GB2072659A

GB2072659A - Cephalosporin derivative

Info

Publication number: GB2072659A
Application number: GB8040808A
Authority: GB
Original assignee: Ferrer Internacional SA
Current assignee: Ferrer Internacional SA
Priority date: 1980-01-09
Filing date: 1980-12-19
Publication date: 1981-10-07
Also published as: FR2473309A1; IT8119027A0; IT1134955B; DE3100292A1; NL8100053A; JPS56108797A; BE886715A

Abstract

The invention provides a novel cephalosporin, 8-oxo-7-(2-thienyl- acetamido)-3-(1,2,4-triazol-3-ylthio- methyl)-5-thia-1-azabicyclo[4,2,0]oct-2- ene-2-carboxylic acid of the formula <IMAGE> The compound has antibiotic activity and may be used as a medicament, e.g. in a pharmaceutical composition. Methods for preparing the novel cephalosporin are also described.

Description

SPECIFICATION Cephalosporin derivative The present invention relates to a medicament formed by a novel cephalosporin, 8-oxo-7-(2thienylacetamido)-3-(1 ,2,4-triazole-3-ilthiomethyl)-5-thia-1 -azabicyclo[4,2,0]octo-2-ene-2-carboxyl ic acid of formula I:

and its pharmaceutically acceptable addition salts.

The invention also extends to the process for producing the above compound in accordance with the following diagram:

The process for obtaining 8-oxo-7-(thienylacetamido)-3-(l ,2,4-triazole-3-ilthiomethyl)-5-thia-l azabicyclo[4,2,0]octo-2-ene-2-carboyxlic acid (I) is mainly based on the displacement reaction of the acetoxy group either of 3-acetoxymethyl-7-amino-8-oxo-5-thia-1 -azabicyclo [4,2,0]octo-2-ene-2-carboxylic acid, also called 7-aminocephalosporanic acid, or 3-acetoxymethyl-8-oxo-7-(2-thienylacetamino)-5-thia-1-1azabicyclo[4,2,0]octo-2-ene-2-carboxylic acid (III) by 3-mercapto-1 2,4-triazole in aqueous solution or acetone: water in a basic medium like that constituted by alkali metal bicarbonates, the base being unnecessary if it comes from an alkali metal salt of the initial cephalosporin. In the first of these two cases, once the acetoxy group has been displaced by the 3-mercapto-l ,2,4-triazole, the 7-aminocephalosporanic acid is acylated with an acitivated derivative of 2-thienylacetic acid such as its mixed anhydride or chloride, in a basic medium preferably formed by a tertiary amine. As the carboxylic acid residue can react with acid halides, it is advantageous to protect the carboxylic residue from the 7-aminocephalosporanic acid by esterification. The trimethyl-silanic ester is preferred and is hydrolyzed at the end of the process.

A number of examples will now be described in non-limitative manner to illustrate the invention and naturally larger quantities than those indicated can be used in industry.

Example 1 7-amino-8-oxo-3-(1 ,2,4-triazole-3-ilthiomethyl)-5-thia-l -azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (II).

1.689 of sodium bicarbonate (0.02 mole) are dissolved in 20ml of water, followed by the addition of 2.72g of 7-aminocephalosporanic acid (0.01 mole), 20ml of water and 1 oil of acetone. The thus obtained solution is heated at 450C, followed by the addition of 1.549 of 3-mercapto-1 ,2,4-triazole (0.0152 mole) in 20ml of acetone and 4ml of a 5% sodium bicarbonate solution. Refluxing takes place and a mixture is kept at pH 7.5.

The solution is cooled to 10"C and the pH is adjusted 3.5 with 3N hydrochloric acid. The solid precipitate is separated, washed with acetone and dried in vacuo on phosphorus pentoxide. The thus obtained product is 7-amino-8-oxo-3-(1 ,2,4-triazole-3-ilthiomethyl)-5-thia-1 -azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid - Yield: 73.5%. iR (BrK):1795cm-' (C=0 of p-lactam), 1630 cm-l (C = N) and 1150 cm-' (C = 0 acid, hybrid ion).

UV(E1i'c'm = 200.5 in ethanol) = 260nm.

Example 2 8-oxo-7-(24hienylacetamido)-3-( 1 ,2,44riazole-3-ilthiomethyl)-5-thia-1 -azabicyclo[4,2,0]oct-2-ene-2- carboxylic acid (I).

It is necessary to prepare two solutions, which will be designated A and B hereinafter. Solution A is prepared with 1.429 of 2-thienylacetic acid (0.01 mole) and 1.019 of triethylamine (0.01 mole) in 20ml of anhydrous tetrahydrofuran. The solution is cooled to - 10 C and 1 .365g of isobutyl chloroformate (o.01 mole) dissolved in 10ml of an hydros tetrahydrofuran are added slowly and accompanied by stirring.

Solution B is formed by 1.01 g of triethylamine (0.01 mole) in a suspension of 3.1 3g of 7-amino-8-oxo-3-(1 2,4- thiazol-3-ilthiomethyl)-5-thia-1 -azabicyclo[4,2,0] oct-2-ene-2-carboxyl ic acid (0.01 mole) in water.

