DE2607681A1 - THENYL AND TETRAZOLYLMETHYLCEPHALOSPORINS - Google Patents

Description

"Thenyl- and Tetrazolylmethylcephalosporins" Priority: February 27, 1975, V.St.A., No. 553 722

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

The term "lower alkyl" means groups of 1 to 4 Carbon atoms, preferably the methyl and ethyl group,

Preferred compounds of the invention have the general formula I, in which Het represents a tetrazolyl group represented by

P -r is, in ρ the group - (CHR) COR is substituted / the R is a hydrogen atom

and R ^ is a hydroxyl, amino, lower alkylamino or di-lower-alkylamino group and m represents an integer with a value from 1 to 10

Preferred compounds are also the compounds of the general

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common formula I in which Het is a tetrazolyl group which ^{is substituted by the group - (CHR 2} ) _m COR ⁵ , in which R ^{2 is} a hydrogen atom and R is a hydroxyl or amino group and m is an integer with a value of 1 to 5 is.

Particularly preferred compounds are 7- (2-thienylacetamido) -3- (1-carboxyme thy It et razol-5-ylthiome thy l) -3-cephern- ⁱ l-carboxylic acid, 7- (2-thienylacetamido) -3-Zl - (2-carbamoylethyl) -tetrazol-5-ylthiomethyl7-3-cepheni ~ 4-carboxylic acid, 7- (l-tetrazolylacetamido) -3- (l-carboxymethyltetrazol-5-ylthiomethyl) -3-cephem- ¹ l -carboxylic acid, 7- (2-Thienylacetamido) -3-Zl- (2-carboxyethyl) -tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid and 7- (l-tetrazolylacetamido) -3-Zl- (2-carboxyethyl) - tetrazol-5-ylthiome thy iZ ^ -cephem- ^ J -carboxylic acid.

Cephalosporin derivatives with a thienylacetamido or tetrazolylacetamido group in the 7-position are known. The compounds of the invention substituted by a S-heterocyclic Thiomethyl radical substituted in the 3-position of the cephem nucleus fall under those specified in NL-OS 69.I6151. benen general formula in which Het, among other things, an optionally by a carboxyl, carbalkoxy, alkoxyalkylaminocarbonyl or dialkylaminoalkylaminocarbonyl group means substituted triazolyl or tetrazolyl group. This general Formula also includes an optionally substituted heterocyclic acetamido group in the 7-position, among which the tetrazolylacetamido- and thienylacetamido group falls. Specifically, only an ester is one substituted by a carboxylic acid

^L 609 8 3 7/0971 ^J

TetrazoIylthiomethy! Cephalosporins described.

A general formula for cephalosporins is given in JA-PS 72.05550, in which Het denotes a triazolyl or tetrazolyl group, which _{is substituted by a group of the general formula - (CH 2} ) _n Fr, in which η has the value 0 to 3 and R- ⁵ denotes, inter alia, an alkoxycarbonyl, carboxyl, N-alkoxyalkylcarbamoyl or dialkylamino group, and which also has a 7-thienylacetamido or 7-tetrazolylacetamido group. Examples are 7-tetrazolylacetamido-3-thiadiazolylthiomethylcephalosporin as ester and acid.

In U.S. Patent 3,819,623 there is a general formula for cephalosporins of the invention indicated that a 7-Heterocycloacetamido- or 7-heterocyclothioalkylacetamido group and in the 3-position inter alia a tetrazolylthiornethyl group have, which are characterized by a carboxyl, alkoxycarbonyl, carboxyalkyl, Alkoxycarbonylalkyl or dialkylaminoalkylaminocarbonyl

alkyl group is substituted. Among the connections described there is an ester of a compound of the invention and a thiadiazolylthiomethyl analog, -

The process according to the invention is carried out in a manner known per se. The method used according to thienyl or Tetrazolylacetic acid is activated by customary methods, for example in the form of mixed anhydride, acid chloride, Acid imidazolide or an activated ester. Furthermore, for example, dicyclohexylcarbodiimide can be used, so-

^L r »η ί * m ν / η α 71 ^J

far the carboxyl group on the cephem nucleus by an easily cleavable one Protective group, such as a benzhydryl, tert-butyl, trichloroethyl, benzyl, benzyloxymethyl, p-nitrophenyl, p-methoxyphenyl, p-methoxybenzyl or p-nitrobenzyl ester group is,

The compounds of general formula I can also be prepared by acylating 7-aminocephalosporanic acid with thienyl or tetrazolylacetic acid and subsequent substitution of the acetoxy group in the 3-position by the corresponding substituted one Mercaptotriazole or mercaptotetrazole can be produced.

The protective groups can be split off by customary methods, for example when using a tert-butyl group as a protecting group with trifluoroacetic acid. The salt obtained is made by means of a basic ion exchange resin such as a polystyrene amine ion exchange resin (Amberlite IR-JJ5) or by 'Making an aqueous solution of the salt into the free alkaline Acid transferred

The thienyl and tetrazolylacetic acid used according to the method are known or are prepared by customary methods, 7-thienyl and 7-tetrazolylacetamidocephalosporanic acid are known from US Pat. No. 3,516,997.

The compounds used according to the process of the general Formula II are obtained by reacting 7-aminocephalosporanic acid with a substituted mercaptotriazole or mercaptotetrazole

ß09837 / 0971 ^J.

2607601

manufactured,

The substituted 1,2,3-mercaptotriazoles can by rearrangement the corresponding aminothiazoles according to the in Chem. Be'r., Vol. 99 (1966), pp. 1618, by converting the corresponding 1,2,3-hydroxytriazoles to the corresponding Mercaptans according to the in J. Am. Chem. Soc. 78 (1956), pp. 5832 or by reacting an acetylenecarboxylic acid. with a substituted azide and subsequent decarboxylation and introduction of the mercapto group will.

• The substituted mercaptotetrazoles in which R is a hydroxyl group means, are by reacting an isothiocyanate, for example isothiocyanoacetate, or an N-alkyldithiocarbamate ^ such as methyl 2-carboxyethyldithiocarbamate with an azide such as sodium azide. When the radical R is an amino, lower alkylamino or di-lower alkylamino group means, the mercaptotetrazoles are by customary methods for the preparation of amides from acids from the corresponding mercaptotetrazoles prepared in which R represents a hydroxyl group. For example, a mercaptotetrazole, in which R represents a hydroxyl group, with 1,1-carbonyl-

5 6 diimidazole and an amine of the general formula NHR R reacted, in which R and R are hydrogen atoms or lower alkyl radicals or a mercaptotetrazole in which R represents a hydroxyl group is converted into the corresponding acid chloride and then with an amine of the general formula

^L 609837/0971 ^J.

r '26,076 t -ι

NHR R implemented. The mercaptotetrazoles can also by reaction of the correspondingly substituted HydroxytetrazzoIs to the corresponding Mercaptan according to the method described in J. Am. Chem. Soc, vol. 78 (1956), p. 5832 '.

The compounds of general formula I form salts, for example Alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium salts or ammonium salts. The salts are produced according to the usual methods.

