-formamidophenylacetamido) -cephalosporanic acid, 7_ (oi. -Amino-4-ureidophenylacetamido) -cephalosporanic acid, 7_ (c ^ _Amino-3-ureidophenylacetamido) -cephalosporanic acid, 7_ (cC -amino-4-hydroxymethyl) -cephalosporanic acid and

7- (c <~ -amino-1,4-cyclohexadienylacetamido) -cephalosporanic acid reacted with 1- (2-hydroxyethyl) tetrazole-5-thiol. Afterward the protective group is split off. The following connections are obtained:

709810/1179

263938Q

7-r ( rf- -amino-4-hydroxypheny! Acetamido) -3- / 1- (2-hydroxyethyl) -tetrazol-5-ylth.iomethyl7-3-cepliem - ^ - carboxylic acid,

7- C cL -Ajiiino-4-formamidopheny! Acetamido) -3-Z ^> 1- (2-hydroxyethyl) -tetrazol ^ -ylthiomethy ^ - ^ - cephem ^ -carboxylic acid, 7- (c * -amino-3- formamidophenylacetamido) -3-Zi- (2-hydroxyethyl) -te trazol-5-y ltMome thy l7-3-cephem-4-carboxylic acid, 7_ (oc-amino-4-ure idophenyl lace t amido) -3 -Z ^y l- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-carboxylic acid, 7- (oc-Ämino-3-ureidophenylacetamido-3-zi- (2-hydroxyethyl) tetrazol-5-ylthiomethyl / -3-cephem- ⁱ J-carboxylic acid, 7_ (ο? -Amino- ² ! -Hydroxymethylphenylacetamido) -3-zi- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid and 7- ( <3 ^ -amino-1,4-cyclohexadieny / acetamido) -3- / ΐ- (2-hydroxyethyl) -tetrazol-5-ylthiomethyl / -3-cephem-4-carboxylic acid.

Example 4

According to Example 1, by reacting 7- (4-Hydroxyraandelamido) -ce'phalosporanic acid with 1- (2-hydroxyethyl) tetrazol-5- "thiol the 7- (4-hydroxymandelamido) -3-zi- (2-hydroxyethyl) tetrazol-5-ylthiomethyl / -3-cephem-4-cicic acid manufactured.

Example 5

A mixture of 2.5 g (7.7 mmol) of D- ^ N-tert-butoxycarbonylamino) -4-aminophenylglycine, 1.8 g (9 »2 mmol) of tert-butyl bromoacetate and 2, 5 g (19j2 mmol) Ν, ΙΤ-Diisopropyläthylaiain in 15 ml ethanol is stirred at 25 ° C for 48 hours. Thereafter, the solvent is distilled off under reduced pressure, the residue is diluted with ethyl acetate and sodium bicarbonate and

_J 709810/1179

- 263938Q ^Π

the pH adjusted to 2.5. Thereupon the layers separated, and the aqueous phase is extracted again with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and used for Evaporated to dryness. What remains is the D-o <- (N-tert-butoxycarbonylamino ) -4 ~ tert. -butoxycarbonylmethylaminophenylglycine.

A solution of 0.380 g (1.0 mmol) D - <* - CN-t er t.-Butoxy carbonyiamino) -4-tert .. -butoxycarbonylmethylaminophenylglycine, 0.296 g (1.0 mmol) 7 - ^ ^a i ^Noce Pkalosporansäure tert-butyl ester and 0.210 g (1.0 mmol) of dicyclohexylcarbodiimide in 25 ml of a mixture of ethyl acetate and methylene chloride (9: 1) is stirred for 1 hour at 0 ⁰ C. The reaction mixture is then filtered, the filtrate is washed with 2.5 percent strength sulfuric acid, 5 percent strength sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness. What remains is the 7_ (p_ <x-tert-butoxy carbony lamino-4-carboxymethy laminopheny 1-acetamido) -cephalosporanic acid tert-butyl ester. This compound is stirred as a mixture with 2 ml of thiophenol in 10 ml of trifluoroacetic acid at 25 ° C. for 1 hour. As a result, the protective group is split off. The reaction mixture is then evaporated to dryness. The 7- (D - ^ - amino-4 - carboxymethylaminopheny lac et amido) -cephalosporanic acid remains.

