RU2406498C2 - Pharmaceutical composition exhibiting anti-inflammatory, particularly antiasthmatic action, applications of pharmaceutical composition (versions) and drug (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to the development of new drugs for inflammatory diseases, particularly asthma. The pharmaceutical compositions under the invention contain 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-oxy-6-bromoindole in the effective amount or its pharmaceutically acceptable salts and/or hydrates as an active ingredient. The drug can be presented in the form of tablets, capsules, injections or aerosol.

EFFECT: provided anti-inflammatory and antiasthmatic action, as well as practically absolute absence of by-effects proper for the formerly known drugs administered for the same intended purpose.

10 cl, 4 tbl, 7 ex

Description

Technical field

The invention relates to the field of medicine, namely to pharmaceutical compositions having anti-inflammatory, in particular anti-asthma activity, for the preparation of pharmaceutical preparations in the form of tablets, granules, capsules, suspensions, solutions, injections or aerosols.

State of the art

Inflammation (inflammatio) is a complex, complex local reaction to tissue damage caused by various factors. Depending on the properties and strength of the influencing factor, the structure and properties of the affected tissue and its reactivity during inflammation, a wide variety of injuries and changes in tissues can occur. In general human pathology, inflammation is considered to be the most important general pathological and, at the same time, biological process. Inflammation is the basis of most human diseases.

Therefore, one of the most important tasks of modern medicine is to identify signs of inflammation at the cellular level, explain the causes and mechanism of development of inflammatory reactions, as well as search for new anti-inflammatory drugs for the treatment of diseases that are based on inflammation.

There are three main ways of developing inflammation:

- with uncomplicated inflammation, the tissue returns to normal life by liquefying and removing exudate and cellular detritus by macrophages and the lymphatic system;

- if tissue inflammation is pronounced during inflammation, then its restoration occurs by regeneration or replacement with connective tissue with the formation of a scar;

- when the damaging agent is not neutralized in the inflammatory response, an immune response develops, which leads to the development of chronic inflammation. The latter case is the most dangerous for the body, as it often leads to the development of chronic diseases.

The meaning of inflammation is twofold. From the biological point of view, this reaction has a protective and adaptive character, it is aimed at destroying the agent that caused the damage, and at restoring the damaged tissue, and this is undoubtedly its positive value. From a clinical point of view, inflammation is a disease or a harbinger of a possible disease. Inflammation, as a local reaction of the body, is characterized not only by local, but also by general manifestations: fever, leukocytosis, changes in the composition of blood proteins, intoxication phenomena, which increase with increasing damage area and the severity of alteration due to the resorption of toxic products and can even lead to death. Chronic inflammation is often associated with tissue necrosis and can lead to serious clinical disorders, such as liver failure in chronic active hepatitis. Chronic inflammation is the basis of a large number of chronic diseases, which are characterized either by insufficient tissue repair, or by a long recovery period (months or years).

Among the diseases caused by inflammatory processes are asthma, chronic obstructive pulmonary disease, hepatitis, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neurodegenerative diseases, etc.

Bronchial asthma is a chronic inflammatory disease of the respiratory tract characterized by a variety of symptoms, such as airway obstruction, bronchial hyperreactivity and inflammation. The interaction of these symptoms determines the clinical manifestations and severity of asthma. Thus, the modern definition of bronchial asthma includes the main provisions that reflect the inflammatory nature of the disease.

Asthma occurs in response to various stimuli, such as antigens, pollutants, cold air, physical exposure. The treatment of asthma is to suppress bronchospasm and inflammation, and also to eliminate the effects of allergens or allergy mediators. The total number of patients with bronchial asthma worldwide is 300 million people. And, despite the achievements of modern medicine, this number is growing, especially among children. In this regard, it is especially important to search for new drugs with pronounced anti-asthma activity, reduce inflammation and bronchospasm.

Currently, glucocorticosteroids, β2-adrenergic agonists, antagonists of leukotriene receptors, xanthines, and also combinations thereof are used to treat bronchial asthma. As the disease develops, sensitivity to the drug used decreases, which makes it necessary to prescribe more and more potent drugs.

