Geroprotecting agent based on hydrogenated pyrido[4,3-b]indoles (variants), pharmacological agent based on thereof and method for its using

FIELD: organic chemistry, medicine, gerontology.

SUBSTANCE: invention relates to using hydrogenated pyrido[4,3-b]indoles of the formula (1) and the formula (2) as an agent for prophylaxis of premature aging. Also, invention relates to a pharmacological agent based on thereof possessing with the geroprotective activity and to a method for prophylaxis of premature aging.

EFFECT: valuable medicinal properties of agents.

20 cl, 6 dwg, 5 tbl, 2 ex

 

The invention relates to the use of chemical compounds in the field of medicine and can be used as a geroprotective tool in the manufacture of pharmaceutical preparations for the prevention of premature aging of the body and prolong life and improve its quality by reducing the number and intensity of pathologies that are compatible with life, characteristic of elderly and senile age.

Elderly age is characterized by a significant increase in the probability of death. In addition, dramatically increases the probability of the manifestations of various pathologies, compatible with life, decreasing its quality. In mammals such pathologies include, in particular, loss of vision (cataract), deterioration of skin and hair (alopecia), senile weight loss due to loss of muscle and fat cells.

In recent years, the world has seen considerable interest in the search for new drugs and tools aimed at addressing this problem.

Increased life expectancy in the experiment vitamins a, C. E. (Baker G.T. Effect of varios antioxidants on aging in Drosophila // Toxicol Ind. Health. - 1993 - Vol.9. - P.163-186). However, the oversaturation of the body with these vitamins can lead to rapid development of hypervitaminosis and adversely affect the functional state of organs and systems./p>

Known drugs, manifesting geroprotective and anti-oxidant activity on the basis of idoxifene (Santorin). Introduction to food increased the lifespan of mice SN (Comfort A., Youhotsky-Gore J., Pathmanatchan K., Effect of ethoxyquin on the longevity of C3H mice // Nature. - 1971. - Vol.229. - R-255). The lifespan of laboratory animals was also increased when receiving a low water - soluble antioxidant hydrochloride 2-ethyl-6-methyl-3-oksipiridina, a structural analogue of vitamin B6 (Obukhov L.K. Chemical geroprotectors, life extension // USP. Chemistry - 1975. - T.44 - c.1914-1925.) A slight increase in life expectancy was observed in experiments with 2-mercaptoethylamine, cysteine, centrophenoxine, butylhydroxytoluene, glutathione, 3-hydroxypyridine, lactic and gluconic acids (Frolkis CENTURIES, Muradyan H.K.RAKISHEV Experimental ways of prolonging life. - Leningrad, Nauka, 1988; Obukhov L.K., Emmanuel NM Molecular mechanisms of anti-aging antioxidants // General problems of biology. / VINITI. - v.4, - p.44-80.)

However, these chemical compounds not found their application in medicine as a drug.

As geroprotective tools used drug containing procaine, Gerovital (Mashkovsky PPM Drugs - M.: Medicine, 1993, - part 1, p. - S). However, it is sometimes possible manifestation of its negative effects on the function of the cardiovascular system, the deterioration of sleep, cause feelings of anxiety, pain in muscles and joints.

Compounds with geroprotective properties opened in recent years are endogenous substances melatonin and N-acetylserotonin (NAC). These compounds possess anti-oxidant and one theory of the mechanism of aging must have geroprotective action (Heng-long Hu, Forsey RJ Blades T.J., Barratt R.W., watts, m.e.j., Parmar, P., Powell J.R. Antioxidants may contribute in the fight against ageing: an in vitro model. Mechanisms of Ageing and Development 121 (2000) 217-230). Indeed, in experiments on mice S/it was shown that melatonin and its precursor NAC can increase the life span of males, if they are received from the age of 2 months. At the same time, these substances were not effective in experiments with females of this line, if they received them from the age of 12 months (G. Oxenkrug, Requintina P., Bachurin S. Antioxidant and Anti-Aging Activity of N-Acetylserotonin and Melatonin in the in vivo models. Ann.N.Y Acad. Sci. 2001, v.939, 190-199).