According to Example 2, the N-tert-butoxycarbonyl derivative is the 7- (D- (X-amino-4-carboxymethylaminophenylacetamido) -cephalospo-tranoic acid reacted with 1- (2. ~ hydroxyethyl) tetrazole-5-thiol and then split off the protective group. The 7- (D-O * —Amino-

709810/1179

4-carboxymethylaminophenylacetamido) -3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid obtain.

Example 6

7- (2-aminomethylphenylacetamido) -3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid

According to Example 1, 7- (2-aminomethylphenylacetamido) -cephalosporanic acid is obtained reacted with 1- (2-hydroxyethyl) tetrazole-5-thiol to give the title compound.

Example 7

7-Trifluorme thylmercaptoacetamido-3-Ζ'ΐ- (2-hydroxyethyl) -tetrazol-5-ylthiomethyl / -3-cephem-4-carboxylic acid

A solution of 1.46 g (10.0 mmol) 1- (2-hydroxyethyl) -tetrazol-5-thiol, 0.840 g sodium bicarbonate and 5.4-5 g (12.5 mmol) the sodium salt of 7-trifluoromethylmercaptoacetamidocephalosporanic acid in 60 ml V / ater is heated to 70 to 75 ⁰ ^ for 5 hours and stirred. The pH is adjusted to 6.8 by adding 5 percent aqueous sodium carbonate solution. The reaction mixture is then cooled and diluted with water, ethyl acetate is added and the mixture is adjusted to pH 2.0 with 6N hydrochloric acid. The aqueous phases are extracted further with ethyl acetate, the ethyl acetate extracts are dried over magnesium sulfate and evaporated to dryness. The title compound remains.

7 0 9 8 10/1 179

- ^1? - 263938Q

Example 8

According to Example 7, the sodium salts of 7- (2,2,2-trifluoro-ethylmercaptoacetamido) -cephalosporanic acid and 7- ^ rifluoromethylsulfinylacetamidocephalosporanic acid are reacted with 1- (2-hydroxyethyl) -tetrazol-5-thiol to give the following compounds: 7- ( 2,2,2-trifluoroethylmercaptoacetamido) -3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid and 7-trifluoromethylsulfinylacetamido-3- / 1- (2-hydroxyethyl) tetrazole -5-ylthiomethyl 7-3-cephem- ^z i-carboxylic acid.

Example 9

7-amino ~ 3- ^ ^; T- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem - ^ - carboxylic acid

A is at 45 ⁰ C heated solution of 10.9 g (0.04 mol) of 7-aminocephalosporanic acid in a mixture of 220 ml of water, 50 ml of acetone and 8.4- g (0.01 mol) ITatriumbicarbonat with a solution of 8.76 g (0.06 mol) of 1- (2-hydroxyethyl) tetrazole-5-thiol in 120 ml of acetone were added. The temperature is then increased to 65 ° C. and the pH is adjusted to 7 * 4 to 7 »6 by adding aqueous sodium carbonate solution. After 3 hours, the acetone is distilled off under reduced pressure, the residue is ^{cooled to 10 °} C. and adjusted to a pH of 3 »5 with dilute hydrochloric acid. The product is filtered off, washed with water and acetone. The title compound is obtained.