The action of glucocorticosteroids, the main group of drugs for the treatment of bronchial asthma, is based on the suppression of the production of anti-inflammatory cytokines, the reduction in the number of inflammatory cells, the suppression of their migration and activation. Glucocorticosteroids are used inhaled or orally. The use of glucocorticosteroids often leads to side effects; with inhalation use - such as hoarseness, candidiasis of the oral cavity and pharynx, skin manifestations, angioedema of the face and oropharynx; with systemic use - bradycardia, arterial hypotension, dizziness, headaches, cramps, nausea, vomiting, the development of a steroid ulcer of the stomach, decreased immunity (for example, see the Vidal Handbook Medications in Russia: Handbook, M .: AstraFarmService, 2002, pp. B-69-73, as well as Wagener M. Neue Entwicklungen in der Asthma therapic, Wie wirken die sinzelnen Leukotrien antagonisten // Schweiz.-Rundsch. Med Prax., 1998, 87 (8), pp. 271-275) . To reduce the risk of side effects, glucocorticosteroids are administered by inhalation. But this necessitates the use of an inhaler, which is inconvenient and requires skill in handling. Glucocorticosteroids for oral administration begin to be prescribed with the ineffectiveness of inhaled glucocorticosteroids. Moreover, bronchial asthma is characterized as steroid-dependent.

In addition to glucocorticosteroids, β2-adrenergic agonists are actively used to treat asthma, which relax the smooth muscles of the bronchi and, thereby, facilitate breathing. β2-adrenergic agonists have their own set of side effects: palpitations, headache, abdominal pain, nausea, vomiting. And if monotherapy with β2-adrenergic agonists is prescribed less and less, combinations of glucocorticosteroids and β2-adrenergic agonists are the most popular drugs for the treatment of asthma and similar symptoms of chronic obstructive pulmonary disease. Such combinations can more effectively relieve the symptoms of the disease. But the use of such combinations is accompanied by frequent side effects characteristic of both groups of drugs. Thus, Glaso-Smith-Klein's Seretide, a third of the US and European markets, causes headaches in every tenth patient. Oral and pharyngeal candidiasis, palpitations, muscle cramps (Seretide Accuhaler. Package Leaflet:

Information for the User).

The action of the following group of drugs, antagonists of leukotriene receptors, is based on blocking the signal of leukotriene receptors, which leads to dilatation of the bronchi and a decrease in inflammation. These drugs are used as an adjunct to basic treatment, for example with glucocorticosteroids, to relieve residual asthma symptoms. Or, more often, for the treatment of asthma in children, since the use of glucocorticosteroids in this case is undesirable due to the negative impact on vision and bone growth (The Asthma, COPD & Allergic Rhinitis Market Outlook to 2011. Business Insights, 2006). Among the side effects of leukotriene receptor antagonists are: abdominal pain, nausea, headache, cough, drug hepatitis (for example, the Vidal Handbook Medications in Russia: A Handbook. M: AstraFarmService, 2002, p. B-17).

Xanthines are also used to reduce bronchospasm. But their use is very limited due to a long list of side effects:

dizziness, headache, insomnia, agitation, anxiety, irritability, tremor, palpitations, tachycardia, arrhythmia, decreased blood pressure, cardialgia, increased frequency of angina attacks, gastralgia, nausea, vomiting, heartburn, exacerbation of peptic ulcer, diarrhea, etc. (for example , Vidal Handbook Medications in Russia: A Handbook. M .: AstraFarmService, 2002, pp. 3-17, 3-290).

Given all of the above, the search for new drugs for the treatment of asthma remains very relevant, since the currently used drugs often do not cover all the clinical manifestations of asthma and have a significant number of side effects.

Currently, in addition to the already known classes of compounds, such as glucocorticosteroids, β ₂ -adrenomimetics, antagonists of leukotriene receptors and xanthines, a sufficiently large number of compounds have been proposed that have activity as anti-asthma agents. For example, derivatives of substituted 3-amino-1H-indole-2-carboxylic acid (WO 03091214, WO 03091215), pyrazoloantrone derivatives (WO 0112609), heterocyclic compounds (WO 020724548), etc.

However, since many of the listed compounds exhibiting anti-asthma activity have not yet been clinically tested, and therefore can only potentially be drugs, we selected the glucocorticosteroid fluticasone (INN), which has proven anti-inflammatory and anti-asthma activity, as the closest analogue.

Fluticasone (trade name Flixotide (Glaxo) is used to treat asthma and chronic obstructive pulmonary disease and belongs to the latest generation of glucocorticosteroids. It is administered by inhalation to reduce the side effects inherent in this class of drugs. Inhalation therapy is inconvenient in itself and requires patient education for accurate dosing of the drug, but even it does not completely avoid the effects of fluticasone. According to published clinical trials (h ttp: //us.gsk.com/products/assets/us_ftovent.pdf) the use of fluticasone led to a number of side effects, including oral irritation (up to 22%), upper respiratory tract infection (up to 21%), and headache (up to 14%).

