Method of treating benign hyperplastic endometrial processes in patients with metabolic syndrome

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gynaecology, and can be used for treating hyperplastic endometrial processes in patients with metabolic syndrome. A method involves enzyme immunoassay of blood serum to determine a progesterone level, and if its concentration is 8.0 nmol/l and higher, metabolic therapy including administration of methphormin 1000 mg × 2 times a day, hypo-calorie diet with calorage limited to 1500 kcal a day and increased physical activity in the form of intensive walking. The progesterone concentration lower than 8.0 nmol/l requires additionally another enzyme immunoassay of blood serum to evaluate a leptin level, and if its value is lower than 57.18 ng/ml, the metabolic therapy described above is prescribed. If the leptin level exceeds 57.18 ng/ml, the patients require a combined metabolic and hormonal therapy consisting in administration of methphormin 1000 mg × 2 times a day, dufaston 10 mg × 2 times a day starting with the 16th for 25th day of a menstrual cycle, hypo-calorie diet with calorage limited to 1500 kcal a day and graduated physical activity in the form of walking starting with 10 minutes to be gradually increased to 40 minutes in day.

EFFECT: method allows preserving the reproductive function.

1 dwg, 3 ex

 

The invention relates to medicine, in particular to the gynecologist, and for the treatment of benign endometrial hyperplastic processes occurring on the background of metabolic syndrome.

The problem of choosing a rational therapeutic strategy in hyperplastic processes of the endometrium continues to be one of the most important in modern gynecology. It is well known that the most significant risk factor for their development is the presence in women of metabolic disorders. To date, the efforts of researchers of various specialties formulated the concept of the metabolic syndrome X, according to which obesity mainly Android type, arterial hypertension, dyslipidemia, impaired glucose tolerance are links of one chain of metabolic disorders, a major driver of which is insulin resistance and compensatory hyperinsulinemia (.Mozzanega, R.Mioni, M.Granzotto, 2004; R.G.Richards, D.M.Klotz, M.R.Bush, 2001).

Significant challenges in the treatment calls himself the metabolic syndrome, as it is accompanied by somatic disorders (obesity, diabetes, hypertension etc)that restricts the use of drugs, increased side effects from therapy, complicates the selection of doses of the drugs used (Aravaca, 2008).

Analysis of the patent is Oh and scientific and medical literature has allowed to establish, for the treatment of endometrial hyperplastic processes are mainly used either hormonal treatment or surgery, aimed at radical removal of the endometrium or uterus as a whole.

There is a method of treatment of endometrial hyperplastic processes (patent RF №2347567, 27.02.2009), which consists in intravenous solution of photosensitizer "Photoditazine" in a dose of 0.5-1.0 mg/kg in 1.5-2 hours after infusion is injected into the uterus intrauterine fiber and is exposed to the uterine cavity laser fractional within 30-45 minutes.

The disadvantage of this method is that this method deprives the patient of reproductive function.

Known method of gestalttherapie endometrial hyperplastic processes (patent RF №2325911, 10.06.2008). To do this, make an individual assessment of their binding properties of progesterone receptor in endometrial cytosol fraction of endometrial biopsy. The level of progesterone receptor determine radioligand method. Calculate the amount of specific binding of the drugs received by the progesterone receptor. The drug of choice consider the connection with the highest value of specific binding. The disadvantages of this method are expensive radioligand method of identifying receptors that require special laboratory.

WPI the walls of the treatment of hyperplastic endometrium, combined with uterine myoma (RF patent No. 2317103, 20.02.2008). To do this, in addition to histological examination of scrapings of the endometrium, which determine the quantitative content and density distribution of the receptors of sex steroid hormones, calculate the percentage and density distribution of estrogen-induced protein - PS2. At low concentrations of receptors for sex hormones and at the same time due to low or negative indicator PS2 conduct radical surgical treatment or ablation of the endometrium; in inflammatory process and at low or negative content of the receptors for sex hormones, but a positive indicator PS2 previously conducted anti-inflammatory therapy, then hormone therapy; at normal and high content of sex hormones receptors and positive level PS2 take into account the size and nature of myomatous nodes and diameter nodes less than 3 cm (except for submucous myomas) are hormone therapy, if you have a single node with a diameter of 3-5 cm and submucous myomas hold conservative myomectomy followed by hormone therapy, when the diameter of myomatous nodes more than 5 cm and/or multiple fibroids appoint agnrs and conservative myomectomy, and then hormone therapy.