If the side chain in the 3-position is an asymmetrical one Has carbon atom, the compounds of general formula I can occur in optical isomers (epimers). the Invention includes all isomers and their mixtures »

The compounds of general formula I are valuable antibiotics with activity against gram-positive and gram-negative germs, their serum levels and half-lives of the serum level are high. The MIC in in vitro tests is 0.2 to more than 200 ug / ml. The results for some compounds of the general formula I are summarized in Table I. The values for the ED ₁ -Q in infected mice are summarized in Table II. The names of the compounds tested are given in Table III.

_L "GREEN

609837/0971

- 7 - Table I.

MIC in vitro (pg / nil)

Bacteria 1 2 3 4th 5: 6th 7th S. aureus HH 127 3.1 0,4,0,4 1.6 3.1 6.3 3.1 0.8 S. aureus SK 23390 0.8 0,2,0,4 0.8 3.1 6 _; 3 3 * 1 0.2 S. irnialua 50 0.4.3.1 3.1 100 200 100 3.1 Strep faecalis HH 34358 50 12,5,6,3 25th 100 200 100 3.1 E, co! Ί SK1214O 3.1 1,6,0,8 1.6 0.8 3.1 0.8. 50 E. coil HR 33779 6.3 6.3.3.1 .3 / 1 6.3 12 _f 5 3.1 ' 100 ^ t Glue, pneumo. SK 4200 3.1 1,6,1,6 0 _; 8th 1 _; 6th 6.3 0 _; 8th 6.3 Glue, pneumo. SK ι200 0.4 0.8,0.8 0.8 0.4 3.1 0.8 100 Pseudo, sp. HH 63 > 200 > 200,> 200 > 200 > 200 > 200 > 200 > 200 Salmonell'a ATCC 12176 O ₁ S 0,2,0,8 0.2 O ₇ S 6.3 1.6 50 Shisella KH 117 3 * 1 0,4,0,2 0.8 3.1 6.3 0 _r 4 25th Entero. aerog. ATCC 13048 25th 50 _/ 3.1 12.5 12.5 200 6.3 100 Serra. marc. ATCC 13880 200 > 200, 50 25th > 200 > 200 > 200 > 200 cd Entero. cloacae HH 31254 3.1 5,3,1,6 3.1 1.6 12.5 1.6 CD
25 ^
cn Proteus morgani 179 > 200 50.200 > 200 > 200 > 200 200 > 200 &>

- 8 - Table II

link E. coli 12140 Glue pneumo. 4200 S.C. P., - Pr. S, C. 1 21.2 2 1.56 46 1.56 35 3 7.2 35 1.0 40 4th 0.4 > 50 1.8 > 50 5 21 _r 2 • ■ Ca OK · 25th 6th 1.12 > 50 l _t 56 7th

Table III

link
1

2 3

6 7

7- (2-Thienylacetamido) -3- (1-carboxy-methyl-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

7- (2-Thienylacetamido) -3-Zi- (2-carbamoylethy1) -tetrazol-5-ylthiomethyl7-3-cephem- ⁱ l-carboxylic acid

7- (2-Thienylacetamido) -3- / 1- (2-carboxyethyl) -tetrazol-5-ylthiomethyl7-3-cephem- ⁱ l-carboxylic acid

7- (1-Tetrazolylacetamido) -3- (1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

7- (1-tetrazolylacetamido) -3- (5-carboxymethyl-1,2, il-triazol-3-ylthiome thy I) -3-cephem - ^ - carboxylic acid

7- (1-Tetrazolylacetamido) -3-Z "1 - ('2-carboxyethyl) -tetrazol-5-ylthiomethyl / -3-cephem-4-carboxylic acid

7- (2-Thienylacetamido) -3- ΓΑ- (10-carbamoylde cyl) tetrazol-5-ylthiomethyl12-3-CeDhCm - ^ - carboxylic acid.

G D Π 8 3 7/0 9 7 1

The compounds of general formula I can be administered subcutaneously or intramuscularly or administered intravenously.

The examples illustrate the invention.

example 1

7- (1-Tetrazoly / acetamido) -3- (5-carboxymethyl-1 _t 2,4-triazol-3-ylthiomethyl) -3-cephem-4-carboxylic acid

A solution of 1.05 g (12.5 mmol) sodium bicarbonate in 30 ml Water is mixed with 1.36 g (7.5 mmol) of the sodium salt of .3-Carboxymethyl-1,2,4-triazole-5-thiol (produced by adding 1 equivalent of sodium hydroxide solution to a solution of 3-carboxymethyl-1,2,4-triazole-5-thiol in aqueous ethanol) and 1.91 g (5.0 mmol) of 7- (l-tetrazolylacetamido) -cephalosporanic acid are added. The mixture is heated to 67.5 ° C. for 4 hours. The pH is adjusted to 7.6 by adding glacial acetic acid. The reaction mixture is then cooled to 20 ° C., adjusted to a pH of 3.5 with acid and lyophilized. Of the The residue is digested with ethanol. The product obtained is dissolved in 15 ml of anhydrous methanol and with 0.196 μm solution sodium methylate in methanol is added until the pH is about 6.0. Ethyl acetate is then added to the solution and the resulting precipitate is filtered off and dried under reduced pressure. It becomes the disodium salt of the title compound obtain.

CHNS

C ₁₅ H ₁₁ N ₉ O ₅ S ₂ . 2 Well 3.5 H ₂ O; calc .: 31.98 3.74 21.18 10.54

found: 32.53 3.14 20.72 10.55 ^L 60983 7/0971 - ¹

The disodium salt is used in the smallest possible amount of water dissolved and the solution mixed with ethyl acetate. 3 η hydrochloric acid is then added with stirring until the pH is 2.5. The layers are separated, the aqueous phase is extracted with ethyl acetate and the combined extracts are washed with water washed, dried over magnesium sulfate and evaporated to dryness. The title compound remains,

"B e i s ρ i e 1 2

7- (2-Thieny / acetamido) -3- (5-carboxymethyl-1,2,4-triazol-3-ylthiomethyl) -3-cephem-4-carboxylic acid

When using an equivalent amount of 7- (2-thienylacetamido) -cephalosporanic acid in the process according to Example 1, the title compound is obtained. The title compound can according to example 1 can be converted into the corresponding disodium salt by adding sodium methylate solution.

Example 3

7- (1-Tetrazolylacetamido) -3- (4-carboxy-1,2 ^ - methyl) -3-cephem- ⁱ t-carboxylic acid

A solution of 4.6 g (0.20 mol) of sodium in 250 ml of anhydrous ethanol is under nitrogen as protective gas with 8.65 g (0.05 Mol) 5-amino-4-carbethoxy-1,2,3-thiadiazole added. The mixture is stirred for 1 hour, then 5 ml of water are added and refluxed for 12 hours. After cooling, the reaction mixture is filtered and the filter residue with

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Ethanol and ether washed and dried. It becomes the trisodium salt obtained from Jl-Carboxy-ljZ ^ -triazol-S-thiol.

By acidifying an aqueous solution of 4-carboxy-1,2,3-triazole-5-thiol-trisodium salt 4-carboxy-1,2,3-triazole-5-thiol is obtained. The corresponding monosodium salt is according to Example 1 manufactured.

When using an equivalent amount of the sodium salt of 4-carboxy-l _> 2,3-triazol-5-thiol in the process according to Example 1, the title compound is obtained.