Disclosure of invention

The technical result of the present invention is the creation of a pharmaceutical composition having anti-inflammatory, in particular anti-asthmatic action with a minimum of side effects, based on an indole derivative, which has a structure different from the structure of compounds traditionally used to treat asthma, which will expand the arsenal of drugs for treatment asthma, chronic obstructive pulmonary disease, as well as other inflammatory diseases.

This result is achieved by creating a pharmaceutical composition having anti-inflammatory and anti-asthma action, for the preparation of pharmaceutical preparations in the form of tablets, granules, capsules, suspensions, solutions, injections or aerosols containing 1-methyl-2-phenylthiomethyl-3-carbethoxy-as an active substance 4-dimethylaminomethyl-5-hydroxy-6-bromoindole, or its hydrates and / or pharmaceutically acceptable salts, as well as a pharmaceutically acceptable carrier and / or excipient.

1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromindole hydrochloride monohydrate (trademark "Arbidol") was previously known as a drug for the treatment of influenza A and B viruses (RF Patent No. 2008004) SARS (RF Patent No. 2256451), rotavirus infection (RF Patent No. 2266742), which also has an immunomodulating effect (RF Patent No. 2033157).

However, to date, it was not known that 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole (hereinafter Compound I) exhibits anti-inflammatory, in particular anti-asthmatic activity, which was first shown by the authors of this invention.

One of the objectives of the present invention is the search for compounds that suppress the activity of the transcription factor NF-κB, which allows, on the basis of the laws known from the prior art, to offer them as drugs for the treatment of diseases directly related to the onset of the inflammatory process by enhancing the transcription of inflammatory protein genes by NF-κB. Similar conditions occur not only in asthma, but also in chronic obstructive pulmonary disease, hepatitis, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, and neurodegenerative diseases. Therefore, based on the presence of a common mechanism for the development of inflammation, we hypothesized that Compound I may become a potential drug with the ability to reduce inflammation in the aforementioned diseases.

In a most general embodiment, the present invention discloses pharmaceutical compositions having anti-inflammatory, in particular anti-asthmatic, active ingredient containing an effective amount of compound I, or its pharmaceutically acceptable salts and / or hydrates.

To obtain a pharmaceutical composition, the distinguishing feature of which is that as the active component use compound I or its pharmaceutically acceptable salts and / or hydrates, preferably mixing the active substance with inert excipients with respect to the substance, followed by tableting, granulation, encapsulation, suspension, dissolution or dilution and placed in a suitable package,

The dosage of a pharmaceutical composition containing compound I as an active ingredient in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body. In addition, the effective dose may also depend on the weight, age, gender of the patient and the presence of concomitant diseases. The daily dose in adults may be 10-1000 mg, preferably 50-250 mg. In accordance with the instructions of the doctor, this drug can be taken several times a day, for example, from one to five times, preferably from one to three times.

The term "pharmaceutically acceptable salt" means sufficiently non-toxic organic and inorganic salts of acids and bases commonly used for these purposes. In particular, such salts can be prepared starting from the free base of the claimed compound and the corresponding organic or inorganic acid. The most preferred salt options are: hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, mesylates, tosylates, citrates, benzenesulfonates, etc. (A more detailed description of the properties of such salts can be found in Pharmaceutical Salts, J. Pharm. Sci. 1977, 66: 1-19). The term “pharmaceutically acceptable salts” also includes pharmaceutically acceptable solvates, preferably hydrates.

The term "pharmaceutical composition" means a composition comprising compound I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible carriers, excipients, excipients, solvents or diluents, delivery vehicles, preservatives, stabilizers and other targeted additives, as shown, for example, in the "Handbook of Pharmaceutical Excipients" (2 "ed. London: The Pharmaceutical Press; 1994). Humidifiers, emulsifiers, zagu can also be used as excipients. colorants, sweeteners, flavors, flavors, sustained release regulators (e.g., aluminum monostearate and gelatin), suspending agents (e.g., ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, and also mixtures of these substances) fillers like lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate; shredders such as starch, alginic acid and its salts, silicates; antibacterial and antifungal agents (e.g. parabens, chlorobutanol, sorbic acid).

