The method of obtaining biologically active substances from the blood serum

 

(57) Abstract:

The invention relates to medicine and can be used to obtain biologically active substances from the blood serum of animals and birds, are useful for the treatment or correction of a hearing impairment, sexual activity, spatial memory; and to increase physical endurance, stimulate proliferation of embryonic brain cells; useful in Parkinson's disease. The active substance is a fraction of relatively low molecular weight peptides (M m 2-4 thousand daltons), obtained by processing (in vitro), blood, x-rays, followed by the separation of the target product. Effect: method provides for obtaining biologically active substances useful in the treatment of a wide range of diseases. 9 N. and 20 C.p. f-crystals, 21 PL.

The technical field to which the invention relates

The present invention relates to medicine, more specifically to the production of biologically active substances from the blood serum and can be used in the treatment of a wide range of diseases, including correction of the symptoms of parkinsonism, hearing at its lower and spatial memory, as well as to improve s the production of a biologically active blood serum, based on drawing blood from donors, incubation, separation and subsequent preservation. The methods involve obtaining immune serum or blood serum, current in addition to the immune system, increase the body's resistance to such exogenous and endogenous factors, such as atmospheric pressure, temperature, gravity, light, and hunger, thirst, sleep and sexual needs and others. - Patents EP 0542303, EN 2096041, EN 2120301. In these known technical solutions, the serum should be prepared from a donor who previously entered into a certain functional state, while depending on the nature of the exposure to get the serum with the biological activity of different nature: myogenic, somnogenic oftalmologii, audioactive, thermosetting, detectivey, exactive, antihypoxic, anti-alcohol and antinicotine. A remarkable feature of sera disclosed in the cited sources is their absolute safety, non-toxicity, serum does not have, as the authors state, contraindications for use.

The relative disadvantage of these serums is that the user, including the attending physician, as a rule, does not know how to the orracle the status of a particular patient.

The present invention was the selection of biologically active substances from the blood serum and the development of a new method of its receipt.

Another object of the invention was to expand the range of sources that can be allocated to the active substance, thereby obtaining the possibility of cheaper final product.

Another object of the invention was the development of dosage forms of the active substance, applicable for practical use.

An additional object of the invention was to establish reference intervals doses of the active substance useful for the correction of the patient's condition under pathological conditions.

Short presentation of the invention

Unexpected was that the processing of serum gamma-rays leads to her previously missing biologically active substances that provide a beneficial effect on several body functions of the patient. This is all the more surprising that to date has been generally accepted that ionizing irradiation quantity 25 kilo-gray is a sterilizing dose. This dose is recommended for sterilization of medical products in the Russian Federation (State the e beam sterilization on the physico-chemical properties of the hemostatic gauze and biochemical activity of the protein preparations // Radiation medicine. - M, Atomizdat. - 1972 - S. 123-125; Gergely J., et al. Studies of gamma-ray-irradiated human immunoglobulin G. // Radiosterilization of Medical Products, - 1967. - Vierma. - P. 115-124) that the blood and its preparations, as well as medications peptide radiocaster, unstable and inactivated under the influence of ionizing radiation. All together it was not possible to expect that result, what did the authors of the present invention.

It turned out that, if the venous blood of animals (particularly horses) and humans, as well as arterial blood birds to preincubate for about days at a low temperature, approximately 4-8C, then after the retraction of the clot and its affiliates to obtain serum, liofilizirovanny her and to irradiate mode from about 10 to about 30 kilo-gray, you can select the biologically active substance useful in the treatment of several pathologies. According to mass spectrometry as a result of processing the claimed method there are fractions of peptides with a molecular weight of 2-4 kDa, which were previously lacking in native serum, and there is a significant increase in the level of peptides with the indicated molecular weight contained in native serum.

Thus, the aim of the present invention is to develop a method of obtaining the e is directed to a new biologically active substance, obtained from the serum of a number of animals and birds.

In a preferred implementation, the invention is directed to the substance and its receipt from the blood serum of horses.

In another aspect of implementation of the invention is directed to the substance and method of reception of serum birds.

In another implementation, the invention is directed to the substance and its preparation from human serum.

Another objective of the present invention is to develop a dosage form of a new biologically active substance. The invention involves various dosage forms, including oral, parenteral, nasal, buccal, in the form of suppositories etc. introduction.

The invention provides for the use of suitable physiologically acceptable carriers such as distilled water, fillers, such as cocoa butter. The biologically active substance can be used both independently and in combination with other biologically active agents.

An additional aim of the invention is a pharmaceutical composition in which the active principle is the substance according to the present invented exert a positive influence on the patient's body, i.e., to contain it in an effective amount.