The task to be solved by the invention, is expanding Arsenal of tools that can be used as a new effective geroprotectors, prolonging life and improving its quality.

The problem is solved by the use of hydrogenated pyrido ([4,3-b]indoles form the s (1) or formula (2) as a means to prevent premature aging - of the preparation of a mammal

In the case of using compounds of formula (1) R1choose from the group consisting of CH3-, CH3CH2or PhCH2;

R2choose from the group consisting of H, PhCH2or 6-CH3-3-PY-(CH2)2-;

R3choose from the group consisting of N, CH3- or Br- (this wording means that the combination of these radicals can be any).

These compounds may be a salt with pharmaceutically acceptable acids.

One of the compounds that can be used as a geroprotector, may be the compound of formula (1)in which R' represents CH3-, R2-N-, and R3- CH3-.

This compound is in the form (±) CIS-isomer

In the case of using compounds of the formula (2) R1choose from the group consisting of CH3-, CH3CH2or PhCH3-,

R2choose from the group consisting of H, PhCH2- or 6-CH3-3-PY-(CH2)2-and

R3choose from the group consisting of N, CH3- or Br-.

These compounds are salts with pharmaceutically acceptable acids.

One of the compounds that can be used as a geroprotector, may be the compound of the formula(2), in which R1corresponds CH3CH2or PhCH2-, R2corresponds to N, and R3'N'.

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

Or connection, where R1corresponds CH3-, R2match 6-CH3-3-PY-.

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- N or CH3-.

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

Any of the above compounds can be used as a geroprotector for humans, in particular to prevent cataracts, as well as, in particular, to prevent alopecia.

The compounds of formula (1) and (2) are known compounds, are widely used in pharmacological practice. Extensive investigations have been made of a number of known compounds which are derivatives of Tetra - and hexahydro-1H-pyrido[4,3-b] indole and exhibiting a wide range of biological activity. In a series of 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles were detected following types of activity: antihistamines (OS-DE No. 1813229 from December 6, 1968, No. at 20 October 1969), Central depressanta, anti-inflammatory (USP No. 3718657 December 13, 1970), adjunct (Herbert C.A., Plattner S.S., Wehch N. W., Mol. Pharm., 1980, v.17, No. I, p.38-42) and others. Derivatives of 2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b] indole are psychotropic W.H. Welch, Herbert CA, Weissman A., CFU C.V., J.Med.Chem., 1986, vol.29, No. 10, R-2099), antiaggressive, anti-arrhythmic and other activities.

Based on the derivatives of Tetra - and hexahydro-1H-pyrido[4,3-b] indole produced several medicines: diasorin (mebhydroline), Dimebon, Dorsten, carbides (decarbon), Slobodin, Genotropin. Diasorin (2-methyl-5-benzyl-2,3,4,5-Tetra-hydro-1H-pyrido[4,3-b]indole) dihydrochloride (Klyuev M.A. Medicines used in medical practice of the USSR. - M.: Medicine, 1991, str) and Dimebon (dihydrochloride 2,8-dimethyl-5-(2-(6-methyl-pyridyl-3)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole) (Mashkovsky PPM Medicines. In 2 hours, part 1, 12th ed. - M.: Medicine, 1993, p.383), and its close analogue of Dorsten (2-methyl-8-chloro-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole) dihydrochloride (USAN and USP dictionary of drugs names (United States Adopted Names 1961-1988, current U.S. Pharmacopeia and National Formular for Drygs, and other nonproprietary drug names), 1989, 26th Edition, p.196) known as antihistamines. Carbide (decarbon) - dihydrochloride Cys(±)-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole is otechestvenny a neuroleptic with antidepr santim effect (Yakhontov, L.N., Glushkov RG Synthetic drugs. Edited Agiotage. - M.: Medicine, 1983, s -237), and its (-)-isomer, storedin known as an antiarrhythmic agent (Kitlova M, Gibela P., Drimal J., Bratisi. Lek. Listy, 1985, V.84, No. 5, R-546); Genotropin (dihydrochloride 8-fluoro-2-(3-3-pyridyl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole) is an antipsychotic and anxiolytic agent (Abou-Gharbi M, U.R. Patel, M.B. Webb, Moyer J.A., Ardnee T.N., J.Med.Chem., 1987, v.30, p.1818-1823).