709810/1179

example

According to Example 1, equivalents are used instead of ethanolamine Quantities of 3-amino-i-propanol, ^ - amino-i-butanol, 5-amino-1-pentanol, 7-amino-1-heptanol, 8-amino-1-octanol and IO-amino-1-decanol used. The dithiocarbamates obtained are converted into the corresponding acetoxy derivatives, which with sodium azide implemented. The acetyl group is then split off. The following substituted tetrazole-5-thiols are used obtain:

1- (3-hydroxypropyl) tetrazole-5-thiol _t 1- (4-hydroxybutyl) tetrazole-5-thiol, 1- (5-hydroxypentyl) tetrazole-5-thiol, 1- (7-hydroxyheptyl) - tetrazole-5-thiol, 1- (8-hydroxyoctyl) -tetrazole-5-thiol and 1- (10-hydroxydecyl) -tetrazole-5-thiol.

The implementation of the tetrazole-5-thiols listed above provides according to Example 1 with 7-D-mandelamidocephalosporanic acid following connections:

7-D-Mandelamido-3-Z'i ~ (3-hydroxypropyl) -tetrazol-5-ylthiomethyl7 3-cephem-4-carboxylic acid, 7-D-Mandelamido-3- / 1- (4-hydroxy butyl) tetrazole -5-ylthiomethyl / ~ 3-cephem-4 ~ carboxylic acid, 7-D-mandelamido-3- / 1-C5-hydroxypentyl) tetrazol-5-ylthiomethyl7 3-cephem-4-carboxylic acid, 7-D-mandelamido -3- / ^: T- (7-hydroxyheptyl) -tetrazol-5-ylthiomethy 3-cephem-4-carboxylic acid,

709810/1179

7-D-Mandelamido-3- ^ ~ (8-hydroxy-octyl) -tetrazol-5-yl-methyl-methyl-7-3-cephem-4-carlic acid and

7-D-Mandelamido-3-Zi-CiO-liydro3cydec7l) -tetrazole-5-7lthiomethyl7-3-cephem-4-carboxylic acid.

The reaction of the substituted tetrazole-5-thiols listed above with 7 - ^ inocephalosporanic acid or one of the aforementioned 7 - A-cylcephalosporanic acids gives the corresponding
Compounds of the invention.

Example 11

7- (2,2,2-trifluoroethylsulfynylacetamido) -3- / 1- (2-hydroxyethyl) tetrazol-5-yl "thiomethyl / -3-cephem- ⁱ l -carboxylic acid

A solution of 5.7 g (0.03 mol) of 2,2,2-Trifluoräthylsulfinylessigsäure and 3 ^ 5 g (0.03 mol) of F-hydroxysuccinimide in 50 ml tetrahydrofuran is added at 0 ⁰ C under stirring with 6.2 g (0.031 mol) of dicyclohexylcarbodiimide were added. Thereafter, the reaction mixture is stirred for 1 hour at 0 ^0C and 12 hours at 25 ° C. the
The resulting precipitate is filtered off and treated with tetrahydrofuran
washed. The filtrate is evaporated to dryness. The activated ester of 2,2,2-trifluoroethylsulfinyl-r remains
acetic acid.

A suspension of 3.58 g (0.01 mol) of 7-amino-3- ^ 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl / -3-cephem-4-carboxylic acid 2 ml of triethylamine are added to 50 ml of anhydrous dimethylformamide and the mixture is stirred at 25 ° C. for 15 minutes. After that, the mixture

J 7098 10/1179

with a slight excess of 0.01 mole of the activated Ester of 2,2,2-Trifluoräthylsulfinylessigsäure added and stirred for another hour. The reaction mixture is then evaporated to dryness and the residue with water and ethyl acetate offset. The layers are separated, the ethyl acetate layer is discarded, the aqueous phase with fresh ethyl acetate added and adjusted to a pH of 2.5 with 6N hydrochloric acid. After that, the mixture is filtered to remove the layers are separated and the aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts are combined with water washed, dried over magnesium sulfate and evaporated to dryness. The title compound remains.

Similarly, the 7- (2,2,2-trifluoroethylsulfinylacetamido) derivatives of other above-described Jm. ± no-3- hydroxyalkyltetrazole cephalosporins can be prepared.