Another aim of the invention is the determination of the effective dose of the active substance according to this invention. It is believed that this dose is in the range from 0.15 to 1000 mg/kg weight of the patient, mainly from 15 to 120 mg/kg. it is Obvious that the specific dose will be determined by the attending physician depending on the patient's condition, its age, weight and treatment.

Detailed disclosure of the invention

Further, the invention disclosed in detail preferred embodiments, specific performance, with examples of active substances, methods for their preparation, pharmaceutical compositions, dosage forms should not become the basis for the limitations of the claims, and is intended only to demonstrate the feasibility of the invention and the aforementioned assignments. Every specialist in this field will certainly make sure that can be offered numerous modifications of the described embodiment of the invention which fall within the claims reflected forth in the claims.

1. The method of obtaining biologically active substance serum

To obtain Sivori (bird). Blood is collected in glass vials and then incubated at a temperature at low temperature, preferably at 4-8C for approximately 18-24 hours, mostly 24 hours. After the retraction of the clot bottles centrifuged at 3000 rpm for approximately 20-30 minutes, the serum was separated from blood clots and lyophilizers in normal mode. Vials liofilizirovannoe serum is irradiated on the installation of the RC-100 (bio-technology, Russia) at 10, 20, 30 pounds-gray using With60. Thus obtained substance stored at 4-8C.

2. Evidence stimulating effects of gamma irradiation on serum birds, horses and humans

2.1. Serum birds.

The experiments were performed on WISTAR rats, male, weighing 220-240 g In the first series of experiments, animals are divided into 6 groups of 20 rats each: group 1 - the rats were injected with saline; group 2 - the rats were injected not irradiated serum: 3 group rats were injected serum, irradiated at 10 kilo-gray. group 4 - the rats were injected serum, irradiated mode 20 kilo-gray. group 5 - the rats were injected serum, irradiated mode 30 kilo-gray.

Saline, non-irradiated serum and substance of bodiless rats. All substances were administered 30 minutes prior to experimental testing. Preliminary testing was carried out for 48 hours prior to experimental testing.

We studied the influence of substances on physical endurance, determined by time-swimming animal with a load in the form attached to the tail of the goods, amounting to 10% of the weights of the rats. For this purpose, rats were placed in pairs in a thermostatic vessel with water, separated into 2 parts. The water temperature was +25C. The air temperature was +20C.

We determined the voyage of animals before the advent of convulsions and final refusal from swimming and diving to the bottom of the vessel.

As follows from table 1, the introduction of the active substance at a dose of 100 mg/kg rats at exposure mode in 10 kilo-gray already causes a statistically significant increase in physical endurance of animals. The study of the dependence of the dose-effect under different conditions of exposure (tables 2, 3, 4) showed that a statistically significant positive effect is observed starting with doses of less than 15 mg/kg

2.2. Serum horses

The experiments were carried out according to the technology disclosed in paragraph 2.1, except for the mode of gamma radiation. Radiation processing carried the g weight of rats.

2.3. The human sera

The experiments were carried out according to the technology disclosed in paragraph 2. 1. Serum without radiation and the substance was applied in a dose of 100 mg/kg of body weight of the rats.

The data of tables 5 and 6 allow you to definitely assert the existence of a positive effect from the introduction of substances horse blood and human endurance in rats, as in the case of substance birds.

2.4. Stimulation of proliferation of embryonic cells of the human brain substance birds

Tools and reagents. Growth environment: Wednesday Needle modified Dulbecco (DMEM) or RPMI-1640 (Gribco, Grand Island), 10% fetal cow serum (Sigma, USA). The mother solution of the substance S-1 20.0 mg/ml is prepared by dissolving in DMEM and contribute in various concentrations in-growth environment or the environment of the experiment with cells on 96-well culture plate.

The environment of the experiment. Needle modified Dulbecco containing 0,58 g/l glutamine, 50 mg/l gentamicin and 0.2% bovine serum albumin.

The removal of organs. The embryo 10-12 weeks of Hitachi, lessons curette normal procedure of abortion, is placed in a sterile container with Hanks solution containing 200 μg/ml of gentamicin, the container is closed, is placed in was built in the Petri dish in a laminar flow Cabinet, pre-treated with UV irradiation for 60 minutes Use instruments sterilized by either boiling or treatment with 70% ethanol. The brain is placed in a sterile tube with cooled to +4C hibernation solution (270 mm KN2RO, 975 mm D-sorbitol, 25 mm D-glucose, 100 mm sodium lactate, 100 μg/ml gentamicin). The tube body stored in a refrigerator at +4C to the next stage of processing no more than 8-9 hours.