In recent years, it has been found that derivatives of hydrogenated pyrido[4,3-b] indoles of formula (1) or (2), in particular Dimebon also possess properties antagonists of NMDA receptors, which makes them useful for treatment of neurodegenerative diseases, especially Alzheimer's disease (patent RF №2106864 C1, MKI 6 And 61 To 31/475, 20.03.98, bull. No. 8).

All the above compounds are known from the literature and include the following specific compounds:

1. Cys (±) 2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido/4,3-b/indole and its dihydrochloride;

2. 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

3. 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

4. 2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its hydrochloride;

5. 2-methyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its monohydrate sesquisulfate;

6. 2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its dihydro what lore (Dimebon);

7. 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8. 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its methyliodide;

9. 2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its hydrochloride.

About obtaining and neuroleptic properties connection 1 is known, for example, from the publication: Yakhontov LN. and Glushkov RG Synthetic drugs. Ed. Agiotage. - M.: Medicine, 1983, str-237. The formation of compounds 2, 8 and 9, as well as information about what they have properties of serotonin antagonists are described, for example, C.J.Cattanach, A.Cohen & B/H/Brown in J. Chem.Soc. (ser.C), 1968, 1235-1243. Synthesis of compound 3 is described, in particular, article N.P.Buu-Hoi, O.Roussel, P.Jacquignon, J.Chem.Soc., 1964, No. 2, str-711. Nefkwoorbu and Nccadv in "General chemistry", 1956, t, str-3154 describe the synthesis of compounds 4 and about how to obtain the compounds 5 and 6 is known, for example, from the article Angot, Mauresque, Tveritnikova in "Chemistry of heterocyclic compounds", 1973, N 2, str-212. In publications U.Horlein, Chem.Ber., 1954, Bd. 87, hft. 4, 463-472 describes the synthesis of compound 7. Mauresque, Illarionov in "Chemistry of heterocyclic compounds", 1981, No. 8, str-1078 describe getting under the conditions of the connection 8.

It has been unexpectedly found that the compounds of formula (1) and formula (2) are anti-calcium activity. In particular, it was found that these compounds are able to inhibit the entry of calcium ions into the ner the data cells, stimulated by activation of glutamate receptors. On the other hand, it is known that hypernormal an increase in the concentration of calcium ions in cells initiates a cascade of degenerative processes that accompany the aging process and the development of related degenerative diseases. Disturbance of calcium homeostasis underlies the so-called calcium theory of aging and dementia (Calcium Hypothesis of Ading and Dementia. Ann. N.Y.Acad.Sci., 1994, v.747).

Thus, the compounds of formula (1) and formula (2) due to the discovery of new and unexpected properties that are not derived from the chemical structure of these compounds, can be used as geroprotectors.

According to the invention, the pharmacological agent with geroprotective activity, containing the active principle and a pharmaceutically acceptable carrier as the active agent contains an effective amount of hydrogenated pyrido (4,3-b) indole of the formula (1) or formula (2)

The concept of "geroprotective activity"as used in this application means a biologically active, slow aging and prolong life by preventing premature aging and improve water quality by reducing the number and intensity of pathologies that are compatible with life, characteristic of elderly and senile age, so is x as loss of vision (cataract), the deterioration of the skin and hair (alopecia), senile weight loss due to loss of muscle and fat cells.

The term "pharmacological agent" means the use of any pharmaceutical form containing the compound of formula (1) or formula (2), which could find a prophylactic or therapeutic use in medicine as a means to geroprotective activity for the prevention of aging.

The term "effective amount", as used in this application involves the use of a number of compounds of the formula (1) or formula (2), 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) or formula (2) 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.

According to the invention a method of preventing premature aging is the introduction to the patient a pharmaceutical containing an effective amount of hydrogenated pyrido[4,3-b] indoles of formula (1) or formula (2)at a dose of 1-10 mg/kg of body weight at least once a day during the period required to achieve a prophylactic effect.

