Agent for neutralising toxic action of tumour necrosis factor on basis of hydrated pyrido(4,3-b)indoles, pharmacological agent on its basis and method of treating autoimmune disease on basis of neutralising toxic action of tumour necrosis factor

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns an agent for neutralising toxic action of tumour necrosis factor on the basis of hydrated pyrido(4,3-b)indoles of formula (1), a pharmaceutical agent on the basis thereof, and a method of treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

EFFECT: preparing the agent for treating autoimmune diseases on the basis of neutralising toxic action of tumour necrosis factor.

13 cl, 1 tbl, 1 ex

 

The invention relates to medicine, namely to use chemical compounds to create medicines for the treatment of any autoimmune diseases, mechanisms of pathogenesis involving the tumor necrosis factor (TNF), in particular rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis.

The most widely accepted methods of biological treatment of a wide range of autoimmune diseases in our day found anticytokine therapy. It started with neutralization of tumor necrosis factor (TNF) (old terminology - TNF-α), whose role in the development and clinical manifestations of autoimmune disease there is no doubt, monoclonal antibodies. The use of this treatment principle has enabled us to achieve results that significantly exceed the results of the destination of the classic basic tools (Elliot M.J., R.N. Maini, M. Feldmann et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumour necrosis factor α. Arthritis Rheum, 1993, v.36, 1681-1690; Maini R, Breedveld F., J. Kalden et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor a monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthr.Rheum., 1998, v.41, p.1552-1563.). Subsequently, these drugs were used for treatment of other inflammatory diseases, especially ankylosing spondylitis is psoriatic arthritis (D. Furst, Keystone e, Breedveld F. et al. Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis and other rheumatic diseases. Ann.Rheum.Dis., 2001, v.60, suppl.III, iii 2-5).

All these drugs represent a large protein molecules obtained by the methods of genetic engineering that defines the path of their introduction (only parenterally, intravenously or subcutaneously) and possible side effects, including serious infusion and allergic reactions. In addition, in some cases these protein drugs produced neutralizing antibodies, which leads to reduction of therapeutic action of the discussed tools (Van der Laken C.J., A.E. Voskuyl, J.C. Roos et al. Imaging and analysis of serum immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann.Rheum.Dis., 2007, v.66, p. 253-256). Due to the complexity of the production of genetically engineered biological products, their cost is very high, significantly limits the field of use of these drugs. Therefore, the search for synthetic low molecular weight inhibitors of TNF, which could be used inside, were not as roads and did not cause these adverse events, it is very urgent

The task to be solved by the invention, is expanding Arsenal of tools that can be used as a new effective drugs to counteract the toxic action of the actor tumor necrosis in the treatment of several autoimmune diseases, for example, such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis.

The problem is solved by the use of hydrogenated pyrido ([4,3-b]indoles of formula (1) as a means to neutralize the toxic effects of tumor necrosis factor

where R1selected from the group consisting of CH3-, CH3CH2-, PhCH3-;

R2selected from the group consisting of H, PhCH2- or 6-CH3-3-Py-(CH2)2-;

R3selected from the group consisting of H, CH3- or Br-.

One of the compounds that can be used as a means to neutralize the toxic effects of tumor necrosis factor, may be the compound of formula (1), in which

R1corresponds CH3CH2-, R2corresponds to the H-and R3- H-.

Or in which R1corresponds PhCH3-, R2corresponds to the H-and R3- H-

Or connection, where R1corresponds CH3-, R2corresponds PhCH2-, a R3-CH3-.

Or connection, where R1corresponds CH3-, R2match 6-CH3-3-Py-(CH2)2-, and R3'N'.

Or connection, where R1corresponds CH3-, R2match 6 - CH3-3-Py-(CH2)2-, and R3-CH3-.

Or connection, where R1corresponds CH3-, R2corresponds to N, and R3-H-.

Or connection, where R1corresponds CH3-, R2corresponds to N, and R3-CH3-.

Or connection, where R1corresponds CH3-, R2corresponds to N, and R3- Br-.

Or dihydrochloride 2,8-dimethyl-5-[2-(6-methyl-pyridyl-3)ethyl]-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (Dimebon).

Specified in the formula 1 compound can be a salt with pharmaceutically acceptable acids.

