CEPHAPIRIN SALTS WITH AMINO ACIDS

SELS DE CEPHAPIRINE AVEC ACIDES AMINES

English Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to salts of cephapirin with an amino acid
selected from the group consisting of L - lysine, L - arginine and acetylcy-
steine. Said salts are obtained reacting an aqueous solution of cephapirin
with an aqueous solution of an amino acid or its derivative, selected from the
group consisting of L - lysine, L - arginine and acetylcysteine. To isolate
the salt, the aqueous solution is submitted to lyophilization. The salts of
the invention can be injected without causing such as pain as when the sodium
salt of cephapirin is injected.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a salt of cephapirin with an amino acid
selected from the group consisting of L - lysine, L - arginine and acetylcy-
steine which comprises reacting cephapirin with respectively L - lysine,
L - arginine or acetylcysteine or a reactive derivative thereof.
2. A process according to claim 1 wherein cephapirin is reacted with the
amino acid or reactive derivative thereof in aqueous solution, and the cephapir-
in salt is solated from the aqueous solution by lyophilization.
3. A salt of cephapirin and an amino acid selected from the group
consisting of L - lysine, L - arginine and acetylcysteine, when prepared by a
process according to claim 1 or 2 or an obvious chemical equivalent thereof.
4. A process for preparing cephapirin lysinate which comprises reacting
cephapirin with L - lysine in solution in distilled water, followed by lyophili-
zation to obtain the required salt.
5. Cephapirin lysinate when prepared by a process according to claim 4
or an obvious chemical equivalent thereof.
6. A process for preparing cephapirin arginine which comprises reacting
cephapirin with arginine in solution in distilled water, followed by lyophili-
zation to obtain the required salt.
7. Cephapirin arginine salt when prepared by a process according to
claim 6 or an obvious chemical equivalent thereof.

8. A process for preparing cephapirin acetylcysteinate which comprises
reacting cephapirin with acetylcysteine in solution in distilled water followed
by lyophilization to obtain the required salt.
9. Cephapirin acetylcysteinate when prepared by a process according to
claim 8 or an obvious chemical equivalent thereof.

Description

1133~-71
The present invention relates to novel cephapirin salts with amino
acids, said salts having antibiotic activity.
Cephapirin is a well known antibiotic, which is described in United
States Patent 3,422,100 and in Japanese Patent publication 44-26107.
Cephapirin is usually administered parenterally as its sodium salt.
It is well known that sodium salts of this kind of antibiotics, and
in particular of cephapirin, are painful on administration by injection.
It is an object of the present invention to provide new salts of
cephapirin, which are injectable without inducing painful reactions when
administered.
It is another object of the present invention to provide new salts of
cephapirin which increase the absorption of the antibiotic substance and which,
when absorbed by organism, are able to give and to join with the antibiotic
activity ~hich is peculiar to cephapirin their own specific activity, which may
have some interest from the pharmacological point of view.
The present invention provides salts of cephapirin with an amino acid
; selected from the group consisting of L - lysine, L - arginine and acetylcy-
steine.
The salts can be obtained by reacting cephapirin with the amino acid
or a reactive derivative thereof in aqueous solution. The reaction can be
carried out at room temperature or at 0C, with stirring. The preferred method
of isolating the salt from the aqueous solution is lyophilization.
In order that this invention may be readily available to and under-
stood by those skilled in the art, methods of preparing each of the three salts,
~hich are obiects of the present invention, are described in the following
e~amples, which are given merely in illustration of the present invention.

113~
EXAMPLE 1
Cephapirin lysinate having formula
N/~-S-CH2-CONH' ~ ~
L CH20COCH3
COOH. H2N-~CH2)4 -c~l-cooH
NH2
~ idistilled ~ater ~500 ml) and cephapirin as acid ~42.3 g, 0.1 mole)
~ere charged at 0C in a reaction vessel; pH was measured and was 3.5. A 50%
L - lysine base aqueous solution, containing 14.6 g ~0.1 mole) of L - lysine
base, ~as added; the mixture was kept under stirrlng for 1 hour at 0C. A
complete dissolution ~as obtained and the pH value raised up to 8. Decolorizing
car~on ~1.5 g~ was added to the resultant solutlon, ~hich ~as filtered through
filter plates and poured into a tray, till a 1 cm layer ~as obtained~ The
solution was then freezed at -40C and lyophilized. After 24 hours the result-
ing material was discharged and screened; cephapirin lysinate ~54 g) was obtain-
ed.
K~ 1.5%
TLC slngle product
~]D ~c = 1 , H20) : ~ 127
Micr~biological titer = 730 mcg/mg as cephapirin as acid.
Cephapirin arginine salt having formula
-S-CH2-CO-NH ~ ~ S
N ~ CH20C0C113 NH2
COOH. H2N
C-NH-~CH2)3-CH-COOH
NH
--2--

~13347'1
Bidistilled water (450 ml) and cephapirin as acid (42.3 g , 0.1 mole)
were charged at 0C in a reaction vessel; pH was 3.5.
A 10% L - arginine aqueous solution ~210 ml), containing 21 g of
L - arginine, was added at 0C.
The reaction mixture was kept at 0C or 30 minutes, the pH value
raised up to 8.5. Decolorizing carbon (5 g) was added to the resultant
solution which was filtered through filter plates and poured into a tray, till
a 1 cm layer was obtained. After pre-freezing at -45C, lyophilization was
started. Lyophilization ended after 24 hours, the resulting material was dis-
charged and screened; cephapirin arginine salt (55 g) was obtained.
Kp 1.2%
TLC single product
~]D ~c = 1 , HzO~ : + 120
~icrobiological titer - 687 mcg/g as cephapirin as acid.
EXAMPLE 3
Cephapirin acetylcysteinate having formula
HS-CH2-CH-COOH.N, ~ -S-CH2-CO-NH ~ S ~
NH-COCH3 0 ~ N ~ CH20COCH3
COOH
; ~ater ~500 ml) and cephapirin as acid ~42. g, 0.1 mole~ were charged
in a reaction vessel. After cooling at O C, an aqueous solution containing
16.3 g ~0.1. mole) of acetylc~steine was added. A complete dissolution was
o~tained the resultant pH was 2.1. The mixture was allowed to react for 1 hour;
then carbon ~3 g) was added. The resultant solution was filtered through
filter plates, poured into a tray till a 1 cm layer was obtained and subjected
to prefreezing.
At -40C solution was completely frozen and was lyophilized. L~ophili-
zation was finished in 36 hours.
__3__

11334~71
The resultant material was screened and cephapirin acetylcysteinate
~55.6 g) was obtained.
KF 1%
TLC single product
[~ p ~c = 1 , H20 : + 118
Microbiological titer = 707 mcg/mg as cephapirin as acid.
-4~