DE2106500C3 - their salts and processes for their preparation - Google Patents

Description

or a salt thereof.

2. disodium salt of the compound according to claim 1.

3. Process for the preparation of the compound or the salts of the compound according to any one of the preceding Claims, characterized in that the compound of the formula

H ₁ Ni

20th

COOH

their salts or their easily cleavable esters in a manner known per se

25 amines such as triethylamine, procaine, dibenzylamine, N-benzyl - /? - phenethylamine, 1-ephenamine, Ν, Ν'-bisdehydroabietylethylenediamine or other amines, provided that these have been used for salt formation with benzylpenicillin.

The compound of the invention has two asymmetric carbon atoms in the molecule and exists in two optically active forms, the D- and L-diastereomer, since the «carbon atom of the als Starting material used «-sulfophenylacetic acid is asymmetric

The compound or its salts are active against Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Proteus morganii, Proteus mirabilis, KlebsieUa pneumoniae, Staphylococcus aureus, Bacillus subtilis, Sarcina lutea, in particular against Pseudomonas, and can be administered orally, by subcutaneous injection, or intravenous injection. The daily doses are about 5 to 500 mg / kg, preferably about 10 to 200 mg / kg, with 2 to 4 times application per day, for example against Pseudomonas infection.

The compound according to the invention or its salts are produced by the condensation reaction of 7-aminocephalosporanic acid, their salts or their easily cleavable esters with a-sulfophenylacetic acid or their functional derivatives produced

The Λ-sulfophenylacetic acid, one of the starting substances, has the formula:

CH-COOH

SO ₃ H

30th

or with a functional derivative thereof. 4. Pharmaceutical preparation, characterized in that that it is as an active ingredient the compound or a salt of the compound according to a of claims 1 to 3 contains.

40

The invention relates to a new cephalosporanic acid derivative and its salts, which are effective against both gram-positive and gram-negative pathogens Bacteria are active as well as on their production.

Since the discovery of cephalosporin C, numerous antibiotics have been made from cephalosporanic acid derivatives developed; however, none of the previously known derivatives was effective against Pseudomonas.

The invention relates to the compound of the formula

50

SO., H

55

COOH

or a salt thereof.

The compound according to the invention and its salts f> o are new with regard to the fact that they have the Λ-sulfophenylacetamido group in the 7-position.

The salts of the compound according to the invention are preferably acidic or neutral, optionally mixed salts of non-toxic f> 5 alkali or alkaline earth metals such as sodium, potassium, Calcium or magnesium (especially the disodium salt) as well as such non-toxic organic -COOH

SO ₃ H

It is commercially available and is made by treating phenylacetic acid with sulfur trioxide sulfonated. If desired, the sulfo group can in the condensation with 7-aminocephalosporanic acid in the form be protected by sulfonamide or sulfonate.

Functional derivatives of Λ-sulfophenylacetic acid are carboxylic acid halides, such as chloride or Bromide, mixed anhydrides, such as lower alkyloxy or aralkyloxycarboxylic anhydrides, the «-toluenesulfonic anhydride, the azide or activated esters, for example esters with p-nitrophenol, 2,4-dinitrophenol, Pentachlorophenol, or carbazide. These derivatives can be derived from the Λ-sulfophenylacetic acid known methods can be obtained. For example, an acid halide is prepared by using the Λ-sulfophenylacetic acid with a halogenating agent such as thionyl chloride, phosphorus oxychloride or phosphorus oxybromide.

Salts of 7-aminocephalosporanic acid are salts of the amino group, e.g. B. the hydrochloride, sulfate, acetate, or salts of the carboxyl group, e.g. B. sodium, potassium, triethylamine salts.

Easily cleavable esters of 7-aminocephalosporanic acid are given by the general formula:

YNH

O ^ = J

CH ₂ OCOCH.,

COOX-R ₁

reproduced, wherein X is a silicon atom or

Is tin atom; wherein Ri, R ₂ and R _{3 are the} same or different hydrocarbon groups, one of which may be a halogen atom and in which case they may further combine with an active hydrogen atom to form a polymer; and wherein Y is a hydrogen atom or

-XR1R2R3
is

These esters can be obtained from 7-aminocephalosporanic acid by known processes. For example becomes the compound in which Y is hydrogen and X is tin and Ri-R3 are all n-ButyJgruppen, prepared in that one a mixture of 7-aminocephalosporanic acid and 0.5 molar equivalents of bis (tributyltin) oxide over cooked in dry benzene for a short period of time

In the process according to the invention, the amino group of 7-aminocephalosporanic acid is known per se Way with the carboxyl group of a-sulfophenylacetic acid condensed

The following procedures are preferred:

1. 7-Aminocephalosporanic acid or its salts are condensed with Λ-sulfophenylacetic acid in the presence of a dehydrating agent. The dehydrating agent is, for example
Ν, Ν'-dicyclohexylcarbodiimide,
Ν, Ν'-diisopropylcarbodiimide or
Ν, Ν'-carbonyltriazole;

2. the functional derivatives of Λ-sulfophenylacetic acid are condensed with 7-aminocephalosporanic acid or its salts; or

3. The easily cleavable esters of 7-aminocephalosporanic acid are combined with functional derivatives the iX-sulfophenylacetic acid condenses.

