IE44608B1 - 7-aminocephalosporin derivatives - Google Patents

Description

This invention relates to 7 - aminocephalosporin derivatives which are intermediates for the production of cephalosporin compounds having antibacterial activity when administered parenterally, and to processes for preparing these intermediates. The compounds are characterised by having a sulfo- or sulfamoyl- alkyl substituted tetrazoyl - thiomethyl group at the 3-position of the cephem nucleus, and can be converted into 7 - acylami nocephalosporins as described in our Patent Application No. 557/76.

The compounds of this invention are cephem carboxylic acids of the structural formula in which each individual R1 is hydrogen or lower alkyl, n is from 1 to 10, and R is hydroxy, amino, (lower alkyl) - amino or di (lower alkyl)amino. 6 0 8 By lower alkyl is meant an alkyl group having from 1 to 4 carbon atoms; such a lower alkyl group is preferably methyl or ethyl.

Preferably each is hydrogen and n is from 1 to 5. Preferably 2 also R is hydroxy or amino.

In a process of the invention the 7 - amino - 3 - substituted tetrazolylthiomethyl cephalosporins of Formula I are prepared by reaction of 7 - amino- or 7 - formamido - cephalosporanic acid with a corresponding substituted tetrazole -thiol of the structural formula Formula II (CHR1)n-S02R2 and where the product has a 7 - formamido group, this is then converted into an amino group by reaction with an acid. Thus the formyl group can be removed by treatment with hydrochloric acid.

Where there is an asymmetric carbon atom in the tetrazole side15 chain, racemic or resolved products are obtained depending upon whether a racemic or resolved tetrazole thiol is used. All of the optical isomers, including mixtures thereof, are included within the scope of this invention.

- Formamidocephalosporanic acid can be prepared by reaction of 7 - aminocephalosporanic acid with formic acid and acetic anhydride.

The substituted tetrazole - thiols of Formula II are described and claimed in our Patent Specification No. 1253/80. The substituted o tetrazole-thiols where R is hydroxy, (lower alkyl)amino or di - (lower alkyl)amino can be prepared by reaction of an N-substituted alkyl di th iocarbamate., such as methyl 2 - sulfoethyldithiocarbamate or methyl 3 - (N - t - butylsulfamoylpropyl)dithiocarbamate or its corresponding sodium or potassium salt, with an azide such as sodium azide. The N - substituted alkyl dithiocarbamates can be prepared by treatment of an amino - alkanesulphonic acid, for example 2 - aminoethane sulfonic acid, or an arainoalkane (N - alkyl or N,N - di alkyl) sulfonamide such as 3 - aminopropane - N - t - butyl sulfonamide or its corresponding salt with carbon disulfide and an alkyl halide such as methyl iodide in the presence of a base such as sodium or potassium hydroxide.

The aminoalkane (N - alkyl or N,N - dialkyl)sulfonamides can be prepared by reaction of hydrazine with an N - alkyl or N,N - di alkyl - phthal imi tioal kyl sulfonamide, obtained by treatment of a phthalimidoalkylsulfonyl halide, preferably chloride, with an alkyl- or dialkyl amine. The phthalimidoalkylsulfonyl halides are known or can be prepared as described by Winterbottom et al_., J.· Amer. Chem. Soc. 69: 1393 (1947) and Griffin and Hey, J_. Chem. Soc., 3334 (1952). 4 6 0 8 When R is amino, the compounds of Formula II can be prepared by removal of the N - alkyl group from the corresponding 1 - (N - alkylsulfamoylalkyl)tetrazole - 5 - thiol, preferably a 1 - (N - £ - butylsulfamoylalkylJtetrazole - 5 - thiol, with, for example, anisole and trifluoroacetic acid.

Compounds of Formula I can be converted by methods standard in the cephalosporin art into corresponding compounds in which the hydrogen of the carboxylic acid group COOH is replaced by a protecting ester-formi ng group, for example benzhydryl, t-butyl, trichloroethyl, benzyl, benzyloxy - methyl, £ - nitrophenyl, £ - methoxyphenyl, £ - methoxybenzyl and £ - nitrobenzyl.

The following Examples illustrate the invention. Temperatures are in °C.