The compounds of formula (1) or formula (2) may be introduced mammals in the form of conventional oral compositions, such as tablets, coated tablets, gelatin capsules, hard and soft coating, emulsion or suspension. 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, moreover, the pharmaceutical preparations 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 properties. Preparative form can be a standard dose and can be prepared with known pharmaceutical methods.

The technical result that can be obtained by carrying out the invention are considerably prolong life and improve its quality by reducing the number and extent of integration is cunosti pathologies, compatible with life, typical for middle-aged and elderly, in particular, loss of vision (cataract), deterioration of skin and hair (alopecia), senile weight loss due to loss of muscle and fat cells.

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 information.

Example 1. Determination of calcium-blocking properties of the compounds hydrogenated pyrido ([4.3-b]indoles of formula (1) or formula (2).

Evaluation of the calcium-blocking properties of the compounds were carried out at P2-fraction synaptosomes structures isolated from the brain of the newborn (8-11 days) rats according to the following procedure [Bachurin S. and al: Neuroprotective and cognition enhancing properties of MK-801 flexible analogs. Structure-activity relationships. // Ann. N.Y Acad. Sci. 2001, v.939, P.219-235]. This was determined by the ability of compounds to inhibit the specific capture of calcium ions through the ion channels associated with glutamate receptors.

Synaptosome were placed in incubation buffer (132 mM NaCl, 5 TM KCl, 5 mM HEPES) and was maintained at a temperature of 0°during the whole experiment. The aliquots synaptosomes structures (50μl) were placed in a medium containing the analyte and the preparation of the radioisotope45Sa. The capture of CA2+stimulated by the introduction of a mixture of 20 μl of 10 mM solution of glutamate. After minutei incubation at 30° The process was stopped by filtration through GF/B filters, washing three times with cold buffer solution (145 mM KCl, 10 mM Tris, 5 mM Trilon B), after which the scintillation counter "SL-4000 Intertechnic" was carried out for detection of radioactive labels. Primary testing of the substances was carried out at the concentration of the substance in 5 μm. Specific capture of CA2+was measured by the following formulas:

(43/21)=[(CA4-Sa)/(Ca2-CA1)]·100%,

where CA1 - capture of CA2+in the control experiment (without glutamate and test substance);

Ca2 - capture of CA2+- in the presence of glutamate (glutamate-induced seizure CA2+-Gissa)

Sa - capture of CA2+- in the presence of a test substance (without glutamate).

CA4 - capture of CA2+in the presence of glutamate, and the test substance.

The results of the experiment are presented in table 1.

Table 1

The influence of the studied substances on glutamate-induced seizure45CA2+in synaptosome rat brain
No.Structure% Sa control
1Cys (±) 2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-IH-pyrido[4,3-b]indol the dihydrochloride40,5±1,0
22-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 36,5±0,5
32-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole28,5±2,5
42,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride22,5±3,5
52-methyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole monohydrate of sesquisulfate33,5±1,5
62,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol the dihydrochloride (Dimebon)48,5±2,5
72-methyl-2,3,4,5-tetrahydro-1H-pyrido/4,3-b/indole35,5±2,5
82,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol methyliodide18,0±2,5
92-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride;30,0±3,0

As can be seen from the table, all the studied compounds have a pronounced calcium-blocking properties, which allows them to claim under the above calcium theory of aging and dementia (Calcium Hypothesis of Ading and Dementia. Ann. N.Y.Acad.Sci., 1994, v.747) to use as geroprotectors.

Example 2. Data geroprotective activity of Dimebon.

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

which has been tested by us as compounds which prolong life and improve quality of life (which was characterized by the change in the number of pathology associated with aging) of experimental animals.

The experiments were conducted on female line S/starting from the age of 12 months. The mouse was in the cells for 10 pieces each. In the control and experimental groups were 50 animals. Animals had free access to water and food. Cycle day - night consisted of 12 hours.

You have previously determined what quantity of water consumed by the animals in one cage per day, for 7 days. Dimebon was dissolved in drinking water to the animals received it in an average dose of 3 mg/kg per day. Bottle portion of Dimebon were placed in cells every 7 days. Animals in the control group received normal drinking water.