The selection of brain cells. Brain in vitro resuspension by pipetting and rough, the suspension is poured onto a nylon sieve with pores 80-100 μm, after which wipe with a pestle or the plunger from the syringe 10 ml with constant flushing of the screen hibernation solution. The suspension is centrifuged at +4C, 1500 rpm, 5 min and resuspension in hibernation solution. Count the number of living cells by exception Trifanova blue. The suspension is centrifuged at +4C, 1500 rpm, 5 min and resuspension in the medium for cultivation (DMEM + 10% fetal cow serum + of 10.0 μg/ml gentamicin) at a concentration of 3.10 cells/ml Suspension make 100 μl to the wells of 96-well culture tablet, pre-coated with collagen. Cultural tablet placed in CO2the add 100 ál of media for culturing.

Measurement of mitochondrial respiration method Mosman and Monks. In 96-well culture the tablet make the analyzed cells in the growth medium and add 50 ál of 1 mg/ml solution of MTT in SFR to a final concentration of 200 μg/ml in 2-4 hours, depending on the activity of mitochondrial respiratory analyzed cells at the bottom of the hole formed purple insoluble in water crystals. 96-well culture plate with loose crystals centrifuged 10 min at 1500 rpm and the supernatant carefully removed by suction and contribute 200 μl DMSO to dissolve the crystals and education of the colored solution. The values of optical density shoot at a wavelength of 540 nm, which is an indicator of the activity of the mitochondrial cell respiration.

The conditions of the experiment. A cell culture is grown in growth medium at S in CO2the incubator atmosphere with 5% CO2and 95% humidity. When the experiment cell suspension is poured into centrifuge tubes, centrifuged 5 min at 1500 rpm in a bucket-rotor, the supernatant liquid is drained and the sediment cells resuspension by pipetting in the environment of the experiment. Then the cell suspension digging the wells of 96-hole to the cult of the cultural tablets 24-48-72 hours or more in a volume of 200 µl/well. To cells add a solution of MTT (3-(4,5-dimethylthiazol-2-ate)-2,5-diphenylether solium bromide; thiazolyl blue) method Mosman to measure mitochondrial respiration. By direct counting the number of cells with staining Trifanova blue counting error is +/-10 to 15%, while the definition of mitochondrial respiration has a variance of +/-1.5 to 2.0%. Therefore, the number of cells in the sample usually take a quantitative assessment of the level of mitochondrial respiration, which is more accurately measured. For accurate measurements the measurements are carried out on 3-4 holes at each measurement point.

The results of the research.

All tested concentrations of the biologically active substance birds (0.1 to 10.0 mg/ml) stimulated the proliferative activity of a complex system of fetal human brain cells (table 7). The stimulating effect of the substance in a concentration of 0.2 mg/ml) was comparable with the stimulant effect of 0, 1 IU/ml of insulin, and in a concentration of 1.0 mg/ml is close to the effect of a 1% solution of albumin.

This reaction fetal human brain cells to the effects of the substance indicates that at this stage of cytogenesis cells in the brain substance acts as a trophic shall tatelnosti astrocytic cells to this effect.

However, analysis of combinatorial effects of substances with albumin and insulin suggests that these substances are competitive relationship with cellular receptors, as the combined effect of all three drugs at concentrations optimal for separate use, does not give the desired effect.

Moreover, the joint use of 1.0 mg/ml substance and 0.1 IU/ml of insulin causes more pronounced proliferation than adding to this mixture 0.5% solution of albumin.

These data indicate that the substance of birds has a significant impact on the growth and activity of the cells, probably by influencing the regulatory and trophic mechanisms. At the same time as trophic agents peptide components of the substance can be used as the constituent amino acids (as amino acid albumin), while regulatory effects can be implemented at the levels of external receptors of cell membranes and mitochondria, affecting energy metabolism.

The method of sample preparation for mass spectrometry

Dry weighed samples were dissolved in 0.1% triperoxonane acid (TFA) at a concentration of 10 mg/ml price is phase column with 1 ml LiChrosorb C18( 10 μm). Followed by stepwise elution at 1 ml consistently: 10%, 30%, 80%, 100% acetonitrile (AN), containing 0.1% TFA. The obtained fractions were subjected to mass spectrometric analysis method MALDI-TOF.

After irradiation in the serum of birds clearly revealed elevated levels of low molecular weight peptides.

Differences between the major peaks in the mass of spectrometrie serum of birds before and after ’-irradiation are presented in table 8.