The condensation can be carried out in the presence of solvents. The solvents are water, dioxane, acetone, dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, ethylene dichloride, Toluene, benzene or a mixture of these solvents. In procedures 1 and 3 above water is not desired In Methods 2 and 3 above, the presence of bases is preferred The bases are organic bases such as triethylamine, tributylamine, dimethylaniline, pyridine, Picoline or quinoline, but inorganic bases such as sodium carbonate, potassium carbonate, Be sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or calcium hydroxide.

The condensation is conducted at a temperature of -5 ° to 40 ⁰ C, preferably at from -2 ° to 10 ° C, the upper limit is carried out at 50 ° C because the compound of the invention or their salts decompose easily.

In the above method 3, the product produced by the reaction is mixed with water or a treated lower aliphatic alcohol to decompose and split off the ester group.

After the condensation has ended, the product can be purified by known methods. Such Processes are solvent extraction and concentration, chromatography, crystallization or Recrystallize. The product can thus be obtained in the form of the free acid or its salts. The salts can, if desired, be converted to other non-toxic salts by known methods. One Embodiments of the invention are pharmaceutical preparations which contain the compound as an active ingredient or a pharmaceutically acceptable salt thereof.

The invention is explained in more detail by the following exemplary embodiments:

example 1

2.5 ml of 1N NaOH solution and 5 ml of water are placed in a flask equipped with a stirrer.

The mixture is in an ice water bath at 0 ° to 5 ° C cooled, and 680 mg of 7-aminocephalosporanic acid are added with mechanical stirring. Then a solution is separated by dissolving 585 mg of Λ-sulfophenylacetyl chloride in 7 ml of diethyl ether The mixture was added dropwise to the mixture over 15 minutes is stirred for 15 minutes. Then the aqueous layer is separated from the reaction mixture and the The pH of this layer was adjusted to 1.5 with Jn-HCl The layer is then extracted twice with 15 ml of n-butanol each time. The extract is extracted twice with Washed 5 ml of water and then further extracted with a saturated aqueous NaHCC> 3 solution. Of the The extract is adjusted to a pH of 6.5.

After purification by chromatography with packed polystyrene powder, the fractions of the Eluats, which contain the desired compound, lyophilized, whereby the sodium salt is in the form of a white powder. The product is dried and analyzed, and the following are obtained Results:

Yield: 385 mg

IR, ν ™ '(cm-'):

1755 (lactam, acetate), 1612 (-COO-),
1680 (-CONH-), 1225 (-SO ₂ -),
1046 (-SO ₃ Na)

Nuclear Magnetic Resonance Spectrum (D ₂ O), (ppm):

2.09 (3 H, singlet),

3.42 (2 H, quadruple «, Ji = 18.0 FJz,

J ₂ = 18.0 Hz),
approx 4.75 (2H), 5.09 (1H, singlet),

5.10 (IH, doublet, J = 4.5 Hz),
5.70 (IH, oc, J = 4.5 Hz),

7.52 (5 H, multiple «),

UV, λ ¹ Ji ₁ V: 259 nm (7.1 χ 103)

Example 2

3.78 g of 7-aminocephalosporanic acid are suspended in 30 ml of chloroform, and 2.3 g of hexamethyldisilazane are added. The mixture is heated in a hot water bath ^{at 65 ° C. for 1.5 hours.} The clear solution obtained is distilled under reduced pressure at 4O ⁰ C. The remaining substance is redissolved in 50 ml of chloroform, and 1.94 g of triethylamine are added. Then, this solution is cooled, and is added dropwise 30 ml of a chloroform solution were added, 4.3 g ac-Sulfophenylessigsäurechlorid contains The mixture is stirred for 15 min at 15 ⁰ C. After the reaction is over, the reaction mixture is concentrated at room temperature under reduced pressure. The product is then dissolved in 50 ml of water. The aqueous solution is on a

b5 pl value of 1.5 set and twice with 35 ml each n-butanol extracted. The butanol layer is washed with a small amount of water and then again with an aqueous sodium carbonate solution

After extracting the pH of the solution 6 has set, the final substance is removed from the solution crystallized out and dried. 43 g of des Sodium salt of the desired compound. The result of the infrared absorption spectrum analysis is the same as in example 1.

Investigation of the effectiveness against Pseudomonas aeruginosa

To investigate the effectiveness of the disodium salt (DL form) of the compound according to the invention its minimum inhibitory concentration against Pseudomonas aeruginosa (NCTC-10490) was determined where carbenicillin was used as comparison substance. In both cases, the minimal inhibition

concentration 5μg / ml. The compound of the invention therefore has the same effectiveness as the well-known penicillin derivative but has in comparison with penicillin the additional advantage that it is better tolerated by patients and has no allergies evokes.

Claims (1)

Patent claims: 1. 7- (At-sulfophenyiacetamido) -cephalosporanic acid the formula CH, OCOCH; SO ₃ H 10