6-(3-acetylphenyl)aminouracil

 

The invention relates to new 6-(3-acetylphenyl)aminouracil formula I, which stimulates the immune system and antiviral properties and can be used in the treatment of viral diseases caused by chlamydia, as well as diseases caused by immunodeficiency, in particular malignant tumors, and also in veterinary medicine. table 2.

The invention relates to medicine, more specifically to pharmacology, veterinary medicine, particularly to synthetic biologically active derivative of 6-aminouracil. Specified derivative has, in particular, expressed activity as inducer of interferon, as well as activity against herpes simplex viruses. The main purpose of the connection is the use in medical practice. The connection is indicated for the treatment of viral diseases caused by chlamydia, as well as diseases associated with immunodeficiency, in particular, malignant neoplasms. In addition, the proposed connection can be used in veterinary medicine for the same purposes.

One of the serious problems of modern medicine - diseases caused by microbes. Treatment of infections caused by viruses, westvest, in the fight against viral and bacterial diseases play an important role interferons are produced by cells of the body [Ershov, F. I. the interferon System in normal and pathological conditions. Medicine, Moscow, 1996, 240 pages ]. In the treatment of microbial infections are used as exogenous interferons and inducers of endogenous interferon. The latter is extremely limited. One of the urgent problems of the fight against microbial diseases is the development of new products, suitable for induction of synthesis in the human body's own endogenous interferon. It is also known that stimulation of the synthesis of interferon contributes to the struggle of the body against malignant tumors [Ershov, F. I. the interferon System in normal and pathological conditions. Medicine, Moscow, 1996, 240 pages].

Some derivatives of 6-aminouracils [ed. St. USSR 170061, MKI 4 C 07 D 239/10, published BI 08,65; ed. St. USSR 176910, MKI 4 C 07 D 239/10, published BI 24,65; Application Germany 206453; M. D. Mashkovsky. Medicines, including 1, Moscow, Medicine, 1993, S. 550 - prototype; Goldner, Dietz, Carstens // Ann. Chem, 1966, 691, R. 142; // Ann.Chem., 1966. 698, R. 145; // Ann. Chem., 1966, 699, R. 145; Rubtsov, M. C., Bizikov A., Synthetic chemical-pharmaceutical preparations, Moscow, Medicine, 1971, S. 2552-7].

In particular, in the work of M. C. Roux 255] described allall (1-allyl-3-ethyl-6-aminouracil) - active diuretic, used as a diuretic at stagnation associated with cardiovascular disease. Its structure is shown belowFor some derivatives of 6-aminouracils specific biological activity, are described, in particular, in the work of M. D. Mashkovsky [M. D. Mashkovsky. Medicines, including 1, Moscow, Medicine, 1993, S. 550 - prototype] - see, for example,, 6-[[3-[4-(2- Methoxyphenyl)-1-piperazinil]propyl] -amino] -1,3-dimethyluracil. In General, chemical, structural analogues of the proposed new substances are derivatives of 6-aminouracil General formulawhere R is phenyl, 2-were, 3-were, 4-were, 4-bromophenyl, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,6-dimetilfenil, 2-chlorophenyl, 3-chlorophenyl, 1-naphthyl, 2-naphthyl, cyclohexyl [Goldner, Dietz, Carstens // Ann. Chem, 1966, 691, R. 142; // Ann. Chem., 1966, 698, R. 145; //Ann. Chem., 1966, 699, R. 145].

Known sources of information do not contain information about any shows they expressed biological activity.

Closest to the claimed compound according to the chemical structure- 6-[[3-[4-(2-Methoxyphenyl)-1-piperazinil] propyl] -amino] -1,3-dimethyl-uracil, the structure of which is shown below.

Object of the invention is the creation of new substances that stimulate the production of endogenous interferon, as well as having antiviral activity, i.e. possessing immunostimulatory and antiviral action.

The problem is solved by the synthesis of a new derivative of 6-aminouracil, namely 6-(3-acetylphenyl)aminouracil. This is a heterocyclic chemical compound number refers to the new group from the class of substituted 6-aminopurine.

The compound has the chemical formula (1)The solvent is DMSO and the results of the analysis, that is more than 300 squareoC. the structure of the compounds was proved by spectroscopy PFP (proton magnetic resonance).

The claimed connection new - details not included in any of the available sources of information.

The claimed compound and its biological activity is not intuitive for a specialist based on the above information about the models and the prototype with biological actionlog effective biologically active substances - a useful result of a large number of experiments, experience and intuition.

The essence of the proposed invention is explained below.

An example of the synthesis of the claimed compounds and the results of its identification.

Experimental studies of the biological activity of the inventive compounds, namely: Experiment 1. Study of antiviral activity (activity of the claimed compounds on the herpes virus).

Experiment 2. Study of interferon-inducing activity of the claimed compounds.

Experiment 3. Determination of acute toxicity.

Table 1 presents the effect of the inventive compounds on the herpes simplex virus at concentrations of test compounds (100 mg/L.

Table 2 presents the quantitative evaluation of the IFN - inducing activity of the claimed compounds: the content of IFN induction mixture after 24 h incubation with different concentrations of the drugs, IU/3104limp./Jr.

The synthesis of the claimed compounds, the Method of obtaining the target product based on the interaction of 6-florouracil with the appropriate aromatic amine in aqueous solution at boiling point.