Example*"

7- (1-Tetrazoly! Acetamido) -3- ( ^j J-carbainoyl-l ^^ - y lthiome thy l) -3-cephein-4-carboxylic acid

According to Example 1, by reacting 7- (l-tetrazolylacetamido) -cephalosporanic acid with the sodium salt of 4-carbamoyl, 2,3-triazole-5-thiol (made from 4-carbamoyl-1,2,3-triazole-5-thiol) and sodium bicarbonate produced the title compound.

Example 5

7- (1-Tetrazoly! Acetamido) -3- / ¹ I- (2-carboxyethyl I) -1,2,3-triazol-3-yl-methyl-7-3-cephem-4-carboxylic acid

A solution of 1.725 g (75 mmol) of sodium in 50 ml of anhydrous Ethanol is mixed with 6.0 g (45 mmol) of benzyl azide and 12.3 g (50 mmol)

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Diethyl 2- (carbomethoxyethyl) malonate was added. The mixture is refluxed for 12 hours, then cooled and evaporated to dryness. The residue is mixed with 100 ml of water added and the mixture heated to a pH of 12. The aqueous mixture is then extracted with ethyl acetate and the aqueous phase acidified with 3 η hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is evaporated to dryness. What remains is l-benzyl-4- (2-carboxyethyl) -5-hydroxy-1,2,3-triazole.

5.0 g (0.02 mol) of the compound obtained are suspended in 300 ml of ethanol. The suspension becomes less anhydrous for 30 minutes Introduced hydrogen chloride. The mixture is then heated on a steam bath for 20 minutes. The solution obtained is cooled and evaporated to dryness. The residue is dissolved in 300 ml of ethyl acetate, the solution is washed with water, dried over magnesium sulfate and evaporated to dryness. After digestion with hexane containing a small amount of acetone contains, the l-benzyl-4- (2-carbäthoxyäthyl) -5-hydroxy-l, 2,3-triazole obtain.

A solution of 0.63 g (2.3 mmol) of l-benzyl-4- (2-carbethoxyethyl) -5-hydroxy-l, 2,3-triazole in 0.70 g (3.5 mmol) of phenylphosphonic acid dichloride is heated to 160 ° C for 90 minutes under nitrogen as a protective gas. After cooling, the reaction mixture is mixed with 2 ml of water and 2 ml of chloroform and kept at 5 ° C touched. At the same time, 6 ml of a 5 percent aqueous sodium bicarbonate solution are added. The mixture is

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extracted form, the chloroform extract dried over sodium sulfate and evaporated. The l-benzyl- ⁱ l- (2-carbethoxyethyl) -5-chloro-1,2,3-triazole is obtained.

A solution of 0.5 g (0.01 mol) of sodium methylate in 50 ml of anhydrous ethanol is saturated with hydrogen sulfide. 2.9 g (0.01 mol) of 1-benzyl-4- (2-carbethoxyethyl) -5-chloro-1,2,3-triazole are then added, and the mixture is refluxed for 2k hours. After cooling, the reaction mixture is evaporated to dryness. The sodium salt of l-benzyl-4- (2-carboxyethyl) -l, 2,3-triazole-5-thiol remains. By acidifying an aqueous solution of the compound, the l-benzyl- ¹ l- (2-carboxyethyl) -l, 2,3-triazole-5-thiol is obtained,

1.1 g (4 mmol) of the compound obtained are suspended in 50 ml of anhydrous liquid ammonia and mixed with sodium until the blue color persists. The reaction mixture is then stirred for 1 ½ minutes and then allowed to warm to room temperature. After the ammonia has evaporated, the residue is digested with diethyl ether and the pesticide is filtered off and dissolved in water. The aqueous solution is acidified and extracted with ethyl acetate. The ethyl acetate extract is over. Magnesium sulfate dried and evaporated to dryness. The 4- (2-carboxyethyl) -l, 2,3-triazole-5-thiol remains. The corresponding sodium salt is prepared according to Example 1.

\
When using the sodium salt of * i- (2-carboxyethyl) -l, 2,3-

triazole-5-thiol in the process according to Example 1, the title

609837/0371 ^J.

- in -

get connected.

Belspiel6

When using equivalent amounts of diethyl 2-carbethoxymethylmalonate or diethyl 2-carbethoxypropylmalonate in the process according to Example 5 and subsequent ester saponification, chlorination, introduction of the mercapto group and debenzylation is 4-carboxymethyl-1,2,3-triazole-5-thiol or 4- (3-carboxypropyl) -l, 2,3-triazole-5-thiol obtain. The corresponding sodium salts are prepared according to Example 1.

When using the sodium salts of the aforementioned compounds in the process. According to Example 1, 7- (l-tetrazolylacetamido) -3- ( ^z J-carboxymethyl-l, 2,3-triazol-5-ylthiomethyl) -3-cephem-4- carboxylic acid or 7- (l-tetrazolylacetamido) -3-ZT4- (3-carboxypropyl) l, 2,3-triazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid.

Example7

/ 1

A solution of 13.8 g (0.6 mol) of sodium in anhydrous ethanol is mixed with a solution of 96 g (0.6 mol) of diethyl malonate added to 500 ml of diethyl ether. The mixture is cooled and 117.1 g (0.6 mol) of ethyl 2-bromo-2-methylpropionate were added. The mixture is heated for 2 hours and then for * J8 hours stirred at room temperature. Thereafter, the reaction mixture with Acetic acid and water are added, the layers are separated, and the ethereal solution is washed with water over magnesium sulfate dried and evaporated to dryness. The 2- (l-carbethoxy-l-methylethyl) malonic acid diethyl ester remains behind.

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. ₁₅ -

from
When using equivalent amounts / 3-bromo-2,2-dimethylpropion-

acid methyl ester, 5-bromo-2-methylvaleric acid methyl ester or Methyl 2-bromo-2-ethylbutyrate when reacted with diethyl malonate the following substituted malonic acid esters

obtain:

2- (2-Carbomethoxy-2-methylpropyl) malonic acid diethyl ester

2- (4-Carbomethoxypentyl) malonic acid diethyl ester

2- (l-Carbomethoxy-l-ethylpropyl) malonic acid diethyl ester.

When using the substituted malonic acid esters listed above In the process according to Example 5, the following mercaptotriazoles are obtained:

4- (1-carboxy-1-methylethyl) -1,2,3-triazole-5-thiol 4- (2-carboxy-2-methylpropyl) -1,2,3-triazole-5-thiol i | - (4-Carboxypentyl) -1, 2,3-triazol-5-thiol and i | - (l-Carboxy-l-ethylpropyl) -l, 2,3-triazole-5-thiol.

When using the sodium salts of the mercaptotriazoles listed above im. Procedures according to Example 1 are as follows

Get cephalosporins:

7- (l-Tetrazolylacetamido) -3-Z ¹ Ml-carboxy-l-methylethyl) -l, 2,3-

triazol-5-ylthiome thy 17-3-CePhBm- ¹ I-carboxylic acid

7- (l-tetrazolylacetamido) -3- / ¹ * - (2-carboxy-2-methylpropyl) -

1,2,3-trlazol-5-ylthiomethyl / ^ - cephem- ¹ ! -Carboxylic acid

7- (l-tetrazolylacetamido) -3 - / ^ - ( ¹ J-carboxy pentyl) -1,2,3-triazole-

5-ylthiomethyl 7-3-pephem-4-carboxylic acid

7- (1-Tetrazolyl acetamido) -3- / ¹ I- (I-Ca ^ oXy-1-ethylpropyl) -1,2,3-

triazo1-5-ylthiomethyl7-3-cephem-4-carboxylic acid.

