NO142913B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE CEPHALOSPOR COMPOUNDS - Google Patents

Description

The present invention relates to the production of therapeutically effective cephalosporin compounds with the general formula:

and pharmaceutically acceptable salts thereof, wherein R 2 is a group of the formula: or

It has been found that conversion of the acyl group in the 7-position of cephalosporin C, i.e. the 5-amino-5-carboxyvaleryl group, to an α-sulfoacyl group gives a compound which is active against Pseudomonas aeruginosa, like the well-known cephalosporin compounds such as cephalothin or cephaloridine are inactive against. It has also been found that said compound has a greater antimicrobial spectrum. In addition, it has been found that such effects as mentioned above are further increased by further substitution of the acetoxymethyl group in the 3-position with a heterocyclic thiomethyl group.

The compounds of formula I are prepared according to the present invention by reacting a cephalosporin compound of the formula: or a salt or an easily cleavable ester thereof, with a compound of the formula:

or a salt thereof, where R 2 has the above meaning, after which any ester group is cleaved off and, if desired, conversion of a compound obtained into a salt thereof.

The sulfocephalosporin compound (II) used as starting material can e.g. is produced by condensing α-sulfophenyl-acetic acid or its functional derivatives in the carboxyl group, with 7-aminocephalosporanic acid or derivatives thereof with easily cleavable ester groups, followed by cleavage of the ester group (Belgian patent no. 762,725).

In these sulfocephalosporin compounds (II), the carboxyl group in the 4-position and/or the sulfo group on the side chain can form a salt with, for example, sodium, potassium, magnesium, calcium, aluminum, triethylamine, etc., as long as no undesirable effects occur during the reaction according to the invention .

In inherited cases, the carboxyl group in the 4-position can be

swoop

protected with an ester that can be easily cleaved off, for example a benzyl, (3-methylsulfonylethyl, benzhydryl or trimethylsilyl group.

The reaction between the sulfocephalosporin compound (II) and the heterocyclic thiol compound (III) is usually carried out in a suitable solvent. For example, one can use acetone, dioxane, chloroform, dimethyl sulfoxide, methylene chloride, tetrahydrofuran, ether, ethyl acetate, nitrobenzene, dimethylformamide, methanol pl 1 pr pfannl AnHrp nrnani clfp onnlMcninfrcmi^lpr c/~* m rrpnorpl f -iL-Vca will affect the reaction, as well as water, can also be used. Among these solvents, substances with strong polarity are preferred. Hydrophilic solvents can be mixed with water for this purpose. The reaction is advantageously carried out at neutral or slightly acidic pH.

For example, the reaction can advantageously be carried out in the presence of an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, a trialkylamine or pyridine. The reaction temperature varies depending on the starting materials used. Usually, however, the reaction is carried out at from room temperature up to 100°C, preferably from 40 to 60°C. In most cases, the reaction is continued for a period of 1-24 hours or more.

The heterocyclic thiol compound (III) is advantageously used in a ratio of from 1 to 10 mol per mol of sulfo-cef alosporinf orb compound (II) .

The reaction products can be purified and worked up using the properties of the final product cephalosporin (I), for example by using phase transfer, concentration, chromatography, crystallization, recrystallization, etc. The compounds of formula I can be obtained as free acids or as salts which,

if desired, can be transferred to another type of salt by otherwise known salt conversion reactions. The salts may be of any pharmaceutically acceptable non-toxic type. Among the usable salts are non-toxic metal salts of sodium, potassium, calcium and aluminium, non-toxic amine salts such as ammonium or substituted ammonium salts, for example triethylamine-, procaine-, dibenzylamine-, N-benzyl-B-phenethylamino-, 1-ephenamine- , N,N'-bis (dehydroabiethyl)-ethylenediamine salt etc, as well as salts of other amines which have hitherto been used for the production of benzyl penicillin salts.

The relevant compound of formula I contains two acid groups, namely a sulfo group and a carboxyl group, and depending on the relative degrees of acidity of these two groups, either an acidic salt or a neutral salt can be prepared. In the α-sulfoacyl group in position 7, there is an asymmetric carbon atom. By using an optically active starting material or by letting the reaction product undergo a known work-up technique such as recrystallization or chromatography, optically active forms of the compound in question can be arrived at.