In the sample of human serum pre-exposure in a significant number are proteins with molecular weight of 33.4, 52. 3. 66.6 kDa - apparently, the first and the last one corresponds sorbirovaniya column albumin. After irradiation, these peaks are absent.

Significant differences are observed in the range of molecular masses from 2.0 to 4.0 kDa, when after irradiation are clearly revealed low molecular weight peptides.

Features of mass spectrometry substance of man is presented in table 9.

THERAPEUTIC EFFECTS of SUBSTANCES BIRDS

A. SPATIAL MEMORY

In the experiment used rats Wistar, males weighing 220-240 mg

The substance is injected intraperitoneally at a dose of 100 mg/kg animal mass for 30 minutes before testing.

Studied 20 rats (10 control and 10 experimental), 10 rats were observed first pace in the left side, and 10 on the right. Subsequently, the pace was as follows (table 10).

The criterion of "3" is the correct approach in a row during the retest was 8 of 10 control rats and all 10 experienced.

Thus, we can talk about stimulating the action of the substance S-1 on the production and preservation of spatial skill in the T-shaped maze, i.e. spatial memory.

CORRECTION of the symptoms of PARKINSONISM

The effectiveness of the biologically active substance was evaluated on experimental modelerami catecholaminergic terminal.

6-DG (6-Hedroxydopamin, 6-HODA) - 10 µg in a volume of 10 µl stereotaxically by the coordinates of the Atlas of the rat brain Fifkaball, the Marshal was introduced for 10 min in a compact part of the black substance (SN). 6-DG was dissolved in saline containing 1% ascorbic acid. The injected solution was brought to pH 7 with sodium bicarbonate solution. Applique substances was carried out under ether anesthesia twice, once in the day to get a stable behavioral effects.

In the experiment rats male Wistar weighing 250-300 g Observations were carried out for 17 days after the first injection. All animals were divided into 2 groups of 20 rats each. Animals of the first group after 1 hour after the second application of 6-DG were injected intraperitoneally substance, dissolved in distilled water for injection at a dose of 100 mg/kg. Animal control (2nd) group was administered 1 ml of distilled water containing 100 mg/kg usually (not irradiated) serum.

The symptoms of Parkinson's disease: tremor, piloerection, inilateral circulatory rotational motion, was estimated by the expert method. These effects have been observed during 3 days after the last application of a solution of 6-DG in animals of the control group the terms 12-14 days.

Introduction substance significantly changed manifestations of Parkinson's disease. A positive effect of the substance on the symptoms of Parkinson's disease are presented in table 12.

THERAPEUTIC ACTIVITY of the SUBSTANCE HORSES

In our experiments we used the rat line "Wistar": sexually Mature males and females weighing 220-240 g

Intraperitoneal injection of substance

Males were divided into 4 groups of 10 rats. A combination of these groups formed 4 groups - CC (control males and control females), KO (control males and experienced females), OK (experienced males and control females), 00 (experienced males and females). First was conducted preliminary testing. After that the males were provided with 15 days of vacation. Females again was not used. The substance was administered 30 minutes prior to experimental testing. Control animals were administered 1 ml of normal serum of horses.

The male was placed for 15 minutes in a separate cage, and then helped him a female in a state of estrus (determined by the status of the external genital organs).

In the experiment we recorded the following parameters:

- the latent period of the first charge (PL corfs),

- latecny period of the first intromission Zadok"),

- latent period ejaculation, use (PL ejaculation, use),

- postejaculatory refractory period (PERP),

- the amount of ejaculation, use experience (Qty ejaculation, use).

Thus, intraperitoneal injection of substance stallions female virtually no effect on copulatory activity of the male, and the introduction of a substance to a male increases the number of intromissive, the number of eyaculaci experience, reduces postejaculatory refractory period.

Intragastric administration of a substance

Males were divided into 4 groups of 10 rats. First was conducted preliminary testing (control). After that the males were given 15 days of rest.

Females again was not used. The substance was administered 60 minutes prior to experimental testing. Used the following doses: 300 mg/kg 500 mg/kg 1000 mg/kg of the test animals were administered 2 ml of saline.

The male was placed for 15 minutes in a separate cage, and then helped him a female in a state of estrus (determined by the status of the external genital organs).

In the experiment we recorded the following parameters:

- the latent period of the first charge (PL corfs),

- latecny the first period of intromissive CLASS="ptx2"> the number of eyaculaci experience (number of ejaculate).

Thus, intraventricular injection of substances increases the number of intromissive, the number of ejaculate in experience, shortens the latent period Zadok and intromissive and PARP.

Conclusion. Substance stimulates sexual activity in experimental rats - males. This substance does not affect the sexual activity of females.