"U09837 / 0971

-ie- 260768Ί

'Example 8

7- (1-Tetrazolylacetamido) -3- (4-N-methylearbamoy1-1, 2,3-triazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

A solution of 7.2 g (44 mmol) 1,1-carbonyldiimidazole in 110 ml of anhydrous tetrahydrofuran and 20 ml of dimethylformamide are added to a solution of 7.7 g (43.8 mmol) of 4-carboxy-1,2,3-triazole-5-thiol added to 110 ml of anhydrous tetrahydrofuran and 20 ml of dimethylformamide. The mixture is saturated with a A solution of methylamine in tetrahydrofuran was added and the mixture was stirred at 25 ° C. for 12 hours. The reaction mixture is then used Evaporated dry, the residue diluted with 200 ml of water and the solution is adjusted to pH 2 to 3 with sulfuric acid. The aqueous solution .wird lyophilized and the

The extract is evaporated. The residue is extracted with acetone. The 4-N-methylcarb-

obtain.

In the reaction of the sodium salt of 4-N-methylcarbamoyl-1,2,3-triazole-5-thiols prepared in the manner described above with 7- (l-tetrazolylacetamido) -cephalosporan acid according to Example 1, the title compound is obtained.

Example 9

When using ethylamine, propylamine or butylamine in the process according to Example 8, the following mercaptotriazoles are obtained:
4-N-Ethylcarbamoyl-1,2,3-triazole-5-thiol

^L fi 0 9 S 3 7/0 9 7 1

4-N-Butylcarbamoyl-1,2,3-triazole-5-thiol.

The reaction of the sodium salts of the above-mentioned mercaptotriazoles prepared according to Example 1 with 7- (l-tetrazolylacetamido) -cephalosporanic acid or 7- (2-thienylacetamido) -

cephalosporanic acid provides the following compounds:

7- (l-Tetrazolylacetamido) -3 - '(4-N-ethylcarbamoyl-l, 2,3-triazole-

5-ylthiomethy ^^ - cephem - *! - carboxylic acid

7- (l-tetrazolylacetamido) -3- (4-N-propylcarbamoyl-l, 2,3-triazole-

5-ylthiomethyl) -3-cephem-4-carboxylic acid

7- (l-tetrazolylacetamido) -3- (4-N-butylcarbamoyl-l, 2,3-triazole-

5-ylthiomethy]) - ^3-cephem-i i-carboxylic acid

7- (2-thienylacetamido) -3- ⁽ⁱ iN-äthylcarbamoyl-l _i 2,3-triazol-5-

ylthiomethyl) -3-cephem- ⁱ l-carboxylic acid

7- (2-Thienylacet amido) -3 - (^ - N-PrOPy lcarbamoyl-Ι, ί :, 3-triazol-5-

ylthiomethyl) -3-cephem-4-carboxylic acid

7- (2-Thienylacetamido) -3- ( ² tN-butylcarbamoyl-1,2,3-triazole-5-

ylthiomethyl) -3-cephem- ⁱ <-carboxylic acid.

Example 10

7- (1-Tetrazolylacetamido) -3- (5-N _i N _{-dimethylcarbamoylmethyll 1} 2 _t 4-triazol-3-ylthiomethyl) -3-cephem-4-carboxylic acid

A solution of 5.3 g ² I (33.8 mmol) of 3-carboxymethyl-l, 2, ⁱ ltriazol-5-thiol in 75 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide is slowly added a solution of 5.49 g of ( 33.9 mmol) of 1,1-carbonyldiimidazole in 95 ml of anhydrous dimethylformamide were added. The reaction mixture becomes 35

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Stirred for minutes, then treated with 250 ml of a solution of tetrahydrofuran saturated with dimethylamine and stirred at 25 ° C. for 12 hours. The mixture is then concentrated to about 200 ml, and tetrahydrofuran and diethyl ether are added to the residue. The resulting precipitate is filtered off and dissolved in 170 ml of water. The aqueous solution is acidified to pH 2.0 with 6 η sulfuric acid and extracted with ethyl acetate. The ethyl acetate extract is evaporated to dryness and the residue is digested with diethyl ether. There is obtained 3-N, N-dimethylcarbamoylmethyl-l, 2, ⁱ i-triazole-5-thiol.

In the reaction of Example 1 .gemäß hergestelllten sodium salt of 3-N, N-dimethylcarbamoylmethyl-l, 2, l ^{i-triazole-5-thiol} with 7- (l-Tetrazolylacetamido) cephalosporanic acid, the title compound is obtained.

Examples

When using diethylamine, dipropylamine or dibutylamine in the process according to Example 10, the following mercaptotriazoles are obtained obtain:

3-N, N-diethylcarbamoylmethyl-1,2,4-triazole-5-thiol 3-N, N-Dipropylcarbamoylmethy1-1,2,4-triazole-5-thiol 3-N, N-dibutylcarbamoylmethyl-1,2,4-triazole-5-thiol.

In the implementation of the sodium salts prepared according to 'Example 1 of the mercaptotriazoles listed above with 7- (l-tetrazolylacetamido) -cephalosporanic acid or 7- (2-thienylacetamido) -cephalosporanic acid, the following compounds are obtained:

609837/0971 ~ "

- 19 - 260768Ί

7- (l-Tetrazolylacetamidö) -3- (5-N, N-dläthylcarbamoylmethyl-1,2, ⁱ ltriazol-3-ylthiomethyl) -3-cephem- ⁱ l-carboxylic acid 7- (l-tetrazolylacetamido) -3- ' (5-N, N-dipropylcarbamoylmethyl-1,2,4-triazol-3-ylthiomethyl) ^ - cephem-i-carboxylic acid 7- (1-tetrazolylacetamido) -3- (5-N, N-dibutylcarbamoylmethyl-1,2 , ⁱ ltriazol-3-ylthiomethyl) -3-cephem - ^ - carboxylic acid 7- (2-thienylacetamido) -3- (5-N, N-diethylcarbamoylmethyl-1,2,4-triazol-3-ylthiomethyl) -3- cephem- ⁱ l-carboxylic acid 7- (2-thienylacetamido) -3- (5-N, N-dipropylcarbamoylmethyl) -1,2,4-

I ■
triazol-3-y It hiomethyl) -3-cophem- ⁱ l-carboxylic acid

7- (2-Thienylacetamido) -3- (5-N, N-dibutylcarbamoylmethyl-1,2,4-trlazol-3-ylthiomethyl) -3-cephem - ^ - carboxylic acid.