Before beginning the experiment, all animals were weighed, was defined as the average weight of each group, in each cell, the weight of all animals in each cage. Was the condition of their skin and hair, the presence of eye damage. All animals at the beginning of the experiment looked healthy and had no visible damage. Measurements of all of these performance parameters is of n each month.

Statistical processing was performed using T-test t-test and criterion χ2("Chi-square").

Results.

The duration of life.

Parameter estimation of the duration of life of animals produced by the methods adopted in demography. This criterion is the probability of death for each age group. The results are presented in table 2.

Table 2

Change in the number of animals (mice SW, females)receiving Dimebon in the amount of 3 mg/kg per day (experience) and receiving drinking water (control), depending on their age
Age1213141516171819202122232425
Experience5050494847474239353228251811
Control5050504642413736222219 15116
The top row is the age of animals in months; lower rows - the number of live animals.

As can be seen from table 2, the death of animals began at the age of 14 months, i.e. within 2 months after the start of the experiment. During the whole time of the experiment from 12 to 26 months of animal life (except for 14 months) the number of animals in the experimental group was greater than in the control. In other words, the probability of death in the case of the use of Dimebon was lower in almost all age groups. In the age group 20-23 months this difference was statistically significant (p<0.05).

Weight change of animals

During the whole time of the experiment is the reduction of body weight in the control group of animals. This phenomenon is a natural character and is called senile weight reduction. In the group of animals receiving Dimebon, this weight loss was not observed (table 3). Weight loss in the experimental group only began on the 23rd month of life animals, but in this case, the weight was higher than in the control group. However, this difference in weight was not the nature of confidence (p>0.05).

Table 3

Weight change of mice depending on what atrasta and application of Dimebon.
Age1213141516171819202122232425
Experience24.724.724.72625.524.725.5262625.625.124.72423.7
Control25.324.724.324.624.523.524.223.523.823.223.72322.822.2
The top row is the age of the mice in months, lower the weight in grams

Impaired vision

Impaired vision in the form of a cataract in one or both eyes was observed in the control group within one month after the beginning of the experiment (photo 1). The number of such animals in this group was growing rapidly with each subsequent month. In the group of animals receiving Dimebon (table 4), these animals were significantly lower (p<0.05 for 13-20 months).

Table 4

Visual impairment (cataract) in mice depending on the age and use of Dimebon.
Age12131415161718192021
Experience00046610131725
Control044111930PpmPpmM.D.Ppm
The top row is the age of the mice in months, the lower ranks - % of mice with cataracts. Ppm - little data.

From the 18th of the month was to increase the number of animals with cataracts and in the experimental group. However, for the last 18-21 months comparison between control and experimental groups was hindered by the fact that many mouse cataract in the control group died, and the pilot had left to live.

The condition of skin and hair.

Also starting with the first month of the experiment in the control group animals appeared violation skin and hair in the form of probles is h, the so-called alopecia (photo 2). The size of these holes ranged in these animals from 1 to 25% of the body surface. The difference in the number of animals with alopecia in the control and experimental groups was for 13 to 21 months (table 5). The difference was statistically significant (p<0.05).

Table 5

Violation skin and hair in mice depending on the age and use of Dimebon.
Age12131415161718192021
Experience0026102012143435
Control02213212432375560
The top row is the age of the mice in months, the lower ranks - % of mice with alopecia.

Further, as in the case of cataract, the number of animals with alopecia in the control group decreased due to the mass death of these animals, while in the experimental g is the group of such animals remained alive.

The data shown in tables 1-4, for clarity, are presented in the form of graphs (Fig.1-4) and photo (1,2). Figure 1. the change in the number of animals (mice SW, females)receiving Dimebon in the amount of 3 mg/kg per day (experience) and receiving drinking water (control), depending on their age. Figure 2. shows the change in the weight of mice depending on the age and use of Dimebon. Figure 3. presents visual impairment (cataract) in mice depending on the age and use of Dimebon. Figure 4. presented violation skin and hair in mice depending on the age and use of Dimebon. Photo 1 shows a view of the control animal with impaired vision in the form of a cataract in one or both eyes within 2 months after the start of the experiment. Photo 2 shows a comparison of appearance of bald spots and hair) for the control group of mice (a) and mice treated daily Dimebon in a dose of 1 mg/kg (B) 18 months after the start of the experiment.