The disadvantages of this method are expensive radioligand way the distribution of receptors, requiring special laboratory.

There is a method of treatment of endometrial hyperplastic processes (patent RF №2214823, 27.10.2003). At diagnosis of hyperplastic process endometrial histological examination to confirm conducted simultaneously with detection of the pathogens of sexually transmitted infections. After that, regardless of the age of the patient spend antibacterial therapy taking into account the identified pathogen in combination with nonspecific immunostimulatory therapy. These process are regularly monitoring the state of the endometrium and cure of infectious, sexually transmitted diseases. Hormone therapy begins when the negative results of monitoring for the presence of pathogens mentioned infections and spend it upon completion of the course of antibiotic therapy after complete update prismatic epithelium. This antibacterial and nonspecific immunostimulirutuyu therapies the patient receives at the same time with a sex partner. For detection of pathogens of sexually transmitted infections, and control of the cure from them produce a complex clinical and laboratory research, which includes at least two diagnostic methods.

The disadvantage of this method is deferred the appointment of hormonal therapy is the patient, in need that may increase the probability of a transition to more serious forms of endometrial hyperplastic processes.

There is a method of treating metabolic syndrome X (patent RF №2143902, 10.01.2000), which is carried out by conducting the sick 5 sessions of plasmapheresis with an interval of 2 days, which in the evacuation of 25% of the circulating plasma per session with a preliminary physiological solution with the antiplatelet agent answered and incomplete compensation plasmopara by introducing 400 ml of physiological solution with the addition of Essentiale in the dose of 10 ml

The disadvantage of this method is an invasive method of treatment that require expensive consumables and admission to hospital.

There is a method of treatment of metabolic syndrome x" (patent RF №2132190, 27.06.1999 to conduct monitoring of blood pressure and patients with pre-hypertension enter drug ZINC at night, and patients with daytime hypertension in the morning. The initial dose is 0.1 mg, and then 0.1 to 0.6 mg.

The disadvantage of this method is that the treatment is only one of many manifestations of the metabolic syndrome, in particular arterial hypertension, and not the underlying disease.

The known method and means for treatment of benign giperplasticheskimi endometrium (RF patent No. 2275194, 27.04.2006). To do this, after hysteroscopy alternatively hormonal drugs enter Indenol at a dose of 200 mg per day for 2 months, then reduce the dose to 100 mg / day and administered for 2 months. At the same time begin the introduction of Kipferon 1 candle intrawaginalno daily for 10 days.

The disadvantage of this method is that the treatment is appointed without regard to the pathogenesis of the development of endometrial hyperplasia.

The prototype of the present invention is elected as a method of treatment of patients with ovarian forms of giperandrogenii and recurrent endometrial hyperplasia, which consists in the use of Metformin (Heteroge, Wpoty. The use of Metformin in patients with ovarian forms of giperandrogenii and recurrent endometrial hyperplasia. Gynecology. 2000; 6 (2)).

The essence of the prototype method is that patients with recurrent endometrial hyperplastic processes and characteristics of the metabolic syndrome in the syndrome of insulin resistance, the presence of abdominal obesity and ovarian giperandrogenii, appoint a 12-week course of Metformin. Treatment with Metformin (Siofor-500, "Berlin-Chemie AG", Germany) was performed after the main course of therapy (GnRH agonists or Progestogens), test hysteroscopy with diagnostice is Kim curettage and histological verification of the disappearance of endometrial hyperplasia. The drug is administered in a daily dose of 1500 mg (500 mg × 3 times a day) for 12 weeks or more. On a background of treatment patients recommend a regular diet and lifestyle.

This method has a number of imperfections:

1. The authors recommended for monotherapy metabolic syndrome, using only Metformin, although it is known that the main types of non-medical effects in IR and MS are exercise, diet (including this, which many referred to simply as "healthy diet") and Smoking cessation (Regano, 2001).

2. Metabolic therapy is carried out after completion of the course hormonal therapy, whereas during therapy remains a cascade of biochemical disorders, such as hyperinsulinism, insulin resistance, dyslipidemia and, as a consequence, hyperandrogenism, which in itself is a prerequisite for recurrence of endometrial hyperplasia.