Example 12

7-fc-'Biienylacetamido) -3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cephem - ^ - carboxylic acid

A solution, cooled to 5 to 10 ° C., of 89.6 g (1.6 mol) of potassium hydroxide in 200 ml of water is mixed with 60 g (0.8 mol) of glycine. When the solution is complete, 60.8 g (0.8 mol) of carbon disulfide are added and the mixture is stirred at 25 ° C. for 3 hours. Then a solution of 113.6 g (0.8 mol) of methyl iodide is added in 200 ml of ethanol at a temperature of 25 to 30 ⁰ C. The mixture is stirred for 2 hours at 25 ° C., then evaporated under reduced pressure and the remaining aqueous phase is adjusted to pH 8.0 with aqueous sodium carbonate solution and extracted with diethyl ether. The aqueous phase is then brought to pH L · J with dilute hydrochloric acid

609837/0971

acidified by 2.5 and extracted with ethyl acetate. The ethyl acetate extract is evaporated under reduced pressure and the residue is recrystallized from toluene. It becomes the methyl carboxymethyldithiocarbamate obtain.

A mixture of 16.5 g (0.1 mol) of the ester obtained and I ¹ J, 3 g (0.22 mol) of sodium azide in 150 ml of water is ^{heated to 56 °} C. for 12 hours. The reaction mixture is then extracted with diethyl ether, then acidified to pH 1 »5 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and evaporated to dryness. The l-carboxymethyltetrazole-5-thiol with a melting point of 178 ° to 179 ° C. is obtained. '

The same compound is also made by refluxing a mixture of 45.95 g (0.316 mol) of ethyl isothiocyanoacetate «Nd 30.8 g (0.475 mol) of sodium azide in 500 ml of water during Made 2 3/4 hours. The cooled reaction mixture is mixed with 400 ml of ethyl acetate and with 3 η hydrochloric acid on one Acidified pH of 1.9. The layers are separated that aqueous phase is extracted three times with ethyl acetate, and the combined extracts are dried over magnesium sulfate and ' evaporated to dryness. The residue is on silica gel with a mixture of chloroform, isopropanol and formic acid (17: 3: 2) as eluent. Chromatographed. The eluate will evaporated. The mercaptotetrazole is obtained.

A mixture of 2.94 g (10 mmol) of the sodium salt of 7-amino-L J

609837/0971

cephalosporanic acid, 2.40 g (15 mmol) of 1-Carboxymethyltetrazol-5-thiol and 2.52 g (30 mmol) of sodium bicarbonate in HQ ml of water is heated for 4 hours at 70 ° C. The reaction mixture is then cooled in an ice bath, acidified to pH 1.8 with 3 η hydrochloric acid and evaporated under reduced pressure. The 7-amino-3- (l-carboxymethyltetrazol-5-ylthiomethyl) - - ^ - carboxylic acid is obtained.

A solution of 1.86 g (5 mmol) of the compound obtained and 1.68 g (0.02 mol) of sodium bicarbonate in 60 ml of water and 50 ml of acetone is mixed with a solution of 0.80 g (5 mmol ) 2-Thiophenacetylchlorid, added in 50 ml of acetone. The reaction mixture is stirred and maintained during the addition at a temperature below -10 ⁰ C. After the addition has ended, the mixture is stirred for a further 3 1/2 hours. Ac3ton is then distilled off under reduced pressure and the aqueous residue is extracted with ethyl acetate. Ethyl acetate is added to the aqueous phase and the pH is adjusted to 1.5 with 3 η hydrochloric acid. The layers are separated and the aqueous phase is extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using a mixture of chloroform, isopropanol and acetic acid (8: 2: 1) as the mobile phase. The eluate is evaporated, the residue is dissolved in ethyl acetate and the solution is digested with hexane. The title compound is obtained.

609837/0971

Γ Π

CHN

C ₁₇ H ₁₆ N ₆ O ₆ S ₃ . Ο _; 25 C ₄ HgO ₂ ; ber .: 4l, 69 '3.49 16.20

found: 4l, 51 3.5 ^ 15.74

The title compound is dissolved in methanol and a 0.196 η solution of sodium methylate in methanol is added -Methanol is distilled off under reduced pressure, the residue dissolved in the smallest possible amount of water and mixed with isopropanol. The sodium salt falls here of 7- (2-thienylacetamido) -3- (1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid the end.

Example 3

7- (2-Thienylacetamido) -3- (1-N -methylcarbamoylmethyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

A solution of 7.0 g (43.8 mmol) of 1-carboxymethyltetrazole-5-thiol in 110 ml of anhydrous tetrahydrofuran and 20 ml of dimethylformamide is mixed with a solution of 7.2 g (44 mmol) of 1,1-carbonyldiimidazole added in 110 ml of anhydrous tetrahydrofuran and 20 ml of dimethylformamide. Then one with methylamine saturated solution of tetrahydrofuran was added and the mixture was stirred at 25 ° C. for 12 hours. Thereafter, the reaction mixture evaporated to dryness under reduced pressure, the residue diluted with 200 ml of water * and the resulting solution adjusted to a pH value of 2 to 3 with 3 η hydrochloric acid. The aqueous solution is extracted with ethyl acetate, the ethyl acetate extract is dried over magnesium sulfate and dried to dryness

609837/0971

evaporated. The residue is mixed with 15 ml of ethyl acetate and 10 ml of diethyl ether and cooled. The crystalline 1-N-Methylcarbamoylmethyltetrazol-5-thibl is filtered off. F. 137 to

The reaction of this compound with the sodium salt of 7-aminocephalosporanic acid and sodium bicarbonate according to Example 12 provides the 7-amino-3- (l-N-methylcarbamoylmethyltetrazol-5-ylthiomethyl) O-cephem- *! -carboxylic acid.

When using this compound in the process according to Example 12 at a pH of 7.6 to 7.3 during the entire reaction the title compound is obtained by adding solid sodium bicarbonate,

Example 1 4

7- (2-Thienylacetamido) -3- (1- N _t N-dimethylcarbamoylmethyltetrazol -5-ylthiomethyl) -3-cephem- * J -carboxylic acid

A solution of 5.1 g (33.8 mmol) of 1-carboxymethyltetrazole-. 5-thiol in 75 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous Dimethylformamide is slowly mixed with a solution of 5, ^ 9 g (33.9 mmol) 1,1-carbonyldiimidazole in 95 ml anhydrous dimethylformamide offset. Thereafter, the reaction mixture is 35 minutes stirred, then treated with 250 ml of tetrahydrofuran saturated with dimethylamine and stirred at 25 ° C. for 12 hours. The reaction mixture is then evaporated to about 200 ml, and tetrahydrofuran and diethyl ether are added. the

L J

60 a 837/0971

Γ Π

The resulting precipitate is filtered off and dissolved in 170 ml of water and adjusted to an OH value of 2.0 with 6 η sulfuric acid. The acidic solution is extracted with ethyl acetate, the ethyl acetate extract evaporated to dryness and the residue with Diethyl ether digested. It becomes the Ι-Ν, Ν-dimethylcarbamoylmethyltetrazole-5-thiol obtained from P. 190 to 200 ° C (decomp.).

The reaction of this compound with the sodium salt of 7-aminocephalosporanic acid according to Example 13 and the subsequent reaction of the 7-amino-3- (IN, N-dimethylcarbamoylmethyltetrazol-5-ylthiomethyl) -3-cephem- ⁱ l-carboxylic acid with 2-thiophene acetyl chloride according to Example 12 gives the title compound.

