Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-05
2001-03-20
Fan, Jane (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S326000, C546S327000
Reexamination Certificate
active
06204276
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to anti-infectious immunomodulating preparations which may find application in human and veterinary medicine.
BACKGROUND OF THE INVENTION
The preservation of homeostasis and resistance to the influence of environmental factors such as infectious agents is determined to a large extent by the functioning of the systems (first of all, the immune system) ensuring nonspecific resistance of the organism. The interferon system is one of the most important parts of non-specific immunity. Interferons are cytokines by means of which intercellular and humoral reactions directed to the preservation of the homeostasis of the organism occur (Gresser, Cell Immunol., 977, .43, No. 2, pp.406-413; Stewart, The Interferon System, Springer-Verlag, N.Y. ,1979; Soloviov et al, Interferons in Medical Theory and Practice, M., Medizina, 1981, p400) The interferon system is an assemblage of cell elements capable of producing different kinds of interferon, changing its functional status by the action of interferon and thereby realizing intercellular and humoral reactions ensuring the preservation of homeostasis of the organism. Defects in the interferon system lead to disorders in the function of the immune system and, as a consequence, to an increased risk of the development of severe infectious and oncological diseases. A selective modulation with interferons, interferon inducers or other immunomodulators of certain parts of the immune system directly participating in protection against one or another disease may result in correction of immuno- and interferon deficiency and greatly enhances the resistance of the organism to infectious diseases. (The Biology of the Interferon System. 1988. Proceedings of the Fifth Annual meeting of the International Society for Interferon Research (ISIR 88), Kyoto, Japan, 14-18 November, 1988, Tokyo, 1989, p.503).
A new group of preparations—interferon inducers -has found wide use as infection control and immunomodulating preparations. Interferon inducers comprise a heterogeneous group of high and low molecular compounds of natural and synthetic origin. Such preparations possess a wide spectrum of biological activity: anti-infectious, anti-tumor, immunomodulating, radiation protection, etc. (Ershov et al, Interferon and Inducers Thereof, M., Medizina, 1980, p.173).
There are known preparations of alpha-, beta- and gamma-interferons which, according to the technology of preparation are divided into natural (interferons of the first generation) and recombinant (interferons of the second generation):
1. Natural interferons: preparations of &agr;-interferon- human leukocyte interferon, egiferon, villferon; preparations of &bgr;-interferon—human fibroblast interferon, feron; &ggr;-interferon—human immune interferon.
2. Recombinant interferons: preparations of &agr;-interferon- reaferon, realdiron, roferon; preparations of &agr;2b-interferon—intron, inrek; preparations of &agr;2c-interferon —berofor; preparations of &bgr;-interferon—beta-feron; preparations of &ggr;-interferon—gamma-feron (Cheknev et al, Interferon System Normally and in Pathologic Conditions, M., Medizina, 1966, pp.196-221).
A significant short-coming of natural interferons lies in the method of obtaining them from human blood which involves the risk of transmission of heterologous genetic information and viral infections. Recombinant interferons have no such short-comings and are quite valuable in specific clinical situations. However, the presence of only one interferon subtype in each specific preparation limits the range of their use. All interferon preparations induce exogeneous interferonization of the organism which is their common limitation.
There are known interferon inducers used in the clinical practice: synthetic compounds such as, for example, amixin (a low molecular compound of the aromatic series, belonging to the class of fluorenones), neovir (a low molecular compound belonging to biobasic heteroaromatic compounds, to acridinones class). Natural compounds are known, such as, for example, megasin (the product of gossypol -condensation via aldehyde group with &bgr;-sodium aminoethylsulphuric acid), larifan (double-stranded RNA of phage &lgr;2); ridostine (double stranded RNA obtained from a lysate of killer yeasts
Saccharomyces cerevisiae
) (Ershov et al, Antiviral Drugs. St. Petersburg, 1993, p.104). The advantage of this group lies in the capacity of inducing autologous interferons. The above-mentioned interferon inducers, however, induce the synthesis of alpha- and beta-interferons only. At the present time, no sufficiently effective inducers of gamma-interferon suitable for use in the clinical practice are known.
Germanium-organic compounds are known to possess different kinds of biological activity. There is a preparation known as carboxyethylgermanium-sesquioxide of the general formula [GeCH
2
CH
2
COOH]
2
O
3
which is capable, upon oral administration, of inducing interferon production in the blood of mice. Later, the preparation was demonstrated to be capable of inducing &ggr;-interferon synthesis in a suspension of mononuclear cells in vitro (Munakata et al, Interferon Res., 1987, v.7, pp.69-76). However, it has toxicity and low effectiveness as an immune interferon inducer. The raw material (germanium-chloroform) for its production is scarce.
The germanium complex 2, 6-pyridinediyl-biscarbonylox-(hydroxypropoxygermanium), possessing the properties of an immune interferon inducer, is described by Ignatenko et al in Russian Inventor's Certificate No. 1622989 of 22.09.90. This substance, however, has a narrow spectrum of the immunomodulating activity.
Thus, it was important to develop a new preparation possessing anti-infectious, interferon-inducing, and immunomodulating activity which could be used in human and veterinary medicine for prevention and treatment of infectious diseases, immuno- and interferon-deficient conditions and which would lack the above-mentioned defects of the known analogues.
SUMMARY OF INVENTION
Germanium complexes according to the present invention are of a saturated or non-saturated, carbocyclic or heterocyclic dicarboxylic acid, the two carboxylic acid groups being relatively in the 1 and 3 positions on the ring. The ring may have 0, 1 or 2 heteroatoms, e.g. N, 0 or S. It may have 4, 5, 6 or 7 members. A specific embodiment of this invention is germanium bis(pyridine-2,6-dicarboxylate) of formula I:
The new compounds possess anti-infectious, interferon-inducing, and immunomodulating activities which may be used in human and veterinary medicine for prevention and treatment of infectious diseases, immuno- and interferon-deficient conditions.
DESCRIPTION OF THE INVENTION
The novel complexes may be produced by reacting the acid, e.g. 2,6-pyridinedicarboxylic acid, with a tetraalkoxygermanium, preferably tetramethoxygermanium or tetraethoxygermanium. The tetraalkoxygermanium may be formed directly in the reaction mixture, for instance, from a germanium tetrahalide and an alkali metal alcoholate, e.g. germanium tetrachloride and sodium (m)ethanolate (obtained by dissolving metallic sodium in (m)ethanol).
The reaction may be performed in an organic solvent medium such as hexane, heptane, methanol or ethanol; the reaction temperature is usually within the range of 60° to 90° C. The reaction is preferably performed under an inert gas atmosphere such as argon or nitrogen, the reaction time being about 3-5 hours. The target product is recovered by conventional methods, for instance, filtration and drying in vacuum, for example, at 1 torr at 40° C.
The invention also provides a pharmaceutical composition containing as the active ingredient an effective amount of the germanium complex with a pharmaceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition may be administered by different routes such as oral, parenteral, intranasal, etc.
For oral application, the composition may be used in the form of tablets, aqueous suspensions, dispersed powders or granules, as well as syrups or el
Amchenkova Aleftina Mikhailovna
Danilov Leonid Leonidovich
Deyeva Anna Valentinovna
Maltsev Serguey Dmitrievich
Narovlyansky Alexander Naumovich
Fan Jane
Primamedic Ltd.
Saliwanchik Lloyd & Saliwanchik
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