3. For hormonal treatment of some patients are expensive analogues of GnRH.

The objective of the claimed invention to develop pathogenetically substantiated method of treatment of endometrial hyperplastic processes in patients with metabolic syndrome without the use of hormonal drugs.

The problem is solved as follows: patients with hyperplastic processes e is dometria, occurring against the background of metabolic syndrome, conduct a study of the level of progesterone in the serum by ELISA. When the progesterone level ≥8.0 nmol/l patients prescribed only metabolic therapy, consisting of a low-calorie diet and increased physical activity in combination with Metformin at a dose of 1000 mg per day. In cases where the concentration of progesterone was determined to be less than 8.0 nmol/l, patients additionally conducting a study of leptin in the serum by ELISA. When leptin values below 57,18 ng/ml appoint the above metabolic therapy. If the concentration of leptin exceeds 57,18 ng/ml, patients receive a combination of (metabolic and hormonal) therapy, consisting of Metformin 1000 mg × 2 times a day, Duphaston 10 mg x 2 times a day with 16 for 25 day of a menstrual cycle, a low-calorie diet with restriction of cellarage to 1500 kcal per day and dosed physical load in the form of a walk starting with 10 minutes and gradually increasing to 40 minutes a day.

Technical result achieved when solving a task, expressed in differentiated tactics of treatment and prevention of endometrial hyperplastic processes occurring on the background of metabolic syndrome, in some cases without the use of hormonal the x drugs.

Antidiabeticheskoe biguanides, among which the most popular Metformin, capable of stimulating peripheral glucose disposal, have moderate hypoinsulinemic, mesoridazine and hypolipidemic effect and influence the production of hormones of adipose tissue, primarily leptin. Increased levels of leptin in the blood, usually correlates with body weight and can prevent ovulation and the development of progesterone in the ovaries (G.E.Hale, C.L.Hugbes, 2002). Metformin is a drug that will inhibit gluconeogenesis in the liver, increase glucose utilization and increases sensitivity to insulin, which over 30 years has been used successfully for the treatment of non-insulin-dependent diabetes mellitus. Metformin should always be used in addition to an overall lifestyle change, not as a replacement for enhanced physical activity and improve diet (Vasuli, 2006).

This approach to therapy of endometrial hyperplastic processes can be explained by the fact that patients with higher levels of leptin, apparently, there is a pronounced increase in subcutaneous fat in comparison with the amount of visceral fat, and, consequently, the less pronounced the degree of the metabolic syndrome, because of the work Antikarov (2007) it is known that leptin is largely characterizes the volume of subcutaneous fat is the first fat, and not visceral, biochemically more active fat. Therefore, to prevent recurrence of endometrial hyperplasia in patients with initial low progesterone and high levels of leptin require a complex effect on all stages of the pathogenesis of endometrial hyperplastic processes.

Detailed description of the method:

Patients with hyperplastic processes in the endometrium after hysteroscopy and diagnostic curettage of the walls of the uterus with mandatory histological examination of the material obtained carried out to determine the level of fasting glucose, cholesterol, high-density and triglycerides enzymatic colorimetric method with a set of reagents company "OLIVEX DIAGNOSTICUM" (Russia). Also measure blood pressure and waist measurement according to standard techniques. When confirming the diagnosis of metabolic syndrome with the aim of selecting the adequate treatment survey the level of progesterone in blood serum during the period from 3rd to 8th day of the menstrual cycle by ELISA kits DBC Inc (Canada) appropriate Protocol.

Wash buffer is prepared according to the instructions to the set. In wells coated with antibodies to progesterone person, contribute 25 the CL standard or experimental samples. All wells were made in 200 μl of a solution of enzyme conjugate. Incubate the plate at room temperature for 60 minutes. Washed tablet three times with wash buffer on the washer. In each well bring in 200 µl of substrate solution and incubated at room temperature for 15 minutes, protected from light. Stop the color reaction by adding 100 ál of stopping solution to each well. Measurement of optical density at 450 nm and the calculation of results is performed on the photometer MULTILABEL COUNTER 1420 (Finland). In the software of the device enter the numerical values of concentrations of hormones in the standard solutions and get after measuring the concentration of hormone in the experimental samples. The level of progesterone in the serum of the patient is expressed in nmol/L.