Example 15

7- (2-Thienylacetamido) -3- (1-carbamoylmethyl-tetrazol-5-ylthiomethyl) -3-cephem - ^ - carboxylic acid

According to Example 13, 1-carboxymethyltetrazole-5-thiol is reacted with 1,1-carbonyldiimidazole. A solution of tetrahydrofuran saturated with dry ammonia is added to the reaction mixture obtained. The suspension obtained is stirred for 2 1/2 hours. The resulting pesticide is filtered off, washed with tetrahydrofuran and dissolved in methanol. 50 g of Amberlite IR-I20 ion exchange resin are added to the solution, and the suspension is stirred for 15 minutes. The resin exchanger is then filtered off and washed out with anhydrous methanol. The methanol solution is evaporated to dryness, it remains behind the l-Carbamoylmethyltetrazol-5-thiol, mp 200 ⁰ C (dec.)

L _]

609837/0971

- 25 - 2 6 O 7 fi B 1

The compound obtained is treated with the sodium salt of 7-aminocephalosporanic acid to 7-amino-3- (1-carbamoylmethyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid implemented, which reacted according to Example 12 with 2-thiophene acetyl chloride to give the title compound will.

Example 1 6

7- (2-Thienylacetamldo) -3-Z "1- (2-carboxyethyl) tetrazol-5-ylthiome thy 17 ^ -cephem- *! -Carboxylic acid

A solution of 22% (0.4 mol) potassium hydroxide in 500 ml of water becomes 17.8 at 25 ° C. g (0.2 mol) of ß-alanine are added. Then

(0.2 moles)
12.2 ml / carbon disulfide are added and the mixture is refluxed for 3 hours. The reaction mixture is then cooled, mixed with 28.4 g (0.2 mol) of methyl iodide and 500 ml of ethanol and stirred for 30 minutes. The resulting precipitate is filtered off, the piltrate is evaporated and the aqueous residue is combined with the pesticide and adjusted to a pH of 8.5 to 9 by adding 10 percent sodium hydroxide solution. The suspension obtained is extracted with ethyl acetate and the extract is discarded. Ethyl acetate is added to the aqueous phase and the pH is adjusted to 1.5 with 6 η hydrochloric acid. The layers are separated and the aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated to dryness. The methyl 2-carboxyethyldithiocarbamate is obtained.

^L 6098 3 7/0971

Γ.

A mixture of 25.37 g (0.143 mol) of the resulting methyl ester and 5.6 g (0.13 moles) of sodium hydroxide in 210 ml of water with 9.25 g (0.1 * 13 mol) sodium azide added, 1 hour under Heated to reflux, then cooled, with 100 ml of diethyl ether added and acidified to a pH of 1.7. The layers are separated, the aqueous phase is extracted with diethyl ether, and the combined extracts are dried over magnesium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of acetone and chloroform '. The 1- (2-carboxyethyl) tetrazole-5-thiol from P.158 to 160 ° C. is obtained.

A solution of 4.18 g (0.01 mol) of the sodium salt of 7- (2-thienylacetamido) -cephalosporanic acid in 50 ml of water, 2.51 g (0.015 mol) of 1- (2-carboxyethyl) tetrazole-5-thiol and 1.26 g are added (0.015 mol) sodium bicarbonate added, with further amounts of sodium bicarbonate the pH value of the mixture is adjusted to 7.0 and the mixture is heated to 69 ° C. for 5 hours the reaction mixture was cooled, adjusted to pH 6.0 with dilute hydrochloric acid and extracted with ethyl acetate. The aqueous phase is acidified to pH 2.0, extracted with ethyl acetate and the extract to dryness -. evaporated. The residue is eluted on silica gel with a mixture of chloroform, methanol and acetic acid (90: 10: 3) chromatographed. The eluate is evaporated. It remains behind the title compound.

The title compound is dissolved in ethyl acetate and triethylamine,

609837/0971

The corresponding triethylammonium salt is obtained.

CHN

C ₂₄ H ₃₃ N ₇ O ₆ S ₃ . C ₆ H ₁₅ N. 0.5 H ₂ O; ber .; 46.43. 5.95 15.79

Found: 46.51 5.83 14.98

Example 17

7- (2-Thieny! Acetamido) -3- / ~ l - (2-carbamoylethyl) -te trazol-5-ylt hi ome thy 17-3-ceph6ni-4- carboxylic acid

When using an equivalent amount of 1- (2-carboxyethyl) tetrazole-5-thiol In the process according to Example 15, the 1- (2-carbamoylethyl) tetrazole-5-thiol is from P. 18I to 182 ° C (decomp.) obtain.

A solution of 10.4 g (0.06 mol) of the compound obtained in 120 ml of acetone is in a 45 ° C warm solution of 10.9 g

(0.04 mol) 7-aminocephalosporanic acid added to a mixture of 220 ml of water, 50 ml of acetone and 8.4 g (0.01 mol) of sodium bicarbonate. Then, the temperature of the mixture to 65 ⁰ C is increased and the pH is maintained by addition of aqueous sodium carbonate solution at 7.4 to 7.6. After 3 hours, the reaction mixture is ^{cooled to 10 °} C. and. adjusted to a pH of 3.5 with dilute hydrochloric acid. The resulting precipitate is filtered off, washed with water and acetone and suspended in 95 nil 'of 1.5 η hydrochloric acid. The suspension is stirred for 5 hours at 25 ° C, then filtered and the pH of the piltrate

(j ü 9 8 3 7/0 0 7 1

26Ό7681

adjusted to 3.5 with solid sodium bicarbonate. The plague is filtered off and washed with water and acetone. It becomes 7-amino-3-Zl- (2-carbamoylethyl) tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid obtain.

The compound obtained is according to Example 13 with 2-thiophene acetyl chloride implemented to the title compound. The title compound is dissolved in methanol and washed with a solution of sodium methylate added in methanol up to a pH of 6.9. After the ethanol has evaporated, the title compound remains as the sodium salt.

°> 5 H ₂ Oj ber .: 39 C. 3 H N 13th . N / A . found: 39 , 99 3 , 54 18 60 , 92 , 48 17,

The sodium salt is converted to the title compound in the manner described above.

Example 18

7- (1-Tetrazolylacetamido) -3- (1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

A solution of 0.815 g (9.7 mmol) sodium bicarbonate in 25 ml Water is mixed with 1.41 g (3.7 mmol) of 7- (1-tetrazolylacetamido) -cephalosporanic acid and 0.96 g (6.0 mmol) of 1-carboxymethyltetrazole-5-thiol offset. A further 0.504 g (6.0 mmol) of sodium bicarbonate is then added to the mixture to adjust the pH

G0 9837 / Q071

_ ₂₉ . 26Q76R1

set to 6.7. The mixture is then ^{heated to 63 °} C. for 5 hours, the pH being kept at 6.6 to 6.8 by adding acetic acid. The reaction mixture is then cooled, acidified to pH 1.9 with 3 η hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in ethyl acetate and treated with diethyl ether and hexane. The title compound precipitates here.