An example of the synthesis of the claimed compounds
To 12.7 g is a mortar. When heated to 160oWith the mixture melts and becomes thin, but after 0.5 h hardens, heat stop after 1.5 hours the Mixture is transferred into water, stirred and filtered, washed with water, alcohol, ether, and dried. By recrystallization from a mixture of isopropanol-DMF (1:1) get the target product.

The structure of the compounds obtained demonstrated by NMR spectroscopy on nuclei1H and13C. the Characteristic spectrum of the PMR are the signals of the protons of aminogroup pyrimidine ring in the region of 10-12 M. D. and marinovich protons of the pyridine ring 4-6 memorial plaques In NMR spectra13With characteristic signals With570-100 memorial plaques for the carbon atoms of the aryl ring.

Experimental studies of the biological activity of the claimed compounds
Experiment 1. Study of antiviral activity (activity of the claimed compounds against herpes)
Antiviral activity was studied in relation to herpes virus type I in human cell culture Vero.

Scheme of production experience
The virus was added to cells with medium RPMI-1640 containing 10% calf serum, which were obtained in 96-well plateau. Initial concentration of virus - 10-12 particles per ml. Concentration is removed and changed environment. The results were evaluated by cytopathogenic action of the virus on the cells after incubation at 38oWith CO2-incubator for 36 hours

The results show that the claimed compound has Antiherpes virus effect of activity comparable to that of the most popular drug of acyclovir.

Experiment 2. Study of interferon-inducing activity of the claimed compounds.

The induction of the synthesis of interferons claimed the drug was carried out on primary cultures of human lymphocytes. Used fresh blood of healthy donors (not more than 12 hours after collection). The selection of lymphocytes was carried out as follows. Heparinised blood was centrifugals in the density gradient of ficoll-urografin 1,71 g/cm3to allocate fractions of immunocompetent cells. This fraction after her selection was divorced nutrient medium RPMI-1640. The specified nutrient medium containing 5% fetal calf serum, 0.3 mg/ml L-glutamine, 100 units/ml penicillin, 50 mg/ml streptomycin. Lymphocytes were stained with methylene blue in the camera Goryaeva, and then determined their concentration. Concentrations of substances, after appropriate dilution of the initial solutions of the inventive substances Pete the lymphocytes in the induction of the mixture was 3106cells/ml.

Incubation of control and test samples was carried out 24 h at 37oC. Then they were tsentrifugirovanie at 2000 g for deposition of cellular elements. Of samples were selected IFN-containing supernatant, which was analysed in the quantitative content of IFN. Sediment cells resuspendable in the same volume of nutrient medium were stained with the vital dye - Trifunovi blue and counted the number of cells in the cell Goriaev (as described above) to determine the cytotoxic effect of drugs.

Quantitative determination of IFN in the control and experimental samples were produced using enzyme immunoassay system ProCon IF2 plus (manufactured LLP Protein loop") designed to determine IFN-a. To determine the amount of interferon in the sample used enzyme-linked immunosorbent method using horseradish peroxidase as indicator enzyme. The bound peroxidase activity was measured using an automatic microplate photometer for microprocessor at a wavelength of 450 nm. In parallel, we determined the activity of IFN standard solutions of IFN containing a known amount of the drug. On the basis of the received resultcache photometer data, expressed in International Units (ME) activity of IFN per ml in this induction system containing 3106limp./ml. Each experimental and control point was investigated in 4 Parallels.

As a result of researches it is established that the claimed compound has the ability to induce the synthesis of DETAIL (table 2).

Experiment 3. Determination of acute toxicity
Determination of acute toxicity was carried out on outbred white mice weighing 18-20 g of the Emulsion of the claimed compounds were prepared in different concentrations: 1500, 700, 500, 100, 20 and 5 mg/kg To research each concentration of the compound used in 5 animals. The drug was administered once daily by mouth or intraperitoneally. The observation period was 14 days. 1, 8 and 15 day weighing of animals in each group. For control used animals that were injected emulsion prepared without the tested compounds.

For macroscopic study of the internal organs were opening all animals that died during the experience and survived to the end of the experiment. The claimed compound has a low acute toxicity (LD50) - 470 mg/kg

The results swne has acute toxicity for mice.

Shows an example of a practical synthesis of the claimed compounds confirms the possibility as his laboratory and industrial synthesis tools available to the modern pharmaceutical industry. The results of the analysis show that the conventional control methods allow to clearly identify them. Experiments on determination of the biological activity described in the present report showed that the claimed compounds possess biological activity against herpes simplex virus and interferon-inducing activity. The latter indicates the possibility of their use in the treatment of other viral and some cancers. When receiving through the mouth or intraperitoneally in these concentrations the claimed compound has no acute toxicity for mice.

Provides information convincingly prove the achievement of the objectives of the invention: a new biologically active substance that stimulates the production of endogenous interferon, as well as having antiviral activity, i.e. possessing immunostimulatory and antiviral action.

The problem is solved by the synthesis of o cimetifine)aminouracil - refers to the new group from the class of substituted 6-aminopurine. As was shown in the section "summary of the invention", it is new and non-obvious.

Thus, in our opinion, the claimed substance satisfy all the requirements of the invention: it is new, not obvious and industrially applicable.


Claims

6-(3-Acetylphenyl)aminouracil formula


 

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