The compounds of formula 1 are known compounds, are widely used in pharmacological practice with antiaggressive, anti-arrhythmic and other activities.

In recent years, it has been found that derivatives of hydrogenated pyrido[4,3-b] indoles of formula (1), in particular Dimebon is able to act on two major subtype of ionotropic glutamate receptors in the mammalian CNS. - AMPA and NMDA receptors, which allows their use as a treatment for Alzheimer's Disease and geroprotective funds. Dimebon potentiates transmembrane currents caused by activation of AMPA receptors, and simultaneously blocks the NMDA receptors (HRI, Oiany, Coachin. A comparative study of the mechanism of action of Dimebon and memantine on AMPA and NMDA patibility receptor neurons of rat brain // bull. The experts. Biol. med., 2003, No. 11, s-538).

The inventors unexpectedly found that the compounds of formula (1) have the ability to neutralize the toxic effects of tumor necrosis factor, in particular its cytotoxic effect.

The technical result that can be obtained by carrying out the invention is a significant reduction in disability and mortality of patients above autoimmune diseases.

Another aspect of the invention is a pharmacological tool to neutralize the toxic effects of tumor necrosis factor containing the active principle and a pharmaceutically acceptable carrier, the novelty of which consists in the fact that, as active principle, it contains an effective amount of hydrogenated pyrido(4,3-b) indole of the formula (1).

Another aspect of the invention is a method of treatment of autoimmune diseases based on neutralizing the toxic effects of tumor necrosis factor involving the introduction of a tool according to claim 1 at a dose of 0.001-10 mg/kg of body weight at least once a day during the period required to achieve a therapeutic effect.

The term "pharmacological agent" means the use of any pharmaceutical form containing the compound of formula (1), which could find preventive or is uchebnoe application in medicine as a treatment for AZ.

The term "effective amount", as used in this application involves the use of a number of compounds of the formula (1), which in connection with its performance of the activity and toxicity, as well as on the basis of knowledge of a specialist should be effective in the form of the drug.

To obtain a pharmacological means of one or more compounds of formula (1) mixing the active ingredient with a pharmaceutically acceptable carrier known in medicine in accordance with accepted pharmaceutical methods. Depending on the dosage form of the drug carrier may take various forms.

Examples of media that can be used for the manufacture of such compositions, are lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. are Acceptable carriers for gelatin capsules with a soft coating are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like

In addition, the pharmaceutical agents can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts to change osmoticheskogo pressure, buffers, covering agents or antioxidants. They may also contain other compounds having valuable therapeutic the properties.

Preparative form can be a standard dose and can be prepared with known pharmaceutical methods.

Table 1 shows the results demonstrate a protective effect of Dimebon in a concentration of 10 µg/ml against the toxic effects of TNF on cells L929, where * indicates the reliability of the difference between the survival rates of cells under the influence of TNF and TNF + Dimebon at p≤0.05.

The possibility of carrying out the invention with the implementation of the proposed assignment and the technical result is confirmed, but not limited to the following examples.

Example 1. The study of inhibition of TNF action of Dimebon on the model of the cytotoxic effect of TNF on cells of murine L929 fibroblasts.

As representative compounds of General formula (1) was taken drug drug Dimebon, dihydrochloride 2,8-dimethyl-5-[2-(6-methyl-pyridyl-3-)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole of formula (1.1).

The biological activity of Dimebon (IPD) in a concentration of 1, 10 and 100 μg/ml was evaluated by its ability to modulate the cytotoxic effect of TNF on cells of murine L929 fibroblasts. Cells of murine L929 fibroblasts in the amount of 2×104cells were placed in wells of 96-well plates (Nunc, Denmark) in 100 μl of complete medium 199 (Biolot, Russia)containing 10% fetal Inoi calf serum (Biolot, Russia) and incubated for 18 hours. Then deleted the environment and to the monolayer of cells was added 50 μl of complete medium containing actinomycin D (2 μg/ml) (Reanal, Hungary), Dimebon, and then double breeding TNF (100 ng/ml to 0, 1 PCG/ml) (Reanal, Hungary), and incubated at 37º in CO2- incubator (CEVO Biomed, Sweden). After 18 hours in each well was added 10 μl of MTT solution (Sigma, USA) in PBS (5 mg/ml) and incubated for 2.5 hours. After this time the supernatant was removed, the remaining cells were added to 100 µl of DMSO (Biolot, Russia), the optical density was measured at 540 nm on the device Titertek Multiskan MCC (Flow Laboratories, Finland). Assessment of viability was calculated by the formula C=(A-B):A×100%, where A is the absorption in the control hole, B - light absorption in the test hole. The measurements were carried out in four repetitions.