CHN

^C 14 ^K lAo ° 6 ^S 2 * ° / ^{6 C} 4 ^H. 8 ° 2 ^{J ber} ' ^: 36.79 3.53 26.16

Found: 36.28 3.50 25.85

Example 19

7- (1-Tetrazolylacetamido) -3-ZTl- (2-carboxyethyl) -tetrazol-5 ~ y lthiome thy X7-3 - cephem-4-carboxylic acid

When using an equivalent amount of 1- (2-carboxyethyl) tetrazole-5-thiol in the procedure according to example 18 the title compound is obtained.

36 C. H N , 21 ber .: 35 , 28. 3 24 28 , 16 found: , 80 3.67 24

609837/0071

^Γ -30- 260768Ί

Example 2 0

7- (1-Tetrazolylacetamido) -3 - / "1- (3-carboxypropyl) -tetrazol-5-ylthiomethyl 7-3-cephem -4-carboxylic acid

When using an equivalent amount of 4-aminobutyric acid im Procedure according to Example 16 is the 3-carboxypropyldithiocarbamic acid methyl ester manufactured. The reaction of this compound with sodium azide and sodium hydroxide according to Example 16 deliver.t the l ~ (3-carboxypropyl) -tetrazol-5-thiol from P. 99 to

Using an equivalent amount of the compound obtained in the procedure of Example 18 gives the title compound.

CHN

^C l6 ^H l6 ^N 10 ° 6 ^S 2 · ^{2 Na} · ^{2 H} 2 ° * ⁰ I ^{5 C} 3 ^H 8 ° 5 ^calc . ^: 33.87 3.89 22.57

found: 3 ^, 39 3.46 22.20

Example 21.

7- (2-Thienylacetamido> 3-Zl- (3-carbamoylpropyl) -tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid

When using an equivalent amount of 1- (3-carboxypropyl) tetrazole-5-thiol in the method according to Example 15, the 1- (3-carbamoylpropyl) tetrazole-5-thiol obtained from P. 133 to 136 C.

609837/0071

rait

The implementation of the compound obtained / 7-aminocephalosporanic acid according to Example 17, the 7-amino-3-Zi- (3-carbamoylpropyl) -tetrazol-5-ylthiomethyl7-3-cephem - ^ - carboxylic acid is obtained.

The compound obtained is treated with 2-thiophene acetyl chloride according to Example 13 converted to the title compound.

Example 2 2

7- (l-_T_e trazoly! Acetamido) -3- / 1- (5-carboxypentyl) -te t razol-5-ylthiome thy 1.7-3-cephem-4-carboxylic acid

When using an equivalent amount of 6-aminocaproic acid im Procedure according to Example 16 is the 5-carboxypentyldithiocarbamic acid methyl ester obtain. The reaction of the compound obtained with sodium azide and sodium hydroxide according to Example 16 provides the 1- (5-carboxypentyl) tetrazole-5-thiol with a melting point of 100 to 100.5 ° C

Using an equivalent amount of the compound obtained in the procedure of Example 18 gives the title compound obtain.

. 0.33 CH ₁₁ O. ber .: 40.09
* found: 10.29

H N 50 4.28 25, 78 4.18 25,

009837/0071

_ ₃₂ _ 260768Ί ^π

Example 2 3

7- (1-Te trazoly lacetamido) -3 .- / 1- (5-carbamoylpentyl) -te trazol-5-ylthiomethyl 17-3-cephem-4-carboxylic acid

6.0 g (28 mmol) of 1- (5-carboxypentyl) tetrazole-5-thiol becomes slow dissolved in 20 ml of thionyl chloride and the mixture for 90 minutes stirred at 25 ° C. The reaction mixture is then evaporated to dryness. The residue is dissolved in 30 ml of tetrahydrofuran.

The tetrahydrofuran solution becomes a cold mixture of 60 ml

/
aqueous ammonia solution and 30 ml of tetrahydrofuran, and the mixture is stirred at 25 ° C. for 2 days. The mixture is then extracted with ethyl acetate. The aqueous phase is adjusted to a pH of 1 with 6 η hydrochloric acid. The resulting precipitate of 1- (5-carbamoylpentyl) tetrazole-5-thiol is filtered off. P. 155 to 157 ° C.

The reaction of the sodium salt of the compound obtained, prepared according to Example 1, with 7- (l-tetrazolylacetamido) -cephalosporanic acid and sodium bicarbonate according to Example 1 provides the title compound.

Example 2 k

7- (2-Thienylacetamido) -3- / Ί- (10-carbamoyldecyl) -tetrazol-5-ylthiomethyl7-3-cephem- k -carboxylic acid

According to Example 15, the 1-dO-carbamoyldecyl) tetrazole-5-thiol is produced from 1- (10-carboxydecyl) -tetrazole-5-thiol from F.112 to 1 \ kC.

L _J

ÜQ9837 / 0071

. 33 - 26076R1

A solution of 0.084 g (1.0 mmol) of sodium bicarbonate in 11 ml of water is mixed with 0.285 g (1.0 mmol) of 1- (10-carbamoyldecyl) tetrazole-5-thiol. The mixture is heated to about 66 ° C, with 0.250 g (0.6 mmol) of Natriumsalzes'der 7- (2-thienylacetamido) -cephalosporansaure and heated an additional 5 1/2 hours at 66 C. The reaction mixture is then chromatographed on an XAD-4 resin with V / ater as the mobile phase. The fractions containing / product are evaporated to dryness and lyophilized. The residue is chromatographed on silica gel with a mixture of chloroform, isopropanol and formic acid (9: 1: 0.5). The eluate is evaporated. The title compound remains, which is converted into the sodium salt in the manner described above,

CHN

C ₂₆ H ₃₄ N ₇ O ₅ S ₃ .. Na. 0.5 H ₂ O; calc .: 47.79 5.36 15.01

Found: 48.17 5.37 14.52

Example 25

7- (1-Tetrazoly lace t amido) -3- / 3- (10-carboxydecyl) -tetrazol-5-ylthiomethy17-3-cephem-4-carboxylic acid

A suspension of 56 g (1.0 mol) of potassium hydroxide and 100 g (0.5 mol) of 11-aminoundecanecarboxylic acid in 170 ml of water is Stirred at 25 ° C. for 30 minutes. 40 g (0.52 mol) of carbon disulfide and 80 ml of ethanol are then added, and the reaction mixture is stirred at 25 ° C. for a further 12 hours. Then will

609837 / Q971

the mixture was gently refluxed for 2 hours and then cooled. After adding 71 g (0.3 mol) of methyl iodide and 130 ml Ethanol, the mixture is stirred at 25 ° C. for a further 12 hours. The reaction mixture is then evaporated to separate off the ethanol and the solid residue is filtered off. The potassium salt of 10-carboxydecyldithiocarbamic acid methyl ester remains.

28 g (0.096 mol) of the 10-carboxydecyldithiocarbamic acid methyl ester obtained from the potassium salt in the manner described above are reacted with 6.5 g (0.1 mol) of sodium azide according to Example 16. After working up and acidification which is l- (10-carboxydecyl) tetrazole-5-thiol as a white precipitate, melting at 95 to 98 ⁰ C obtained.

The reaction of this compound according to Example 24 with the sodium salt of 7- (l-tetrazolylacetamido) -cephalosporanic acid and sodium bicarbonate provides the title compound.