Example 12

7-methylmercaptoacetamido-3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl 7-3-cephem-4-carboxylic acid

A cooled to -20 ⁰ C solution of 9.3 g (0.026 mol) of 7-amino-3- ^/: T- (2-hydroxyethyl) tetrazole-5-ylthiomethyl7-3-cephem-4-carboxylic acid in 220 ml 3prozentiger aqueous sodium bicarbonate solution and 220 ml of acetone is added dropwise with a solution of 3 * 66. g (0.029 mol) of methyl mercaptoacetyl chloride in 52 ml of acetone were added. During the reaction, the pH of the reaction mixture is increased to 8.0 by adding 10 percent sodium hydroxide solution

_ 709810/1 179

set. When the addition is complete, the reaction mixture is Stirred for a further 20 minutes at - ~ 15 ° C, then warmed to 25 ° C and extracted with diethyl ether. The aqueous phase is cooled, 250 ml of ethyl acetate are added, and the slurry is added acidified with 3N hydrochloric acid. The layers are separated, and the aqueous phase is extracted twice with ethyl acetate. The combined ethyl acetate extracts are dried over magnesium sulfate and evaporated to dryness. The title compound remains.

Example I3

7_ (D_cx- -Formyloxyphenylacetamido) -3- / 1- (2-hydroxyethyl) -tetrazol-5-ylthiomethyl7-3-cephem- ^z l-carboxylic acid

A mixture of 3.58 g (0.01 mol) of 7-amino-3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid, 3.97 g (0, 02 mol) of the formic acid ester of D-mandelic acid chloride and 5 g of sodium bicarbonate in 100 ml of water and 14-0 ml of acetone are stirred for ^{1 hour in the cold and for 2 more hours at 25 ° C.} The acetone is then distilled off under reduced pressure and the aqueous residue is extracted with ethyl acetate. The aqueous solution is introduced into a cold mixture of 100 ml of water and 200 ml of ethyl acetate with stirring, and the pH of the mixture obtained is adjusted to 2.0 with 6N hydrochloric acid. The mixture is then filtered, the layers are separated and the ethyl acetate layer is washed with water, dried over magnesium sulfate and evaporated to dryness. The title compound remains.

709810/1179

Example 14

According to Example 11 7- ^ itto-3-Z ^ - (2-hydroxyethyl) tetrazol-5-ylthiometnyx7-3-cephem-4-car "bonsäure is reacted with an activated derivative of cyanoacetic acid or cyanomethylmercaptoacetic acid. The 7- Cyanacetamido-3- / 1- (2-hydroxyethyl) -tetrazol-5-ylth.iomethyl7-3-cepliem- ^z t-carboxylic acid and 7-cyanomethylmercaptoacetamido-3- / 1- (2-hydroxyethyl) tetrazole-5- y ItMomethyl7-3 ~ cepliem-4-carboxylic acid.

709810/1 179

Claims (1)