The results of the experiments (table 1) showed that incubation of cells with Dimebon when its concentration 10 µg/ml in the incubation medium followed by the addition of tumor necrosis factor caused a significant protective effect, i.e. the preservation of the life of L929 cells. This cytoprotective effect of Dimebon was manifested in a very wide range of concentrations TNF: from 6.25 ng/ml to 0.8 PCG/ml, i.e. in a 10,000-fold range.

As can be seen from the table, Dimebon has a direct protective effect on the cytotoxic action of TNF on cells of the mouse is different L929 fibroblasts, increasing cell survival up to 5 times.

Conducted additional studies have shown that at concentrations of Dimebon 1 µg/ml protective effect was not found, and at a concentration of 100 μg/ml Dimebon was toxic to L929 cells (not illustrated).

These facts allow us to recommend Dimebon for the treatment of any autoimmune diseases, mechanisms of pathogenesis involving the tumor necrosis factor. This drug is permitted for everyday practical use and well tolerated by patients. It may be regarded as a promising basis antiautorun the drug. Its obvious advantage is the possibility of oral administration.

The use of Dimebon in modern anticytokine therapy can reduce its cost, improve portability and significantly improve the efficiency of the treatment of the most resistant forms, in particular, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis.

Means for neutralizing the toxic effects of tumor necrosis on the basis of a hydrogenated pyrido(4,3-b)indoles, pharmacological tool based on it and the method of treatment of autoimmune diseases based on the neutralization of t is xeonsaga actions of tumor necrosis factor.
Table 1
Breeding TNF (Ln concentration) ng/ml-1-2-3-4-5-6-7-8-9-10-11-12-13-14
Cell survival (%) under the action of TNF0002461835588595100100100
The L929 cell survival (%) under the action of Dimebon + TNF024*6*16*30*56*80*/td> 90*95*100100100100

1. Means for neutralizing the toxic effects of tumor necrosis factor on the basis of a hydrogenated pyrido (4,3-b) indoles of the formula 1

where R1chosen from a number of CH3-, CH3CH2or PhCH3-,
R2selected from the series H, PhCH2- or 6-CH3-3-Py-(CH2)2-,
R3chosen from a number of H-, CH3- or Br-.

2. The tool according to claim 1, where R1corresponds CH3CH2-, R2corresponds to H-, R3- H-.

3. The tool according to claim 1, where R1corresponds PhCH3-, R2corresponds to H-, R3- H-.

4. The tool according to claim 1, where R1corresponds CH3-, R2corresponds PhCH2-, R3- CH3-.

5. The tool according to claim 1, where R1corresponds CH3-, R2match 6-CH3-3-Py-(CH2)2-, R3- H-.

6. The tool according to claim 1, where R1corresponds CH3-, R2match 6-CH3-3-Py-(CH2)2-, R3- CH3-.

7. The tool according to claim 1, where R1corresponds CH3-, R2corresponds to the N-, R3'N'.

8. The tool according to claim 1, where R1corresponds CH3-, R2corresponds to H-, R3 - CH3-.

9. The tool according to claim 1, where R1corresponds CH3-, R2corresponds to the N-, R3- Br-.

10. The tool according to claim 1, where the specified connection is a dihydrochloride 2,8-dimethyl-5-[2-(6-methyl-pyridyl-3)ethyl]-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (Dimebon).

11. The tool according to claim 1, where these compounds are salts with pharmaceutically acceptable acids.

12. Pharmacological agent based on the compound according to claim 1, containing the active principle and a pharmaceutically acceptable carrier, characterized in that the active agent it contains an effective amount of the compounds of formula (1).

13. The method of treatment of autoimmune diseases based on the neutralization of the toxic effects of tumor necrosis factor involving the introduction of a tool according to claim 1 at a dose of 0.001-10 mg/kg of body weight at least once a day during the period required to achieve a therapeutic effect.



 

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