Compositions intended for injection may also include isotonic agents, for example, sugar, sodium chloride, and the like. Suitable carriers, solvents, diluents and delivery vehicles may include: water, ethanol, various polyalcohols, as well as water-alcohol, vegetable oils and injectable organic esters (e.g. ethyl oleate).

Compositions used as aerosols may additionally contain surfactants, propellants, etc.

These excipients can be used in combination with other active ingredients, provided that they do not cause unwanted effects, such as allergic reactions.

The pharmaceutical composition can be used for oral, sublingual, intramuscular, intravenous, subcutaneous, local or rectal administration. Suitable unit dosage forms include: tablets, capsules, pills, powders, granules, chewing gums, solutions or suspensions, aerosols, implants, drops, suppositories, ointments.

The invention is illustrated, but not limited to the following examples. Example 1. Inhibition of the activity of transcription factor NF-κB.

The experiment was performed on κBZ Jurkat cells transformed with the β-galactosidase gene under the control of an enhancer that binds to NF-κB, similar to the experiment set forth in J. Karttunen and N. Shastri (1991). Measurement of ligand-induced activation in single viable T cells using the lacZ reporter gene. PNAS 88 (9), 3972-3976. Compound I was added to the culture medium at concentrations from 0.001 to 10 μM. NF-κB was activated by incubation with A23187 and PMA for 4 hours. The resulting IC ₅₀ (the concentration of compound I needed to inhibit 50% of the receptor) is 3.54 μM.

This example confirms that compound I has the ability to inhibit the NF-κB receptor and thereby the ability to block the inflammatory response.

Example 2. Anti-asthma activity of a pharmaceutical composition containing compound I as an active substance.

Compound I was tested on a model of asthma caused by sensitization by ovalbumin. Compound I and the dexamethasone reference drug were administered orally to mice (male BALB / c, 10 animals in the group, 22 ± 2 grams, 5-6 weeks old) for six days in parallel with sensitization with 5% ovalbumin, which was administered by inhalation for 25 minutes in 1, 3 and 5 days 1 hour after the administration of drugs. On the sixth day, 1 hour after drug administration, an asthma attack was stimulated by inhalation of methacholine. Dexamethasone is selected only as a traditional positive control for experiments of this kind. Being the most potent glucocorticosteroid, dexamethasone is rarely used for asthma therapy, as it has a lot of side effects.

To assess the effect of drugs, plethysmography was used. When plethysmography on special equipment, the pressure on the inhale and on the exhale, the temporary parameters of respiration are measured. The dimensionless complex index Pehn is derived from them.

Table 1 Treatment Dose Pehn Before stimulation with methacholine Metacholine Stimulation 10 mg / ml Metacholine Stimulation 30 mg / ml No sensitization 1.249 ± 0.115 4,482 ± 0,519 8,100 ± 0,751 Placebo 1.459 ± 0.092 14.852 ± 1.777 29.883 ± 2.873 Dexamethasone 3 mg / kg 1,332 ± 0,107 5.382 ± 0.902 12.818 ± 4.476 Compound I 50 mg / kg 1,196 ± 0,097 9.194 ± 2.444 16.983 ± 3.373 Compound I 100 mg / kg 1.458 ± 0.185 9.801 ± 1.036 12.517 ± 1.680

By reducing the Pehn index relative to placebo, the effectiveness of the drug is judged. The effectiveness of therapy through the Pehn index was calculated by the formula:

table 2 Treatment Dose Efficiency Metacholine Stimulation 10 mg / ml Metacholine Stimulation 30 mg / ml Placebo 0,0% 0,0% Dexamethasone 3 mg / kg 96.1% 79.1% Compound I 50 mg / kg 49.7% 50.6% Compound I 100 mg / kg 50.7% 84.8%

As a result of the experiment, a significant improvement in respiration was shown.

Example 3. Anti-inflammatory activity of a pharmaceutical composition containing compound I as an active substance.

The animals used in the experiment from the previous example were taken samples of bronchoalveolar fluid for analysis on the content of cells and inflammatory cytokines.

