CH651050A5 - SALTS OF CEPHAPIRINE WITH AMINO ACIDS. - Google Patents

Description

The present invention relates to new salts of cefapirine with amino acids, having antibiotic activity.

Cefapirine is a well-known antibiotic compound, described in U.S. Patent No. 3 422 100 and in Japanese Patent No. 44-26107.

Cefapirine is normally administered parenterally as the sodium salt of cefapirine itself. It is known that the sodium salts of antibiotics of this type, and in particular of cefapirine, cause a local pain reaction at the time of their administration.

An object of the present invention is to obtain new cefapirine salts which are injectable and do not cause painful reactions upon their administration.

50 Another purpose is to produce cefapirine salts which promote the absorption of the antibiotic and which, once absorbed in the organism, develop and associate their specific activity with the antibiotic activity of cefapirine, which may be interesting from the point of phama-55 cologic view.

These and other purposes are achieved by salification of cefapirine with an amino acid selected from the group consisting of L-lysine, L-arginine and acetylcysteine.

To obtain this salification, cefapirine is made to react in an aqueous solution and at room temperature, with an aqueous solution of an amino acid or its derivative chosen from the group consisting of L-lysine, L-arginine or acetylcysteine, from the aqueous solution being isolated the cefapirine salt, by freeze-drying.

65 In order to clarify the understanding of the present invention, a preparation of each of the three salts forming the subject of the present invention will be described purely by way of example.

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651050

Example 1 Cefapirine lysinate of formula

-CH -CONIf ch20c0ch3

(D

c00h. H2n- (ch2) 4-ch-cooh nh,

500 ml of bidistilled HaO and 42.3 g (0.1 mole) of acid cefapirine are charged into a reactor, the pH being 3.5. A 50% aqueous solution is then added containing 14.6 g (0.1 mole) of L-lysine base and is left under stirring at 0 ° C for Ih. A complete solution is obtained and the pH rises to 8.

To the solution thus obtained, 1.5 of bleaching carbon are added, filtered on a plate filter, then placed on a bowl making a layer of solution 1 cm high, freezing at -40 ° C and freeze-drying. After 24 h, it is discharged, sieved and 54 g of lysinated cefapirine are collected. K.F. 1.5%

Single spot TLC [a] D (C = 1, H20): + 127 °

Microbiological titer = 730 mcg / mg, as acid cefapirine.

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Example 2 Cefapirine arginine salt of formula

• s-ch2-co-nh

■ r

0

'N

ch2ococh3

c00h. h2n nh nh

^ P-NH- (ch2) 3-ch-COOH

(Ii)

450 ml of bidistilled H20 and 42.3 g (0.1 mole) of acid cefapirine are charged into the reactor: the pH is 3.5. Still at 0 ° C, a 10% aqueous solution of 210 ml is added containing 21 g of L-arginine.

30 'is left to react at 0 ° C, the pH rises to 8.5 and 5 g of bleaching carbon are added to the solution thus obtained, filtered on a plate filter with filtering cardboard. The solution is placed on a bowl making a layer 1 cm high, it is frozen at -40 ° C and then the freeze-drying is started. After 24 h the freeze-drying ends, it is discharged, separated and 55 g of cefapirine argininate are obtained. K.F. 1.2%

TLC = single spot [a] D: + 120 ° (C = 1, H20)

Microbiological titer = 687 mcg / mg = as acid "cefapirine.

Example 3 Cefapirine acetylcysteinate of formula hs-cho-ch-c00h.n

2 I

nh-c0ch_

s-ch2-co-nh h2ococh3

(III)

651050

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500 ml of H2O and 42.3 g (0.1 mole) of acid cefapirine are introduced into a reactor. The mixture is cooled to 0 ° C and an aqueous solution containing 16.3 g (0.1 mole) of acetylcysteine is added. A complete solution is obtained and the pH is 2.1, the reaction is left to react and then 3 g of coal are added. It is filtered with a plate filter then the solution is placed on a basin making a layer of 1 cm, it is placed in a pre-freezer. At - 40 ° C there is complete freezing of the solution--

neither. It is freeze-dried and after 36 h the freeze-drying is finished. The obtained product is sieved and 55.6 g of cefapirine acetylcysteinate are obtained.

K.F. Wo s TLC = single spot [«]„ (C = 1, H20) + 118 °

Microbiological titer = 707 mcg / mg as acid cefapirine.

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Claims (5)

651050 1. Salts of cefapirine with an amino acid chosen from the group consisting of L-Lysine, L-arginine and acetylcysteine. 2. Cefapirine salt, according to claim 1, consisting of lysinate cefapirine of formula <Ö> ~ ch2-c0nh C00H. ch20c0ch3 h2n- (ch) -ch-c00h ^ 4 1 nh2 (d 2 3. Cefapirine salt according to claim 1, consisting of cefapirine arginine salt of formula -CH2-c0-NTI ch2ococh3 nh, 00h. h n i d c-nh- (ch „) - ch-cooh ^ d. J nh (Ii) 4. The cefapirine salt according to claim 1, consisting of cefapirine acetylciseinate of formula hs-ch2-ch-cooh. n nh-coch- _ s-ch2-co-nh (III) ch20c0ch3 c00h 5. Process for the production of cefapirine salts according to one of claims 1 to 4, characterized in that the cefapirine is reacted at room temperature with an aqueous solution of an amino acid or its derivative selected from the group consisting of L-lysine, L-arginine and acetylcysteine, the cefapirine salt being isolated by freeze-drying from said aqueous solution.