The results obtained suggest that Dimebon statistically significantly reduces the probability of death in older animals. In the case of the use of Dimebon statistically in older animals slows down the development of the (reduced) level of pathology that does not lead to death, such as loss of vision and Arsenie skin and hair. The weight loss of the animals, which is a characteristic feature of aging in the group of animals treated with Dimebon, is much slower than in the control group of animals. Thus, Dimebon increases the life expectancy of animals, reduces the probability of non-fatal senile pathology. In other words, improving the quality of life of older animals. All this suggests that Dimebon along with its ability to provide a therapeutic effect in Alzheimer's disease is an effective preparation.

1. The use of hydrogenated pyrido(4,3-b) indoles of formula (1) as a means to prevent premature aging of the preparation of a mammal

in which R1selected from the group consisting of CH3-, CH3CH2or PhCH2;

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

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

2. The use according to claim 1, where R1corresponds CH3-, R2-N-, and R3-CH3-.

3. The use according to claim 2, where the connection is in the form (±) CIS-isomer.

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

5. PR is a change in any one of claims 1 to 4, where specified mammal is man.

6. The use according to any one of claims 1 to 4, where the compound of formula (1) is used, in particular, for the prevention of cataract.

7. The use according to any one of claims 1 to 4, where the compound of formula (1) is used, in particular, to prevent alopecia.

8. The use of hydrogenated pyrido (4,3-b) indoles of formula (2) as a means to prevent premature aging of the preparation of a mammal

in which R1selected from the group consisting of CH3-, CH3CH2or PhCH2;

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

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

9. The use of claim 8, where R1corresponds CH3CH2or PhCH2-, R2corresponds to N, and R3'N'.

10. The use of claim 8, where R1corresponds CH3-, R2corresponds PhCH2-, and R3-CH3-.

11. The use of claim 8, where R1corresponds CH3-, R2match 6-CH3-3-PY-(CH2)2-, and R3'N'.

12. The use of claim 8, where R1corresponds CH3-, R2match 6-CH3-3-PY-(CH2)2-, and R3-CH3-.

13. The use of claim 8, where R1 corresponds CH3-, R2corresponds to N, and R3-H or CH3-.

14. The use of claim 8, where R1corresponds CH3-, R2corresponds to the N-and R-Br-.

15. The use of claim 8, where these compounds are salts with pharmaceutically acceptable acids,

16. The use according to any one of p-14, where the specified mammal is man.

17. The use according to any one of p-14, where the compound of the formula (2) apply, in particular, for the prevention of cataract.

18. The use according to any one of p-14, where the compound of the formula (2) apply, in particular, to prevent alopecia.

19. Pharmacological tool with geroprotective activity, containing the active principle and a pharmaceutically acceptable carrier, characterized in that the active agent contains an effective amount of the compounds of formula (1) or formula (2).

20. The way to prevent premature aging, which consists in the introduction to the patient a pharmaceutical containing an effective amount of the compounds of formula (1) or compounds of formula (2) in a dose of 0.1-10 mg/kg of body weight at least once a day during the period required to achieve a prophylactic effect.



 