THERAPEUTIC ACTIVITY of the SUBSTANCE of MAN

In the experiment used rats Wistar, males weighing 240-260 g

Rats were placed one by one in the experimental chamber "shuttle-box, separated by a partition. The sound chip has enabled the presentation of a sound stimulus with a frequency of 7 kHz and a power of from 1 to 10 DB.

84 rats were presented in the cells for 10 experiments on 20 presentation of each. Each presentation included an auditory stimulus with a capacity of 2 dB and a duration of 5 sec. Duration one presentation - 30 C, the duration of the experience - 10 minutes.

Control rats (43 rats) for 5 days was administered 1 ml of normal donor serum, and experienced (42 rats) for 5 days daily was administered streptomycin (streptomycin Sul is an animal.

After testing, the experimental group of rats with hearing intraperitoneally injected substance (exposure mode 20 kilo-gray) in the dose of 10 mg/100 g of animal. Response to an auditory stimulus with a capacity of 2.0 dB was evaluated at 30 min after administration of the substance. The results are presented in table 21.

Thus, the substance has a corrective action on hearing loss caused by the use of streptomycin in the experiment.

1. The method of obtaining biologically active substance in the blood serum, characterized in that the blood is incubated, separate the serum, it lyophilizer, treated With60gamma irradiation mode 10-30 kGy and secrete peptides of molecular weight 2-4 kDa.

2. The method according to p. 1 where the use of animal blood.

3. The method according to p. 2, where the animal is a horse or man.

4. The method according to p. 1, where using the blood of birds.

5. The method according to any of the preceding paragraphs, where the incubation of blood is carried out at a temperature of about 4-8C for approximately one sutoro weight 2-4 kDa, obtained according to the method described in paragraph 1.

7. The substance of the blood serum under item 6, which is obtained from the venous blood of the animal.

8. The substance of the blood serum under item 7, where the blood is the blood of a horse.

9. The substance of the blood serum under item 7, where the blood is human blood.

10. The substance of the blood serum under item 6, which is obtained from the arterial blood of birds.

11. The substance of the serum according to any one of paragraphs.6-10, which shows the biological activity in the concentration of 15 mg/kg up to 1 g/kg of body weight of the animal, including humans.

12. The substance of the serum according to any one of paragraphs.6-11, which increases physical performance, stimulates the proliferation of embryonic human brain cells, correcting the effects of Parkinson's disease, promotes the development and preservation of spatial memory, increases sexual activity of the male, has a corrective action on hearing loss.

13. Pharmaceutical composition, characterized in that it contains an effective amount of a substance in the blood serum, as described in paragraph 6, obtained according to the method according to p. 1, and optionally pharmaceutically acceptable carrier, excipient and/or R will timuerunt the proliferation of embryonic human brain cells, corrects the phenomenon of Parkinson's disease, promotes the development and preservation of spatial memory, increases sexual activity of the male, has a corrective action on hearing loss.

15. The pharmaceutical composition according to p. 13, which is made in the form of a solution, tablet, suppository, powder, capsules.

16. The pharmaceutical composition according to p. 13, where the solvent is distilled water.

17. The pharmaceutical composition according to p. 13, where the carrier is cocoa butter.

18. The way to enhance physical performance, including the introduction of an effective amount of substance of the blood serum under item 6 or pharmaceutical compositions under item 13.

19. The method according to p. 18, where the effective amount is from 15 mg/kg up to 1 g/kg of body weight.

20. Method of stimulating the proliferation of embryonic brain cells, comprising introducing an effective amount of a substance in the blood serum under item 6 or pharmaceutical compositions under item 13.

21. The method according to p. 20, where the effective amount is from 15 mg/kg up to 1 g/kg of body weight.

22. The correction method of the symptoms of parkinsonism, including the introduction of an effective amount of substance of the blood serum under item 6 or pharmaceutical comp 24. The way to develop spatial memory, comprising introducing an effective amount of substance of the blood serum under item 6 or pharmaceutical compositions under item 13.

25. The method according to p. 24, where the effective amount is from 15 mg/kg up to 1 g/kg of body weight.

26. The way to increase the sexual activity of the males, including the introduction of an effective amount of substance of the blood serum under item 6 or pharmaceutical compositions under item 13.

27. The method according to p. 26, where the effective amount is from 15 mg/kg up to 1 g/kg of body weight.

28. Method of correction of hearing loss, including the introduction of an effective amount of substance of the blood serum under item 6 or pharmaceutical compositions under item 13.

29. The method according to p. 28, where the effective amount is from 15 mg/kg up to 1 g/kg of body weight.

 

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