EXAMPLE 1 - Amino - 3 - 0 - (2 - sulfamoyl ethyl )tetrazol - 5 ylthio - methyl] - 3 - cephem - 4 - carboxylic acid A solution of 2.73 g (0,01 mol.) of 2 - phthalimidoethane sulfonyl chloride in 20 ml. of chloroform was added dropwise to a solution of 2.19 g (0.03 mol.) of t - butylamine in 20 ml. of chloroform at 5°. The reaction mixture was warmed to ambient temperature and stirred for three hours. The precipitate was removed by filtration and the filtrate was evaporated to dryness to give a residue which was purified by chromatography on silica with 19:1 chloroform - methanol as eluant to give N - t - butyl - 2 phthalimidoethanesulfonamide. 4 6 0 8 Ν - t - Butyl - 2 - phthalimidoethanesulfonamide (2.10 g., 6.78 mmol.) was suspended in 20 ml. of ethanol and 0.344 g. of hydrazine hydrate was added. The reaction mixture was refluxed for three hours, then evaporated to dryness. The residue was suspended in 45 ml. of water and acidified to pH. 3.0 by addition of dilute hydrochloric acid.

The acid mixture was filtered and the filtrate evaporated to dryness to give 2 - aminoethane N - jt - butylsulfonamide hydrochloride.

- Aminoethane - N - Jk - butylsulfonamide hydrochloride (1.25 g.s 5.78 mmol.) was added to a solution of 1.17 g. (11.56 mmol.) of triethylamine in 20 ml. of ethanol. Carbon disulfide (0.44 g., .78 mmol.) was added, the mixture was stirred at 25° for 1.5 hours, then 0.82 g. (5.78 mmol.) of methyl iodide in 5 ml. of ethanol was added and the resulting mixture was stirred for 1.5 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acidified to pH 2.0 with dilute hydrochloric acid. The aqueous mixture was extracted with ethyl acetate and the extract was dried (MgSO^) and evaporated to dryness to give methyl - (N - _t - butylsulfamoyl) - ethyldithiocarbamate.

Methyl 2 - (N - t - butyl sulfamoyl)-ethyldi carbamate was heated in solution with 4% aqueous sodium azide solution (1.4 molar equivalents) for 35 minutes to give 1 - (2 - N - t - butylsulfamoylethyl)tetrazole 5 - thiol, which was isolated after acidification to pH 3.5. l-(2-N-t- Butylsulfamoylethyl)tetrazole - 5 - thiol (1.0 g.) was suspended in 20 ml. of anisole and 20 ml. of trifluoroacetic acid is added. The solution was heated at 56° for 3.5 hours, then cooled. The precipitate was collected by filtration and washed with petroleum ether to give 1-(2- sulfamoylethyl)tetrazole - 5 - thiol. 4 6 0 8 A solution of 0.210 g. (2.5 mmol.) of sodium bicarbonate in 5 ml. of water was added to a suspension of 0.272 g. (1 mmol.) of 7 - aminocephalosporanic acid in 5 ml. of water and 2.5 ml. of acetone at 15°. The solution was heated to 45°, a solution of 0.314 g. (1.5 mmol.) of 1 - (2 - sulfamoylethyl)tetrazole - 5 thiol in 10 ml. of acetone was added and the reaction mixture was refluxed for two hours while maintaining the pH at 1.4 - 7.6 by addition of aqueous sodium bicarbonate solution. The mixture was cooled and acidified to pH 4.0 with dilute hydrochloric lu acid. The precipitate was collected by filtration to give - amino - 3 - 0-(2- sulfamoyl ethyl)tetrazo1 - 5 - ylthiomethylj - 3 - cephem - 4 - carboxylic acid.

EXAMPLE 2 - Amino -3-0-(2-N-t- butyl sulfamoyl ethyl )tetrazol - 5 - ylthiomethylj - 3 - cephem - 4 - carboxylic acid When an equivalent of amount of 1 - (2 - N - t - butylsulfamoylethyl) tetrazole - 5 - thiol is reacted with 7 - aminocephalosporanic acid as described in Example 1, 7 - amino - 3- 0 - (2-N-tbutylsulfamoyl ethyl)tetrazol - 5 - ylthiomethylj- 3 - cephem - 4 20 carboxylic acid is obtained. 44β08 EXAMPLE 3 - Amino - 3- fl - (2 - N - methyl sulfamoyl ethyl) tetrazol - 5 ylthiomethyfj - 3 - cephem - 4 - carboxylic acid Use of methylamine in the reaction with 2 - phthalimidoethanesulfonyl 5 chloride described in Example 1, followed by the subsequent synthetic steps described therein gives 1 - (2 - N - methylsulfamoylethyl)tetrazole - 5 - thiol.