Table 3 Treatment Dose The number of cells in the bronchoalveolar fluid (thousand / μl) Total amount Neutrophils Lymphocytes No sensitization 0.17 ± 0.01 0.09 ± 0.00 0.00 ± 0.00 Placebo 2.54 ± 0.32 0.34 ± 0.02 0.29 ± 0.03 Dexamethasone 3 mg / kg 0.41 ± 0.08 0.14 ± 0.02 0.03 ± 0.01 Compound I 50 mg / kg 1.09 ± 0.15 0.26 ± 0.04 0.05 ± 0.00 Compound I 100 mg / kg 1.02 ± 0.20 0.25 ± 0.04 0.06 ± 0.01

Continuation of Table 3 Treatment Dose The number of cells in the bronchoalveolar fluid (thousand / μl) Monocytes Eosinophils Basophils No sensitization 0.09 ± 0.09 0.00 ± 0.00 0.00 ± 0.00 Placebo 0.65 ± 0.07 1.27 ± 0.21 0.00 ± 0.00 Dexamethasone 3 mg / kg 0.18 ± 0.05 0,07 ± 0,02 0.00 ± 0.00 Compound I 50 mg / kg 0.43 ± 0.06 0.35 ± 0.05 0.00 ± 0.00 Compound I 100 mg / kg 0.41 ± 0.09 0.30 ± 0.10 0.00 ± 0.00

Table 4 Treatment Dose The content of cytokines in the bronchoalveolar fluid (PG / ml) Interleukin 5 Interleukin 13 No sensitization 0.00 0.00 Placebo 65.36 ± 20.94 253.16 ± 97.11 Dexamethasone 3 mg / kg 10.17 ± 3.81 21.51 ± 7.27 Compound I 50 mg / kg 27.79 ± 7.15 103.72 ± 22.62 Compound I 100 mg / kg 15.71 ± 3.74 71.27 ± 11.84

As can be seen from the results, compound 1 significantly reduces the number of cells and inflammatory cytokines, compared with placebo, thereby demonstrating a decrease in inflammation.

Example 4. Obtaining a pharmaceutical composition for the preparation of tablet mass.

A mixture is prepared consisting of 0.5 kg of compound I; 2.26 kg of potato starch; 5.5 g of polyvinylpyrrolidone; 11.5 g of methyl cellulose; 7 g of calcium stearate; 0.10 g of stearic acid. The mass obtained after mixing is used for tabletting.

Example 5. Obtaining a pharmaceutical composition for the preparation of capsules containing 100 mg of active substance.

100 g of compound I are thoroughly mixed; 28 g of potato starch; 59 g of microcrystalline cellulose; 2 g of silicon dioxide; 9 g of collidone 25; 2 g of calcium stearate. The prepared powder mixture is packaged in 200 mg in a suitable size gelatin capsule.

Example 6. Preparation of a pharmaceutical composition for injection. To 100 ml of the prepared solution of 0.9% sodium chloride, 1 g of compound I was added with stirring. The resulting solution was filtered. The finished product is ampouled and used for intramuscular and intravenous injection.

Example 7. Preparation of an aerosol.

To a perfluorodecanoic acid (2 mg) contained in a glass aerosol ampoule, a cooled propellant, for example trichlorormonofluoromethane, dichlorotetrafluoroethane, dichlorodifluoromethane and the like, is added. in an amount of 36 g. Then, a finely ground powder of compound I (100 mg) is added and the metering valve is screwed. The procedure is performed in a dry box.

Claims (10)

1. The use of 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole or its pharmaceutically acceptable salts and / or hydrates as an active component of pharmaceutical compositions having anti-inflammatory activity. 2. The use according to claim 1, characterized in that the pharmaceutical composition has anti-asthma activity. 3. The use according to claim 1 or 2, characterized in that the active ingredient of the pharmaceutical composition is 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate in an effective amount. 4. The use of 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole or its pharmaceutically acceptable salts and / or hydrates for the preparation of a medicinal product intended for the treatment of diseases based on inflammatory process, including: asthma, hepatitis, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neurodegenerative diseases. 5. A pharmaceutical composition having anti-inflammatory activity, containing as active ingredient 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole in an effective amount or its pharmaceutically acceptable salts and / or hydrates. 6. The pharmaceutical composition according to claim 5, characterized in that the active ingredient of the pharmaceutical composition is 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate in an effective amount. 7. The pharmaceutical composition according to claim 5, having anti-asthma activity. 8. The pharmaceutical composition according to claim 7, characterized in that 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate in an effective amount is used as the active component of the pharmaceutical composition. 9. A medicine in the form of tablets, capsules, injections or an aerosol for the treatment of inflammatory diseases, obtained on the basis of the pharmaceutical composition according to claims 5 and 6. 10. A medicine in the form of tablets, capsules, injections or aerosol for the treatment of asthma, obtained on the basis of the pharmaceutical composition according to claims 7-8.