Example 26

7- (1-Tetrazolylacetamido) -3-Z'l- (2-carboxy-1-methylethyl) - ' tetrazol-5-ylthiomethyl? -3-cephem-4-carboxylic acid

If an equivalent amount of 3-aminobutyric acid is used in the process according to Example 16, methyl (2-carboxy-1-methyl) ethyldithiocarbamic acid is obtained obtain.

The reaction of this compound with sodium azide according to Example 16 yields 1- (2-carboxy-1-methylethyl) tetrazole-5-thiol L _l

609837/0971

from P. 169 to 172 ° C.

The reaction of the compound obtained with 7- (l ~ tetrazolylacetamido) -cephalosporanic acid in the presence of excess sodium bicarbonate according to Example 16 gives the title compound.

Example 2 7

When using alanine, 2-aminobutyric acid, 2-aminovaleric acid or 2-aminohexanecarboxylic acid in the process according to Example 16, the corresponding dithiocarbamates are obtained with Sodium azide can be converted to the following compounds: 1- (l-Carboxyethyl) tetrazole-5-thiol l- (l-carboxypropyl) tetrazole-5-thiol 1- (1-Carboxybutyl) -tetrazole-5-thiol 1- (1-Carboxypentyl) -tetrazole-5-thiol.

The implementation of the above-mentioned mercaptotetrazoles with 7- (l-Tetrazolylacetamido) -cephalosporanic acid provides the following compounds:

7- (l-tetrazolylacetamido) ~ 3- £ l .- (l-carboxypropyl) -tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid 7- (l-tetrazolylacetamido) -3-Zl- (l-carboxypropyl) -tetrazol-5-ylthiomethy17 - ^ - cephem - ^ - carboxylic acid 7- (l-tetrazolylacetamido) -3-Z "l- (l-carboxybutyl) -tetrazol-5-ylthiomethy17-3-cephem - ^ - carboxylic acid 7- ( l-Tetrazolylacetamido) -3 - / "l- (l-carboxypentyl) -tetrazol-5-y lthiome thy 1.7-3-cephem- ⁱ l-carboxylic acid.

ÜÜ9837 / 0971

The implementation of the mercaptotetrazoles described above
with 7- (2-thienylacetamido) -cephalosporanic acid gives the corresponding 7- (2-thienylacetamido) -3- (l-carboxyalkyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acids',

Example 2-8

In the manner described above, the following compounds manufactured:

7- (2-Thieny lace t amido) -3- / 3 .- (3-carboxypropyl) -te trazol-5-ylthiome thy "Q- 3-cephem-4 -carboxylic acid

CHN

C ₁₉ H ₁₈ N ₆ S ₃ O ₆ . 2 Well 2 H ₂ O; calc .: 37.75 3.67 13.89

■ found: 38.25 3.61 13.49

7- (2-Thlenylacetamidc} -3- / i- (5-carboxypentyl) -tetrazol-5-ylthiomethy17-3-cephem-4-carboxylic acid

CHN

C ₂₁ H ₂₂ N ₆ O ₆ S ₃ . 2 Well 0.75 H ₂ O; calc .: 41.34 3.88 13.77

found: 41.30 3.76 13.58

6 0983 7/0971

Claims (1)

260768Ί Claims Ι · / Thenyl- and Tetrazolylmethylcephalosporins of the common Formula I / (D CH ₂ SHet COOH in which R is the thienyl or tetrazolyl group and Het is a group of the general formula or > w I H (CHR ² ) _n -COR ³ means in which R is a hydrogen atom or a lower Al- kyl radical and R represents a hydroxyl, amino, lower alkylamino or di-lower-alkylamino group and η the value 0 to 10
and m is 1 to 10, and their salts. 2, compounds according to claim 1 of the general formula I,
in which Het is a triazolyl group. 3. Compounds according to claim 1 of the general formula I,
in which Het is a tetrazolyl group. 6 09837/0971 4, compounds according to claim 2 of the general formula I, in the R is a hydroxyl group. 5. Compounds according to claim 2 of the general formula Ί, in the R is an amino, lower alkylamino or di-lower-alkylamino group means. 6. Compounds according to claim 3 of the general formula I in the R is a hydroxyl group. 7. Compounds according to claim 3 of the general formula I, in which R is an amino, lower alkylamino or di-lower-alkylamino group means" 8. Compounds according to claim 3 of the general formula I in the R means a hydrogen atom .. 9 «Compounds according to claim 2 of the general formula I, in 2 '3 the η has the value 0 to 5, R a hydrogen atom and R a Means hydroxyl or amino group. 10. Compounds according to claim 8 of the general formula I,
in which m has the value 1 to 5 and R is a hydroxyl or amino group. • 11. 7- (2-Thienylacetamido) -3- / i- (10-carbamoyldecyl) -tetrazol-5-ylthiomethyl-7-3-cephem-4-carboxylic acid. L ■ _ 609837/0971 _ ₃₉ _ 2607ΒΒ1 12. 7- (1-Tetrazolylacetamido) -3- (5-carboxymethyl-1,2,4-triazol-3-ylthiomethyl) -3-cephem-4-carboxylic acid. 13 x 7- (2-Thienylacetamido) -3- (1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cephem-Jj -carboxylic acid. l4. 7- (2-Thienylacetamido) -3- || - (2-carbamoylethyl) tetrazol-5-ylthiome thy5 "-3 ~ cephem- ¹ l -carboxylic acid. 15. 7- (1-Tetrazolylacetamido) -3- (1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cephem- ⁱ 1-carboxylic acid. 16. 7- (2-Thlenylacetamido) -3-Z3 .- (2-carboxyethyl) -tetrazol-5-ylthiomethyl7-3-cephem-4-carboxylic acid. 17. 7- (1-Tetrazolylacetamido) -3- / Tl- (2-carboxyethyl) -tetrazol-5-ylthlomethylX7-3-cephem-4-carboxylic acid. 18. Process for the preparation of the compounds according to claim 1 to 17 »characterized in that one is known per se Way either a) a 7-aminocephalosporanic acid derivative of the general formula II NII ₂ COOR ⁴ Ü09837 / Q071 in the Het has the meaning given in claim 1 and if R represents a hydrogen atom or an ester protecting group, with thienyl or tetrazoyl acetic acid or its reactive derivative or
b) a compound of the general formula III R ¹ -CH ₂ -CONKS O ^lv TCH ₂ OOCH ₃ (III) COOH in which R has the meaning given in claim 1, or its salt with a mercapto compound of the general formula • N — N N —- N / I HS- / ι I or HS - ^ / Y- <2 3 V » ² J-COR ³ H (CHR ² J _n -COR ³ _(CHR 2 _CQR 3 (CHR *) -COR " ³ H ^ ^ΠΛ 'n" ^UUK - (CHR ^) -COR ⁿ IB (IV-a) (IV-b). "(IV-c) 2 3 ' in which R, R, η and m have the meaning given in claim 1 have, or reacts their salt, if necessary splits off the protective group, optionally the reaction, mixed acidic and optionally the compound obtained with an inorganic or organic base in a salt convicted. 19 · Medicines with antibiotic action, containing a compound according to Claims 1 to 17 or a salt thereof. 609837/0971