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1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using one or some unsubstituted or substituted fumaric acid monoalkyl and dialkyl esters as a specific inhibitor of transcription NF-kappa B-dependent gene as a component of pharmaceutical composition used in treatment of NF-kappa B-mediated diseases. Diseases are chosen from the group consisting of diffuse systemic scleroderma, syphilitic osteochondrotis (Veger's disease), Cutis marmorata, (Livedo Reticularis), Behcet's disease, panartheriitis, nonspecific ulcerous colitis, vasculitis, osteoarthritis, gout, arteriosclerosis, Reiter's syndrome, broncho-pulmonary granulomatosis, encephalitis types, endotoxic shock (septic-toxic shock), sepsis, pneumonia, encephalomyelitis, nervous-psychic anorexia, Rennert's T-lymphomatosis, mesangial nephritis, post-angioplasty restenosis, cytomegalovirus retinopathy, adenoviral diseases, such as adenoviral cold diseases, adenoviral pharyngo-conjunctival fever and adenoviral ophthalmia, AIDS, Guillain-Barr syndrome, post-herpetic neuralgia or neuralgia after shingles, inflammatory demyelinizing polyneuropathy, multiple mononeuropathy, mucoviscidosis, Bekhterev's disease, Berret's esophagus ulcer, infection with Epstein-Barr virus (EBV), cardiac re-modeling, interstitial cystitis, diabetes mellitus type II, radio-sensitized malignant tumors, partial resistance of malignant cells to chemotherapeutic agents (resistance to many medicinal agents used in chemotherapy), ring-shaped granulomas and oncological diseases, such as breast cancer, colon cancer, melanoma, primary carcinoma of liver cells, adenocarcinoma, Kaposi's sarcoma, prostate cancer, leukosis, such as acute myeloid leukosis, multiple myeloma (plasmocytoma), Burkitt's lymphoma and Kastleman's tumor. The selective inhibition of indicated receptors provides carrying out the suppression of inflammation in treatment of above enumerated diseases.

EFFECT: valuable medicinal properties of substances.

10 cl, 2 tbl, 7 ex

FIELD: medicine, cosmetics.

SUBSTANCE: invention relates to a composition used for enhancing the growth and/or hardening breast tissue, and/or for inhibition of growth of benign callosities in breast tissue, and/or for promoting in their treatment. The claimed composition comprises hop, L-ornithine, rye, buckwheat, malt and barley taken in the following ratio, wt.-%: hop, 25-40; fennel, 1-10; buckwheat, 5-15; rye, 1-10; barley, 20-35; malt, 5-15, and L-ornithine, 5-15. The composition can be made as a suitable tabletted formulation and it is prepared from natural components. Also, invention relates to a method for preparing a solution of suspension used for enhancing the growth and/or hardening breast tissue, and/or inhibition of the growth of benign callosities in breast tissue, and/or for promoting in their treatment wherein the claimed composition as a tabletted formulation is mixed with water.

EFFECT: valuable medicinal and cosmetic properties of composition.

5 cl, 3 tbl, 9 ex

FIELD: biology, embryology.

SUBSTANCE: invention relates to a method for controlling oocytes quality and a composition for addition in medium for culturing oocytes. Method for controlling the oocytes quality involves placing at least one oocyte in cultural medium and carrying out culturing. The cultural medium comprises at least one anti-sense oligonucleotide of length 17-30 nucleotides wherein each of them is complementary to mRNA of at least one of the following genes: gene-inductors of apoptosis, such as HRK, FAS, FASL, BAX, Caspase-3, genes of growth factors, such as IGF1, gene-receptors of growth factors, such as IGF1R, genes regulating the dividing embryos rate, such as HLA-E, HLA-F, HLA-G, genes of cellular stress, such as HSF1 and HSF2. The composition added in cultural medium comprises one or more an anti-sense oligonucleotide describes above and acceptable solvent. The advantage of invention involves enhancing the quality and viability of oocytes and enhancing the therapeutic effectiveness in treatment of sterility.

EFFECT: improved controlling method, improved properties of composition.

15 cl, 2 dwg, 10 ex

FIELD: medicine, gastroenterology, pharmacology.

SUBSTANCE: invention relates to compositions comprising a substance possessing regulating activity, for example, inhibition of proliferation of cells expressing AILIM, for suppression of onset of intestine inflammatory diseases, in particular Crohn's disease, and colitis. Invention provides enhancing the therapeutic effect.

EFFECT: valuable medicinal properties of agents.