The cephalosporin compounds prepared in the above manner have strong antibacterial effects and are effective in the treatment of various infectious diseases caused by Gram-positive and Gram-negative bacteria, among others Pseudomonas bacteria. The compounds can be administered in any manner, including orally, subcutaneously and intravenously in a manner similar to the known cephalosporin preparations.

Although the correct dosage depends on the type of disease, the recommended dosage for Pseudomonas infections is, for example, 5 to 500 mg/kg/day and preferably between 10 and 200 mg/kg/day, as two or four portions per day. day.

To illustrate that the compounds of formula (I) have advantageous and superior properties in relation to previously known related compounds described in Norwegian application no. 471/71,

comparative tests have been carried out, whereby the following results were obtained:

From this table it appears that the compounds produced according to the invention have a lower minimum inhibition concentration than the known compound, and are therefore preferred.

The following examples illustrate the invention. The abbreviations "g", "mg", "ml" and "me", denote "gram", "milligram", "milliliter" and "microgram", respectively.

Example 1

0.246 g of disodium 7-(α-sulfophenylacetamido)cephalosporanate, 0.149 g of 2,4-dithiopyrimidine and 0.13 g of NaHCO 3 are dissolved in 21 ml of water. The mixture is heated at 40°C for 41 hours. After the reaction is over, the pH of the reaction mixture is adjusted to 2.0 with HCl, after which the reaction is carried out at a constant temperature of 40°C for 8 hours. After the reaction is over, the reaction mixture is concentrated at room temperature under reduced pressure. The concentrate is freeze-dried. The product is purified chromatographically on a column ("Amberlite XAD-2", 30 x 1000 mm, eluent: water). The fractions containing the desired cephalosporin compound are collected and lyophilized, and this yields 0.10 g of 7-(α-sulfophenyl-acetamido)-3-[4'-(21-thio-pyrimidyl)-thio]methyl-3-cephem-4 -carboxylic acid.

IR vKB5 (cm_1): 3380(OH), 3000, 2900(CH),

max'

1750(B-lactam, C=0), 1665 (-CONH-), 1600 (-C00~), 1535 (C-N, NC=S) , 1470(NCS), 1370(S02), 1290(NCS), 1230 , 1190 (SO2), 1115, 1040(-SO3~), 700(C-5).

Minimum inhibitory concentration (mcg/ml).

Pseudomonas aeruginosa 1049 10

Example 2

517 mg of 7-(α-sulfophenylacetamido)disodium cephalosporanate, 522 mg of 2-mercapto-2-thiazolinemethiodide and 1.75 g of KSCN are dissolved in 2 ml of water. The solution is adjusted to pH 6.5-7 and heated at 6<r>0°C for 7 hours. The reaction mixture is purified by column chromatography on "Amberlite XAD-2" to 7-(α-sulfophenylacetamido)-3-(3<1->methyl-2<1->thiazolinium-2<1->thio)methylcef-3 -em-4-sodium carboxylate.

IR vKBf (cm-1): 1769(B-lactam), 1665(-CONH-),

max

1610(CO~), 1530, 1390, 1355, 1320, 1210, 1040(-SO3<_>), 700

NMR, 6(D2O): 2.90(3H, S, N-CH3), 3-4.2(6H, m,

Cg-H), 5.74(1H, d, J = 4.20 eps, C?-H), 7.52 (5H, broad, phenyl).

Minimal inhibition concentration (mcg/ml):

Staphylococcus aureus 2

Bacillus subtilis 5

Sarcina lutea 5

Pseudomonas aeruginosa 5

Claims (1)

Analogous process for the preparation of therapeutically effective cephalosporin compounds of the general formula: and pharmaceutically acceptable salts thereof, wherein R 2 is a group of the formula: or characterized in that a cephalosporin compound with the formula: or a salt or an easily cleavable ester thereof, is reacted with a compound of the formula: or a salt thereof, where R 2 has the above meaning, after which any ester group is cleaved off and, if desired, conversion of a compound obtained into a salt thereof.