Claims V ^ ~ 3- ^{(2 "H} y ^DROX yalkyl) tetrazole-5-ylthiomethyl7-3-cephem-4- carboxylic acids of the general formula I I (CH ₂ ) _n -OH in the E an acyl radical of the general formula O Oo X-CH-C-, Y-CH ₂ -C- or ZS (O) _m -CH ₂ -C- represents, where X is a dihydrophenyl or phenyl group or a hydroxyl, hydroxymethyl, formamido, Ureido or carboxymethylamino group monosubstituted Phenyl group, A an amino, hydroxyl, carboxyl or sulfonic acid group or "when X is a phenyl group, a formyloxy group, Y a cyano or aminomethylphenyl group and Z is methyl, trifluoromethyl, trifluoroethyl or Means cyanomethyl group, m has the value 0, 1 or 2 and. η is an integer with a value from 2 to 10, and its salts with acids or bases. 2. Compounds according to claim 1 of the general formula I, in which η is an integer with a vert of 2 to 5. 709810/1179 3. Compounds according to claim 2 of the general formula I in the E is a group of the general formula Il X-CH-C-A means in which X is a phenyl or hydroxyphenyl group and A is an amino or hydroxyl group. 4. Compounds according to claim 2 of the general formula I in 1
the R is a group of the general formula Il T-CH ₂ -C- and T represents a cyano or aminomethylphenyl group. 5. Compounds according to claim 2 of the general formula I in the E is a group of the general formula Il ZS (O) -CH-Cm t ~ and Z is a trifluoromethyl or cyanomethyl group and m is 0, Λ or 2. 6. 7-Mandelamido-3 ~ ^ 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl / -3-cephem - ^ - carboxylic acid. 7. 7- (o <_- aminopheny / acetamido) -3- / 1- (2-hydroxyethyl) tetrazol-5-ylthiomethyl / ~ 3 ~ cephem-4-carboxylic acid. 709810/1179 8. 7- (d-Amino-4-hydroxyphenylacetamido) -3-zi- (2-hydroxyethyl) -tetrazol-5-yl'fcliiomethyl7-3-cephem- ^z t-carboxylic acid. 9 7-Cyanomethylmercaptoacetamido-3-Zi- (2-hydroxyethyl) -tetra- - carboxylic acid. 10. 7 ~ Trifluoromethylmercaptoacetamido-3-Zi- (2-hydroxyethyl) tetrazol-5-ylthiomethyl7-3- ^ce Phem-4-carboxylic acid. 11. 7-Amino-3- / i :- (2-hydroxyalkyl) tetrazol-5-ylthiomethyl7-3- - ^ - carboxylic acids of the general formula II in which η is an integer with a value from 2 to 10 and E is a hydrogen atom or a carboxyl protecting group means. 12. Compounds according to claim 11 of the general formula II, in which R is a hydrogen atom, a benzhydryl, tert.-butyl, Trichloroethyl, benzyl, benzyloxymethyl, p-mtrophenyl, p-methoxyphenyl, p-methoxybenzyl or p-nitrobenzy group means. 13. Compounds according to claim 12 of the general formula II, in which η is an integer with a value of 2 to 5. 709810/1 179 14-. Connections to. Claim 13 of the general formula II, in which η has the value 2. ) tetrazol-5-ylthiomethyl / -3-cephem-4-carboxylic acid. 16. 1 :-( 2-Hydroxyalkyl) -tetrazol-5-thiols of the general formula III ^HS \ ■ Μ — Ν (III) • ι (CH ₂ ) _n -OH
in which η is an integer with a value from 2 to 10. 17 · Compounds according to claim 16 of the general formula III, in which η is an integer with a value from 2 to 5. 18. 1 ~ (2-Hydroxyethyl) tetrazole-5-thiol. 19 · Medicines with antibiotic action, containing a compound according to claims 1 to 10. 20. Process for the preparation of the compounds according to claim 1, characterized in that one is carried out in a V / eise known per se either a) a cephalosporanoic acid compound of the general formula IV 709810/1179 ti CH ₂ OC-CH ₃ (IV) ΟΟΗ in which R has the meaning given in claim 1, or their reactive derivative with a 1- (2-Hy dr oxy alkyl) tetrazole-5-thiol of the general formula III (IH) HS - (/ -N-N (C. H ₂ ) _n -0H in which η has the meaning given in claim 1, or its salt reacts or b) a 7-amino-3-zi- (2-hydroxyalkyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid of the general formula II COOR ² (II) (CH ₂ ) _n -OH in which η has the meaning given in claim 1 and R is a hydrogen atom or a carboxy protective group, or its reactive derivative with an acylating agent of the general formula Y R ¹ -OH (V) in-the R has the meaning given in claim 1, or- 709810/1179 converts their reactive derivative, optionally present from the compound obtained according to a) or b) Splitting off protective groups and optionally the obtained A compound is converted into a salt with an acid or base, 709 810/1179