Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-imino-methyl...

Details Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-imino-methyl... Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-imino-methyl...

2001-07-20

2002-11-05

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C540S458000

Reexamination Certificate

active

06476036

ABSTRACT:

Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV was synthesized.
The compound shows high activity against Gram-positive and Gram-negative microorganisms, Mycobacterium tuberculosis (including atypical and rifampicin resistant) and may be used in the medical practice. The sodium salt has the following formula:
The process for preparation of the sodium salt consists of reacting equimolar quantities of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV and sodium ascorbate with addition of 30% methanol solution of sodium methylate, followed by filtration and removement of the solvent by distillation under reduced pressure.
The compound can also be obtained from the sodium salt of 3-formil rifamycin SV, which is reacting with N
1
-amino-N
4
-cinnamypiperazine in medium of inert solvent at room temperature.
TECHNICAL FIELD
The invention relates to the sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl-rifamycin SV and process of preparation. The sodium salt shows high activity against Gram-positive and Gram-negative microorganisms, Mycobacterium tuberculosis, (including atypical and Rifampicin resistant) and therefore may be used in the medical practice.
BACKGROUND OF THE INVENTION
The rifamycins are group of antibiotics with high antibacterial activity and they have a wide spectrum of application in the treatment of Mycobacterium infections. Rifampicin is the best known representative of the group of rifamycins.
In document BG No. 36006 (U.S. Pat. No. 4,193,920) are described new azomethyn derivatives of Rifamycin SV with general formula I,
These compounds display high activity against Gram-positive and Gram-negative microorganisms and Mycobacterium tbc. This activity is analogical and in some cases is higher than that of Rifamycin. The document BG No. 87451 (U.S. Pat. No. 5,095,108 (1992)) describes a process for preparing the insoluble crystal form of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV (compound, designed as T-9 in the first quoted BG document). The in vivo investigations of the compound show a higher therapeutic effect in comparison with this of Rifampicin. The therapeutic activity of T-9 in doses 10 mg/kg in generalized tuberculosis in test animals shows full organ sterilization after 60 days of treatment, while a similar therapeutic effect is achieved with Rifamificyn in doses of 80 mg/kg. The compound presents considerably longer serum half life than Rifampicin (T
½
: 31~34 hours) tested on animals.
The acute toxicity of T-9 in mice is 4000 mg/kg, while this of Rifampicin is 1500 mg/kg. This indicates the compound T-9 as the best perspective among the derivatives of Rifamicyn SV, described in BG No. 36006.
DISCLOSURE
The present invention is concerned with the sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV which is new, and a process for its preparation. The new sodium salt provided by the present invention is compound of the general formula II:
The new sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV has increased antibacterial activity and low toxicity in comparison with the compound “T-9”. The new sodium salt has the following advantages: good water solubility and higher bioavalability and possibility for administration as injectable formulation.
The synthesis of the water soluble sodium salt of “T-9” provides better possibilities for administration of the new salt as well in parenteral as in peroral pharmaceutical formulations.
The in vitro studies of the activity of sodium salt (designated T-1 1) in comparison with the initial compound T-9 show good antibacterial activity against the Gram-positive microorganisms including aerobic, anaerobic and Mycobacterium (typical and atypical). The pharmacokinetic properties of the known compound T-9 are improved in the salt—the sodium salt has better resorbtion characteristics resulting from its better water solubility and it maintains higher serum levels. The sodium salt has clearly expressed depo activity and secures the maintenance of constant theurapeutical concentrations in the organism for a longer period of time: 40~50 hours in mice and rats, and about 100 hours in rabbits (Table 1).
TABLE 1
Non-model pharmacokinetic parameters after use of T-11 and T-9
(base 20 mg/kg) in mice, rats and rabbits
Method
C
max
CL
of Application
mg/
T
max
T
1/2
AUC
ml · min/
V
Species of Animals
ml
h
h
mg · h/ml
kg
J/kg
Mice
T-11
i.v
50
1
39.08
3616.7
0.092
0.312
p.o
14.4
8
38.02
977.45
0.092
0.303
T-9
p.o
12.4
8
33.70
734.69
0.092
0.270
Rats
T-11
p.o
9.20
2
20.04
671.352
T-9
p.o
8.20
6
21.18
543.144
Rabbits
T-11
p.o
2.71
2
28.04
298.8
T-9
p.o
2.75
2
56.63
232.6
The advantages of the newly-synthesed sodium salt are the good water solubility and the possibility of its application in the form of injection solutions (which is impossible with the unsoluble starting compound T-9), good stability of the obtained water solutions, faster resorbtion and better pharmacokinetic properties in animal tests.
The sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV can be easily obtained by the following two methods:
Method A.
In this method the sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV is prepared by reacting equimolar amount of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV and of appropriate organic or inorganic base, containing sodium, in aqueous medium or in organic solvent medium. Preferably the reaction can be carried out in the presence of small amount of sodium ascorbate as an antioxidizing agent to prevent the transformation of the phenol structures in the rifamycin derivative into quinine-structures. When the reaction is carried out in an aqueous medium, diluted solution of sodium salt is used as a base and when using sodium alcoholates (sodium methylate, sodium ethylate, sodium isopropilate), the reaction mixture is prepared by adding the corresponding alcohol (methanol, ethanol and the like). More preferably is the use of sodium methylate diluted with methanol or ethanol. The solvent was removed in vacuum (if it is alcoholate) and the resulting solid sodium salt is distillated or is lyophilized (if the reaction is carried out in aqueous medium).
The sodium salt may be isolated using distillation of the solving agent in vacuum (when effecting the reaction in an alcoholic medium), or using lyophilization (when effecting the reaction in water).
The yield of the sodium salt is practically quantitative and with high purity. The obtained the sodium salt may be purified by recrystallization in a suitable solvent.
Method B.
Proceeding as described in Method A is prepared a sodium salt of 3-formil rifamycin SV which subsequently is reacting with N
1
-amino-N
4
-cinnamylpiperazine in medium of an inert solvent at room temperature. The solvent was evaporated by distillation in vacuum and the residual product was purified by recrystallization in suitable solvent.


REFERENCES:
patent: 4193920 (1980-03-01), Konstantinova et al.
patent: 4918066 (1990-04-01), Kump
patent: 2200353 (1988-08-01), None

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