When 1-(2-11- methyl sulfamoylethyl)tetrazole - 5 - thiol is reacted with 7 - aminocephalosporanic acid as described in Example 1 the product is 7 - amino - 3-[l-(2-Nmethylsulfamoy1ethyl)tetrazol - 5 - ylthiomethyl] - 3 - cephem - 4 carboxylic acid.

EXAMPLE 4 - Amino -3-(1- sulfamoylmethyltetrazol - 5 - ylthiomethyl) - 3 - cephem - 4 - carboxylic acid.

A suspension of 15.1 g (0.136 mol.) of aminomethanesulfonic acid and 14.2 g. (0.145 mol.) of anhydrous potassium acetate in 48 ml. of acetic acid is refluxed for ten minutes. Phthalic anhydride (21.4 g., 0.145 mol.) is then added and the resulting mixture is refluxed for 2.5 hours. The product is collected by filtration and washed with acetic acid and ethanol to give phthalimidomethanesulfonic acid potassium salt.

To 41.7 g. (0.15 mol.) of phthalimidomethanesulfonic acid potassium salt in 220 ml. of dry benzene is added 22.5 g. (0.132 mol.) of phosphorus pentachloride. The reaction mixture is refluxed 4 6 0 8 on a steam bath for one hour, then an additional 22.5 g of phosphorus pentachloride is added and heating is continued for 1.5 hours. The reaction mixture is evaporated by dryness, crushed ice is added to the residue and the slurry is filtered. The product is washed with water to give phthalimidomethanesulfonyl chloride.

When phthalimidomethanesulfonyl chloride is substituted in the procedure of Example 1 for 2 - phthalimidoethanesulfonyl chloride, N - t - butylphthalimidomethanesulfonamide is prepared and is converted to 1 - N - χ - butylsulfamoylmethyltetrazole 5 - thiol as described therein. Treatment of 1 - N - t butylsulfamoylmethyltetrazole - 5 - thiol with trifluoroacetic acid as described in Example 1 gives - sulfamoylmethyltetrazole - 5 - thiol.

Reaction of 1 - sulfamoylmethyltetrazole - 5 - thiol with 7 - aminocephalosporanic acid as described in Example 1 gives 7 - amino -3-(1- sulfamoylmethyltetrazol - 5 - ylthiomethyl) 3 - cephem - 4 - carboxylic acid.

EXAMPLE 5 - Amino - 3 - |_1 - (3 - sulfamoylpropyl)tetrazol - 5 ylthiomethyl]- 3 - cephem - 4 - carboxylic acid When 3 - phthalimidopropanesulfonyl chloride is substituted in the procedure of Example 1 for 2 - phthalimidoethanesulfonyl chloride, N-t - butyl - 3 - phthalimidopropanesulfonamide is prepared, and is converted to 1 - (3 - N - t - butylsulfamoylpropyl) - tetrazole - 5 - thiol as described therein. Treatment of 1 - (3 - N - t - butylsulfamoylpropyl) - tetrazole - 5 - thiol with trifluoroacetic acid as described in Example 1 gives 1-(3- sulfamoyl propyl)tetrazole - 5 thio. 4460 8 Reaction of 1-(3- sulfamoylpropyl) tetrazole - b thiol with 7 - amlnoeephalosporanle acid as described in Example 1 gives 7 - amino -3-0-(3- sulfamoylpropyltetrazol - 5 - ylthiomethylj - 3 - cephem - 4 - carboxylic acid.

EXAMPLE 6 - Amino -3-0-(5- sul famoyl pentyl) tetrazol -5yl thiomethyl]- 3 - cephem - 4 - carboxylic acid Use of 5 - ami nopentanesulfonic acid in the procedure of Example 4 in place of aminomethanesulfonic acid, followed by TO reaction of the product thus obtained with phosphorus pentachloride, gives 5 - phthalimidopentanesulfonyl chloride.

When 5 -phthalimidopentanesulfonyl chloride is used as a starting material in the sequence described in Example 1, - (5 - N - t - butylsulfamoylpentyl)tetrazole - 5 - thiol is obtained. Treatment of 1 - (5 - N - t butylsulfamoylpentyl)tetrazole - 5 - thiol with trifluoroacetic acid as described above gives 1-(5- sulfamoylpentyl)tetrazole - 5 - thiol.