10 cl, 12 dwg, 2 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with treating acute anterior and posterior ischemic optic neuropathy due to introducing vasodilators and anticoagulants as caffeine, halidor, dicinon in complex therapy in hospital for 10 d. Moreover, it is necessary to perform parabulbar introduction of 0.3 ml dexasone, 0.2 ml caffeine, 0.3 ml emoxipin successively, fractionally every 20 min once daily in combination with daily intramuscular injections once daily of 2.0 ml dicinon and 1.0 ml halidor and intravenous injection of haemodesum by drops per 200.0 ml on the 1st, 3d and 5th d of therapy. Also, it is necessary to carry out 5 seances of hirudotherapy for temple area every other day under coagulogram control. Then one should introduce milgamma, dicinon and nootropil at age-dependent dosages for 1 mo ambulatorily. The innovation provides complex improvement of microcirculation and metabolicocular and cerebral processes, regeneration of nervous tissue and reconstruction of optic nerve's conductivity at decreased frequency of therapeutic side effects.

EFFECT: higher efficiency of therapy.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves administering pyrimidine nucleotide precursors at a daily dose of 0.05-0.3 g/kg of body weight. The method is applicable under condition that cytotoxic chemotherapy agent does not belong to pyrimidine nucleoside analogs.

EFFECT: enhanced effectiveness in eliminating mitochondrial respiration chain dysfunction.

2 cl

Adaptogen // 2279877

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention proposes using acizol representing bis-(1-vinylimidazol-N) zinc diacetate as an adaptogen. Acizol is known early as antidote. Acizol exceeds plant Eleutherecoccus senticosus by activity with respect to indices of functional state of the body adaptation systems due to providing the higher intensity of tissue respiration, improvement of energetic metabolism and regenerative processes.

EFFECT: enhanced effectiveness and valuable medicinal and biochemical properties of adaptogen.

1 dwg, 8 tbl

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should correct hemostasis disorders intra-operationally due to introducing fraxiparine about 40-80 min against the onset of operation along with intravenous injection of mexidol, by drops at the dosage of about 5-6 mg/kg patient's body weight dissolved in 400 ml 0.9%-NaCl solution at the rate of 60 drops/min. The present innovation enables to create the peak of fraxiparine and mexidol concentrations at traumatic stage of operation that enables to correct hemostasiological disorders during operative interference and at early post-operational period due to combined action of preparations onto different links of hemostasis.

EFFECT: higher efficiency and accuracy of correction.

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a cycloferon-containing medicinal agent used in prophylaxis and treatment of influenza and acute respiratory diseases, herpetic infection, chronic viral hepatitis B and C and prophylaxis of oncological diseases. Agent comprises a physiological solution in the following ratio of components: 10-29 - 10-2 mg of cycloferon in 1 ml of physiological solution. Also, invention relates to a method for preparing this medicinal agent. Proposed medicinal agent enhances antiviral and antitumor activity of natural killers by 1.8-fold, not less.

EFFECT: improved preparing and using method, valuable medicinal properties of agent.

7 cl, 1 dwg, 19 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

63 cl, 3 tbl, 9 sch, 16 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the medicinal preparation zolpidem. Pharmaceutical composition comprises zolpidem hemitartrate as active substance taken in the effective dose and ludipress, aerosil and stearate as special additives. Pharmaceutical composition is made preferably as a tablet covered by envelope. Invention solves the problem for the development of the nonprolonged soporofic medicinal agent based on zolpidem corresponding to all requirements of the State Pharmacopoeia of XI Edition. Proposed nonprolonged formulation of zolpidem is suitable for workers contingent suffering with insomnia, especially, in professions requiring attention and concentration.

EFFECT: improved and valuable medicinal properties of composition.

6 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

EFFECT: improved preparing method, valuable properties of compounds and compositions.

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying antihistamine preparation named mebhydrolin. It is suggested to apply pharmaceutical composition that includes therapeutically efficient quantity of mebhydrolin and target additives as sugar, starch, polyvinyl pyrrolidone and salt of stearic acid. Pharmaceutical composition is designed in tableted form. The innovation provides correspondence of mebhydrolin tablets against all the standards of State pharmacopoeia XI, decreased quantity of additional substances and expiry period of 3 yr, not less.

EFFECT: higher efficiency of application.

5 cl, 3 ex, 2 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: method involves intramuscularly introducing 100 mg of Ketonal before transporting patient to operating room. Then, regional block of femoral and sciatic nerve is carried out by introducing 40 mg of 0.2% Naropin solution. The patient is transported to operating room next to it.

EFFECT: enhanced effectiveness of anesthesia.

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