When the level of progesterone 8.0 nmol/l and above patients spend metabolic therapy consisting of Metformin at a dose of 1000 mg per day, a low-calorie diet (individually calculate daily calories for a low-calorie food according to the Order №330 from 05.08.2003, RF Ministry of health taking into account age, body mass and energy expenditure. Individually constitute menu layout on the day given daily calories, issued a table with the content of nutrients in foods, the list of recommended for a low-calorie food products is tov), also recommend increased physical activity in the form of intense walk: 1 week 10 minutes daily; 2-week 20 minutes a day; 3-week 30 minutes every day; the 4th and subsequent weeks, 40 minutes daily (Anndrea, Organigram, 2006).

In those cases, when the progesterone concentration of less than 8.0 nmol/l, patients additionally conducting a study of leptin in the serum by ELISA kits DBC Inc (Canada) appropriate Protocol. Before the test serum and solutions calibrator diluted in the ratio 1:10 with assay buffer. Wash buffer, and the solution streptomycinresistant conjugate is prepared according to the instructions to the set. All wells coated with mouse monoclonal antibody to human leptin contribute 20 µl of diluted calibrators and samples. In each well contribute 80 ál antiseptirovannogo conjugate. Incubate the plate on a shaker for 1 hour at room temperature. After incubation wash the wells with washing buffer 3 times on the flushing device for microplate ELISA WASHER HUMAN (USA). Then all wells contribute 100 μl of a solution streptomycinresistant conjugate. Incubate the plate at room temperature for 30 minutes on a shaker at room temperature. Washed PL is het 3 times with wash buffer, as explained above. All wells contribute 100 ál of substrate solution and incubated for 10-15 minutes, protecting from direct sunlight. Stop the color reaction by adding 50 µl of stop solution to each well. Measurement of optical density at 450 nm and the calculation of results is performed on the photometer MULTILABEL COUNTER 1420 (Finland). In the software of the device enter the numerical values of concentrations of leptin in the calibration solutions and get after measuring the concentration of leptin in experimental samples in ng/ml.

When leptin values below 57,18 ng/ml appoint the above metabolic therapy. If the concentration of leptin exceeds 57,18 ng/ml, conduct combined (metabolic and hormonal) therapy, consisting of Metformin 1000 mg × 2 times a day, Duphaston 10 mg x 2 times a day with 16 for 25 day of a menstrual cycle, a low-calorie diet with restriction of cellarage to 1500 kcal per day and dosed physical load in the form of a walk starting with 10 minutes and gradually increasing to 40 minutes a day.

The performance of the proposed method is confirmed by the following clinical examples.

Example 1. Patient K-R, 26 years. Case history No. 409/125. Enrolled in the gynecological Department of NIIAP 28.01.2008, the Diagnosis of Hyperplastic process of the endometrium. Metabolic syndrome. During wasterock the FDI signs of hyperplastic process of the endometrium, confirmed histological conclusion (g/and glandular-cystic hyperplasia of the endometrium proliferative type). When examined, were found the following characteristics of the metabolic syndrome: BMI - 35,43, waist circumference of 102 cm, fasting blood glucose was 5.9 mmol/l, triglycerides - 1.5 mmol/l, cholesterol high density lipoprotein - 1.3 mmol/L. the Patient had systolic blood pressure rises to 140 mm Hg When hormonal examination progesterone serum had a value of 8.5 nmol/L.

After the examination the patient is assigned to metabolic therapy which Metformin 1000 mg × 2 times a day, a low-calorie diet with restriction of cellarage to 1500 kcal per day and dosed physical load in the form of a walk starting with 10 minutes and gradually increasing to 40 minutes a day.

After 3 months of ULTRASONIC control and PayPal diagnosis, which noted the absence of endometrial hyperplasia.

After 6 months of repeated hysteroscopy with subsequent histological examination of the endometrium, which was absent hyperplasia. Also, the patient noted normalization of metabolic changes (BMI - 28,95, waist circumference - 89 cm, fasting blood glucose was 5.3 mmol/l, triglycerides - 1.3 mmol/l, cholesterol high density lipoprotein - 1.2 mmol/L. PA who ienda noted normalization of blood pressure).