Reaction of 1-(5- sul famoyl pentyl )tetrazole - 5 - thiol with 7 - aminocephalosporanic acid as described in Example 1 gives - amino -3-0-(5- sulfamoy1penty1)tetrazol - 5 - ylthiomethyl] - 3 - cephem - 4 - carboxylic acid. 4 Ο Ο Η EXAMPLE 7 - Amino -3-0-(10- sulfamoyldecyl)tetrazol - 5 - ylthiomethyl j - 3 - cephem - 4 - carboxylic acid Use of 10 - aminodecanesulfonic acid in the procedure of Example 4 in place of aminomethanesulfonic acid, followed by reaction of the product thus obtained with phosphorus pentachloride, gives 10 - phthalimidodecanesulfonyl chloride.

When 10 - phthalimidodecanesulfonyl chloride is used as a starting material in the sequence described in Example 1, 1 - (10 - N - £ - butylsulfamoyldecyl)tetrazole - 5 - thiol is obtained. Treatment of 1 - (10 - N - £ - butylsulfamoyldecyl)tetrazole - 5 - thiol with trifluoroacetic acid gives 1-(10- sul famoyldecyl) tetrazole - 5 - thiol.

Reaction of 1-(10- sulfamoyldecyl)tetrazole - 5 - thiol with 7 - aminocephalosporanic acid gives the resulting 7 - amino - 3 01 - (10 - sulfamoyldecyl)tetrazol - 5 - thiomethylJ - 3 - cephem 4 - carboxylic acid.

EXAMPLE 8 - Amino -3-(1- sulfomethyl tetrazol - 5 - yl thi omethyl) 20 3 - cephem - 4 - carboxylic acid To a mixture of 97 g (200 ml., 2.1 mol.) of formic acid, distilled from anhydrous copper sulfate, and 37.5 ml. (0,4 mol.) of acetic anhydride was added 25.0 g. (0.1 mol.) of - aminocephalosporanic acid. The mixture was stirred at ambient temperature for 0.5 hour, then evaporated to dryness. The residue was dissolved in ethyl acetate and the ethyl acetate solution was filtered and evaporated to dryness to give a residue which was recrystallized from ether-petroleum ether to give 7 - formamidocephalosporanic acid.

A mixture of 1.0 g. (3.3 mmol.) of - formamidocephalosporanic acid and 0.7 g. (2.6 mmol.) of 1 - sulfomethyltetrazole - 5 - thiol disodium salt in 15 ml. of water was stirred at 65-70° for 3 hours while maintaining the pH at 7.0 by addition of sodium bicarbonate and/or hydrochloric acid. The mixture was cooled, acidified to pH 1.0 with hydrochloric acid and extracted with ethyl acetate. The extract was filtered and the filtrate was evaporated to dryness to give a residue which was dissolved in 30 ml. of methanol. The methanol solution was filtered, 30-40 ml. of isopropanol and ethanol were added, the solution was filtered again and 100 ml. of ether was added. The precipitate was collected by filtration and dried to give the title compound.

C10H12°6N6S3 · °·33 C3H8° ‘ HC1 2 H2° Calculated: 27.0% C 3.50% H; 16.9555 N Found: 26.96% C 3.23% H; 16.55% N

Claims (10)

1. A cephem carboxylic acid compound of the formula in which each individual R^ is hydrogen or lower alkyl, p 5 n is from 1 to 10, and R is hydroxy, amino, (lower alkyl) amino or di-(lower alkyl)amino.

2. A compound according to Claim 1 in which each R^ is hydrogen and n is from 1 to 5. 4 4 6 0 8

3. 7 - Amino -3-(1- sulfomethyl tetrazol - 5 - yl thi omethyl) 3 - cephem - 4'- carboxylic acid.

4. 7 - Amino -3-(1- sulfamoylmethyl)tetrazol - 5 - ylthiomethyi) - 3 - cephem - 4 - carboxylic acid.

5. 5. 7 - Amino -3-0-(2- su1famoylethyl)tetrazol - 5 - ylthiomethyi] - 3 - cephem - 4 - carboxylic acid.

6. 7 - Amino -3-0-(5- sul famoyl pentyl )tetrazol -5ylthiomethylJ] - 3 - cephem - 4 - carboxylic acid.

7. The compound according to Claim 1 of any one of Examples 2, 3, 5 and 7. 10

8. A process for preparing a compound according to any preceding claim, in which 7 - amino or 7 - formamidocephalosporanic acid is reacted with a corresponding tetrazolethiol of the formula US ¢1- Ν' (CHR^-SOgR 2 and where the product has a 7 - formamido group, this is then converted 15 into an amino group by reaction with an acid.

9. A process according to Claim 8 substantially as described in any one of the Examples.

10. A compound according to Claim 1 whenever prepared by a process according to Claim 9.