Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-14
2002-10-15
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...
C544S310000
Reexamination Certificate
active
06465476
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of medicine and more precisely pertains to an immunomodulator exhibiting antimicrobial and antimycobacterial activities of the following formula:
to a method for producing the same and to a pharmaceutical preparation for treating mycobacterioses as well as pulmonary chronic and nonspecific conditions, sexually transmitted diseases and the resulting immunodeficiency.
BACKGROUND OF THE INVENTION
The antileprous preparation diuciphonum (SU author's certificate No 459228) exhibits immunomodulating activities (SU author's certificate No 938442) and has an immunostimulating effect on humoral and cellular immunity (V. P.Leskov et al., “Clinical pharmacology for physicians”, M., 1997, pp. 77-78; N. S. Prosorovsky, “Immunologic effects of diuciphonum and utilization of the latter for analyzing a proliferative response of lymphacytes”, synopsis of a thesis for a candidate's degree in medicine, M., 1985; L. E. Kostyuk, “Immunocorrecting properties of antileprous preparations”, synopsis of a thesis for a candidate's degree in biology, 1986). However, this preparation lacks mitogenetic activity of its own and is capable to increase the proliferation of T-cells only in response to phytohemagglutinin (PHA). The toxicity of diuciphonum amounts to 2600 mg/kg.
It is known that, although exerting an antibacterial action, N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinsulfon)-N′-isonicotinoylhydrazide (SU author's sertificate No 768186) lacks immunotropic activity and, furthermore, it does not withstand prolonged storage conditions due to impurities contained therein. The immunomodulator exhibiting antimicrobial and antimycobacterial activities, the method for producing the same and the pharmaceutical preparation for treating secondary immunodeficiencies and resulting mycobacterioses which are claimed acording to the present invention are novel and have not been described in literature.
DISCLOSURE OF THE INVENTION
The problem taken as a starting point of the present invention is to provide a novel immunomodulator exhibiting antimicrobial and antimycobacterial activities, including the carriage of human immunodeficiancy virus (HIV), which immunomodulator is active not only in respect of mycobacteria of leprosy but also of those of tuberculosis as well as other deseases developing against the background of immunodeficiency, as well as to provide a method for producing this immunomodulator and a pharmaceutical preparation intended to be used at secondarty immunodeficiencies and mycobaterioses.
This problem is solved, in accordance with the present invention, by providing a novel immunomodulator exhibiting antimicrobial and antimycobacterial activities, this immunomodulator representing N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyridioxo-1,2,3,4-tetrahydro-5-pyrimidinsulfon)-N′-isonicotinoylhydrazide hydrate of the following formula:
There is also provided a method for producing a novel immunomodulator exhibiting antimicrobial and antimycobacterial activities, which immunomodulator represents N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinsulfon)-N′-isonicotinoylhydrazide hydrate of the above formula.
According to the invention, the method of the present invention is carried out by reacting equimolecular amounts of 6-methyluracil-5-sulfochloride and isoniazide in acetonitrile at an elevated temperature. The pharmaceutical preparation for treating mycobacterioses, pulnonary chronic nonspecific conditions, sexually transmitted diseases and immunodeficiency, according to the present invention, comprises an immunomodulator exhibiting antimicrobial and antimycobacterial activities as the active substance, said immunomodulator representing N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinsulfon)-N′-isonicotinoylhydrazide hydrate of the above formula, and a vehicle.
The preparation isophonum claimed according to the present invention can be administered per os in any suitable medical form and parenterally. This preparation contains the active substance in amounts of 0.05 to 0.3 g.
As was shown by clinical tests, isophonum normalizes the immune status of persons suffering from leprosy, tuberculosis, chronic nonspecific pneumonia and chlamydiosis by involving the person's organism in the struggle against the disease; isophonum also stumulates the function of the cell by penetrating into it and carries the active substance as far as to the agent of disease and kills it. It is not ruled out that the preparation may have a direct effect on the sexually transmitted agents such as chlamydia, trichomonads, ureaplasmatic infection.
It should be stressed that isophonum is well tolerable, has no side effects and is compatible with modem antimycobacterial drugs (ethionamide, rifampicinum and others), this being supported by results of examination of leprous and tuberculous patients.
The toxicity of isophonum was determined on white unbred mice wheighing 18 to 20 g in an sharp experiment by Litchfild-Wilkokson's procedure and was found to exceed 7000 mg/kg.
DESCRIPTION OF THE BEST EMBODIMENT
The compound of the present invention is a white, sometimes a yellowish-hued light crystalline powder which is difficult to dissolve in water or usual organic solvents. It is soluble in dimethylformamide, dimethylsulfoxide, deluted acids and alkalies; f. p.=255-256° C. The structure of matter is confirmed by the data of PMR-spectroskopy.
The compound of the present invention and the pharmaceutical preparation on its basis were tested in an experiment carried out on animals and clinically on people.
Determination of immunotropic activity of isophonum was carried out. Immunotropic activity of isophonum was determined on a model of immunodeficiency caused by irradiation. To create an immunodeficient state the mice F
1
(CBA×C57BL/
6
) were irradiated with gamma-rays on a radioterapeutic apparatus in a dose of 4 Gy (Gy is the irradiation unit gray) at an irradiation dose power of 0.55 Gr/min. The number of antibody-forming cells (AFC) in the spleens was calculated by Jeme-Nordin's procedure. Isophonum and diuciphonum were introduced per os over a wide range of doses. The investigation results are represented in Table 1.
TABLE 1
Influence of isophonum on the production of
antibody-forming cells in irradiated animals
Immune
Preparations,
response
doses, &mgr;g per
Number of mice
AFC-number
stimulation
mouse
in the group
in the spleen
index
P
Irradiated
18
308 ± 36
—
—
controls
Isophonum
10
18
1013 ± 126
3.63 ± 0.57
<0.001
100
18
1173 ± 125
4.28 ± 0.8
<0.001
1000
18
1216 ± 124
4.46 ± 0.9
<0.001
Diuciphonum
10
18
768 ± 123
2.5 ± 0.2
<0.01
100
18
870 ± 119
2.9 ± 0.12
<0.001
1000
18
647 ± 64
2.1 ± 0.2
<0.001
As shown in the table, isophonum is 1.5 to 2.5 times more effective than diuciphonum in all doses.
The influence on humoral immunity was studied using the method of localized-in-gel hemolysis. The hybrid mice F
1
(CBA/C57BL
6
) were immunized by erythrocites of the drum in a dose of 5×10
6
and immediately after that the substances under study were administered per os in a starch suspenstion because the low solubility of isophonum does not permit introducing this compound intraperitoneally. On the 5
th
day the number of antibody-forming cells (AFC) in the spleen of the mice was calculated and the immune response stimulation index was determined as the ratio of AFC number in the test group to the AFC number in the control group. The respective data are represented in Table 2.
TABLE 2
Influence of the test substances on the accumulation
of antibody-forming cells (AFC) in the spleen of mice
Number
Immune
of
response
AFC-
animals
stimu-
P,
Name of the
Dose, &mgr;g
number in
in the
lation
reli-
preparation
per mouse
the spleen
group
index
ability
Control
0.5 ml in a
500 ± 50
12
1.0
group
starch
suspension
Filipskikh Tamara Petrovna
Goloschapov Nikolai Mikhailovich
Goloschapova Elena Nikolaevna
Grishin Vladimir Kuzmich
Khaitov Rakhim Musaevich
Ford John M.
Kilpatrick & Stockton LLP
Reshetov Alexandr Leonidovich
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