Solution B is slowly added to solution A, accompanied by stirring and whilst maintaining the temperature between -5 and 0 C. Once the operation is complete, the reaction mixture is stirred at 5"C for 1 hour and at ambient temperature for a further hour. The reaction product is filtered. The tetrahydrofuran is eliminated from the filtrate by evaporation in vacuo and washing takes place twice with 20ml of ethylacetate. The aqueous phase is adjusted to pH 2 by acidification with 3N hydrochloric acid, whilst forming a solid precipitate which, after washing and drying, is recrystallized with ethanol. The thus obtained compound is 8-oxo-7-(24hienyl )5-thia-1 -azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid - 1.879, yield: 43%.Melting point 182.2 - 183.8"C. IR (BrK) = 1780 cm-'(C = 0 of t3-lactam), 1680 cm-'(C = 0 of amide) and 1550 cm- (C = 0 of associated amide). UV (E Rcm = 195.1 in ethanol)=269nm. Analysis (Ca6H,5NsO4S3) = C43.43 (calc. 43.92), H3.79 (calc. 3.455) N14,74 (calc. 16.008), S21.08 (calc 21.982).

If the acid chloride is used in the amidification reaction in place of the mixed anhydride, the operating procedure is as follows: A suspension is formed from 4.699 of 7-amino-8-oxo-3-(1 ,2,4-triazole-3-ilthiomethyi)-5-thia-l - azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (0.015 mole) in 150ml of dry methylene chloride. The suspension is then treated with 2.729 of triethylamine (0.027 mole), 4.0g of N,N-dimethylaniline (0.033 mole) and 4.99 of trimethylchlorosilane (0.045 mole). Refluxing takes place until a transparent solution is obtained, which is then cooled to 40C and reacted with 2.89 of 2-thienylacetic chloride (0.0175 mole). The mixture is then stirred for 1 hour at 4"C and a further hour at ambient temperature.This is followed by the addition of 80ml of water and stirring for 1 hour. The organic phase is discarded and the aqueous phase acidified to pH 2 with 3N hydrochloric acid. The precipitate formed is filtered, washed with water, dried and recrystallized with ethanol. The thus obtained compound is 8-oxo-7-(2-thienylacetamido)-3-(1,2,4-triazole-3-ilthiomethyl)-5- - thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (3.789, yield 58%). The melting point and spectroscopic characteristics are the same as those of the sample obtained according to the method with the mixed anhydride.

Example 3 8-oxo-7-(2-thienylacetamido)-2-(1 ,2,4-triazole-3-ilthiomethyl)-5-thia-1 -azabicyclo[4,2,0]oct-2-ene carboxylic acid (I).

3.239 of 3-mercapto-1 ,2,4-triazole (0.032 mole) are added to a solution of 10.039 of sodium 3-acetoxy-8 oxo-7-(2-thienylacetamido)-5-thia-1 -azabicyclo[4,2,0]oct-2-ene-2-carboxylate (0.024 mole) in 48ml of water.

The reaction mixture is heated to 40"C, accompanied by stirring for 48 hours. The solid precipitate formed is filtered and washed with water. The filtrate is acidified with 3N hydrochloric acid to pH 2 and the solid precipitate separated. After separation by filtration, the precipitate is washed with water and then added to that separated beforehand by crystallizing it in the mixture with ethanol. The thus obtained compound is 8-oxo-7-(thienylacetamido)-3-(1 ,2,4-triazole-3-ilthiomethyl)-5-thia-1 -azabicylco [4,2,0]oct-2-ene-2-carboxylic acid (8.59, yield: 81%). The melting point and spectroscopic characteristics are the same as for the samples obtained in example 2.

The compound of the present invention has a powerful antibiotic action against staphylococci, pneumococci, enterococci, E.coli, Klebsiella pneumoniae and Proteus indol of the negative type. Due to its low toxicity (LD50 in the form of sodium salt between 2.8 and 4g/kg intraveneously in the mouse) this medicament is particularly therapeutically useful, because it can be injected at daily doses between 200 and 2000mg.

Claims

1. Novel antibiotic medicament, characterized in that it is constituted by 8-oxo-7-(2-thienylacetamido)-3 (1,2,4-triazole-3-ilthiomethyl )-5-thia-1 -azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid for formula I:

2. Process for the preparation of the compound of formula I and its pharmaceutically acceptable addition salts, characterized in that to obtain compound I 7-amino-8-oxo-3-(1 ,2,4-triazole-3-ilthiomethyl)-5-thia-l - azabicyclo[4.2,0]oct-2-ene-2-carboxylic acid of formula II::

is reacted with an activated derivative of 2-thienyl acetic acid of formula IV

in w.hich Xis a halogen, preferably chlorine, where COOALq orAlq is a straight or branched chain radical which can contain 1 to 5 carbon atoms, in the presence of a tertiary amine, such as triethyl amine or a mixture of triethylamine and N,N-dimethylaniline in an inert solvent, preferably tetrahydrofuran or methylene chloride.

3. Preparation process according to claim 2, characterized in that to obtain compound II esterification takes place with thetrimethylsilanic ester suitable for this purpose if the amidification reaction is performed with IV (X = halogen), the acid group then being regenerated by hydrolysis.

4. Preparation process according to claim 2, characterized in that to obtain compound 11,7aminocephalosporanic acid (7-ACA) is reacted with 3-mercapto-1,2,3-triazole in an acetone:water solution in a basic medium, preferably alkali metal bicarbonates.

5. Preparation process for the compound of formula I, characterized by the action of 3-acetoxy-8-oxo-7 (2-thienylacetamido)-5-thia-1 -azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid of formula Ill:

in the presence of a mineral base, preferably either alkali metal bicarbonates or an alkali metal salt of the starting product, with 3-mercapto-1,2,4-triazole in an aqueous solution.

6. A compound according to claim 1 and substantially as herein described.

7. A compound substantially as prepared in accordance with the method described in any of the specific Examples.

8. A process according to claim 2 and substantially as herein described.

9. A process for preparing a compound of the formula I in claim 1 substantially as described in any of the specific Examples.

10. A pharmaceutical composition comprising a compound of the formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and an inert carrier or diluent therefore.