DE2657652C3 - N-acyl derivatives of cefalexin and their preparation - Google Patents

Description

wherein R represents a nitro or methoxy group or a chlorine atom. 2. Process for the preparation of N-acyl derivatives of cefalexin of the general formula

C ₆ H ₅ "

I ^

CH = CH-CO-NH-CH-CO-NH-CH-CH CH ₂

CO-N C-CH ₃ C

COOH

wherein R represents a nitro or methoxy group or a chlorine atom, according to claim 1, characterized in that characterized in that in a known manner cefalexin or a salt thereof either

a) with a cinnamic acid of the general formula

-CH = CH-COOH

(II)

in the presence of a carbodiimide, or
b) with a halide or mixed anhydride of cinnamic acid of the general formula II.

The "invention relates to what is defined by the claims. The object of the invention is on the other hand

featured item. based on the intensity of action and biological activity

From DE-OS 15 45 796 a method for 50 is to be improved. According to the invention, the task is accomplished

Production of cephalosporins with an acrylic group- new N-acyl derivatives of cefalexins of the general

pe known in the acyl radical. The disadvantage is the relatively low active activity.

- CO - NH- CH- CO - NH- CH- CH CH ₂

i I I

CO-N C-CH ₃

COOH

dissolved, wherein R represents a nitro or methoxy group or a chlorine atom. The making of this N-acyl derivatives of cefalexin are carried out according to the invention

by either cefalexin or a salt thereof in a manner known per se

a) with a cinnamic acid of the general formula

-CH = CH-COOH (II)

in the presence of a carbodiimide, or

b) with a halide or mixed anhydride of cinnamic acid of the general formula II. This achieves a superior healing effect, which is explained by the fact that the ED50 values (mg / kg), which in mice previously infected with bacteria by intraperitoneal route, after oral administration of cefalexin and after oral administration of one of the general form according to the invention! (R = —OCH ₃ ) derived products were calculated, which were:

bacteria

Cctalexin

CIl ₁ O CII = CH - CO - NH -

CHCON! 1

CJU

C 0.11

Staph. aureus
Slaph. ^ yogenes
D. pneumoniac
Proteus spp.
Klebsiella spp.
Salmonella
Esch. coü

1.15-3.7

1.8

58.2

22.1

5.2

15.6

11.7

1.15 -2.5

30-40

20th

4-6

15.5 -

8.2-9.1

The biological activity, in vitro, that these compounds exhibit is in the form of minimum inhibitory concentrations (M.I.C.) expressed in v / ml. The starting substance is used as the reference compound, d. H. Cefalexin. Said minimum inhibitory concentrations (M.I.C.) become two representative pathogens, namely Escherichia coli and Stäphylococus aureus.

E. coli

St. aureus

Cefalexin 6.25 1.56 p-nitrocinnamoylamide
Cefalexin 3.25 1.56 p-chlorocinnamoylamide
Cefalexin 3.25 0.78 p-methoxycinnamoylamide
Cefalexin 6.25 0.78

The following explanations illustrate the manufacturing process:

Reaction conditions

The reaction can expediently be brought about by preparing a solution or suspension from cefalexin or its salts or esters in an aqueous or organic aqueous environment by adding an acid acceptor, such as. B. triethylamine, and then an acylating one Means which is p-nitro or p-chloro or p-methoxycinnamic acid, their halide or mixed Acid anhydride can act, in the first case the reaction in the presence of a condensing agent such as for example dicyclohexylcarbodiimide takes place.

The reaction temperatures can be between -30 ° C and + 70 ° C depending on the particular one used Reactants amount.

The reaction route can be performed using any of conventional methods such. B. polarimetry, electrophoresis or chromatographic Analysis to be tracked.

The separation of the end product from the reaction mixture can, depending on the product, by means of a suitable conventional procedure. For example, this separation can be carried out by acidification or extraction using an organic solvent, wash, dry and dry evaporate.

example 1
p-nitrocinnamoyl-cef alexine

3 millimoles of cefalexin are dissolved in 25 ml of chloroform and 3 ml of triethylamine and the resulting product is cooled to 0.degree. This is followed by the slow addition of a solution of 3 millimoles of mixed anhydride of p-nitrocinnamic and pivalic acid in 20 ml of chloroform. When this addition is complete, the mixture is allowed to warm to ambient temperature and is held at that temperature for 2 hours. Dry vacuum evaporation follows. The solid is suspended in 20 ml of a saturated sodium chloride solution and 15 ml of ethyl acetate. Then 2 ml of 2 η HCl are added and the whole thing is stirred for 10 minutes, after which it is filtered and washed with water until the chloride reaction is negative. This is followed by a further washing with 10 ml of ethyl acetate and a drying treatment.
There are 910 mg of a powder, the melting point (decomposition point) at 192 ⁰ Cliegt.
IR spectrum:

[3300 cm - '(- NH-);
1770 cm - '(= C = O, β lactam)].

5 6

Example 2 Example 3

'p-chlorocinnamoyl-cefalexin p-methoxycinnamoyl-cefalexin

The production is carried out using the same process. The same process as example!, But using

as in Example 1, but using 5-p-methoxycinnamic acid instead of p-nitrocinnamic acid.

p-chlorocinnamic acid. There are 838 mg of a white powder, its

Product accumulation 577 mg. Melting point (disintegration point) melting point (disintegration point) is 204 ° C,

of the product = 249 ° C. IR spectrum:

IR spectrum: [3300 cm - '(- NH-);

[3300 cm - '(- NH-); ^{1 ()} 1780 cm " ¹ (= C = O, S lactam)]. 1775 cm- ¹ (= C = O, jS lactam)].

Claims (1)

Patent claims: ]. N-acyl derivatives of cefalexin of the general formula C ₆ H ₅ R- <V-CH = CH-CO-NH-Ch-CO-NH-CH-CH CH CO-NC-CH ₃ COOH