Example 2. Sick In the first, 31 years. Case history No. 7409/2197. Enrolled in the gynecological Department of NIIAP 27.11.2008, the Diagnosis of Hyperplastic process of the endometrium. Metabolic syndrome. During the hysteroscopy signs of hyperplastic process of the endometrium, which is confirmed by histological conclusion (g/and glandular-cystic hyperplasia of the endometrium proliferative type). When examined, were found the following characteristics of the metabolic syndrome: BMI - 33,09, waist circumference - 89 cm, fasting blood glucose was 6.5 mg/DL, triglycerides - 1.8 mmol/l, cholesterol high density lipoprotein - 1.1 mmol/l rise in the arterial pressure of the patient were noted. Hormonal examination progesterone serum had a value of - 7.9 nmol/L. In this regard, the patient also carried out the determination of the level of leptin. Leptin had a value of 56,96 ng/ml as leptin levels did not exceed 57,18 ng/ml, it is possible to choose the tactics of treatment in the form of metabolic therapy, consisting of Metformin 1000 mg × 2 times a day, a low-calorie diet with restriction of cellarage to 1500 kcal per day and dosed physical load in the form of a walk starting with 10 minutes and gradually increasing to 40 minutes a day.

After 6 months of repeated hysteroscopy followed by histological examination of the CN is ometry, lacking hyperplasia. Also, the patient noted normalization of metabolic changes (BMI - 26,76, waist - 76cm, fasting blood glucose was 4.2 mmol/l, triglycerides - 1.3 mmol/l, cholesterol high density lipoprotein - 1.3 mmol/l).

Example 3. Patients To the ova., 38 years. Case history No. 2294/732. Enrolled in the gynecological Department of NIIAP 22.04.2008, the Diagnosis of Hyperplastic process of the endometrium. Metabolic syndrome. During the hysteroscopy signs of hyperplastic process of the endometrium, which is confirmed by histological conclusion (g/and glandular fibrous polyp on the background glandular-cystic hyperplasia of the endometrium proliferative type). When examined, were found the following characteristics of the metabolic syndrome: BMI - 31,91, waist circumference - 97 cm, fasting blood glucose was 5.9 mmol/l, triglycerides - 2.3 mmol/l, cholesterol high density lipoprotein - 1.2 mmol/L. the Patient had systolic blood pressure rises to 140 mm Hg When hormonal examination progesterone serum had a value of - 7.5 nmol/l as the level of progesterone was less than 8.0 nmol/l assigned study leptin. Leptin was - 57,52 ng/ml due To the fact that leptin levels exceeded the value 57,18 ng/ml, the selected treatment strategy in the form of destination combination (meth Balicasag and hormonal) therapy, consisting of Metformin 1000 mg × 2 times a day, Duphaston 10 mg x 2 times a day with 16 for 25 day of a menstrual cycle, a low-calorie diet with restriction of cellarage to 1500 kcal per day and dosed physical load in the form of walking, starting with 10 minutes and gradually increasing to 40 minutes a day.

After 6 months of repeated hysteroscopy with subsequent histological examination of the endometrium, which was absent hyperplasia. Also, the patient noted normalization of metabolic changes (BMI 26,89, waist circumference of 85 cm, fasting blood glucose was 4.7 mmol/l, triglycerides - 1.8 mmol/l, cholesterol high density lipoprotein - 1.4 mmol/l).

The claimed method we treated 75 patients, 25 of them in a standard way using hormone therapy, 43 patients received only metabolic therapy and 7 people treated with the combined method, combining metabolic and hormonal therapy.

Thus, the claimed method is more effective in comparison with the known and has a number of advantages:

1. Allows you to differentiate between the treatment of patients with endometrial hyperplasia.

2. Allows you to save, and in some cases to restore reproductive function.

3. The proposed method of treatment affects etiopathogeny the political basis for the development of endometrial hyperplastic processes and allows in some cases to avoid hormonal treatment.

4. This treatment method targets the patients on lifestyle changes (weight loss, increased physical activity).

5. Used for the treatment of affordable medicines.

The proposed method is tested on a sufficient volume of clinical material and can be recommended for wide use in clinical practice.

A method of treating benign endometrial hyperplastic processes in patients with metabolic syndrome, including treatment with Metformin, wherein the pre-serum determined by ELISA the levels of progesterone at concentrations of 8.0 nmol/l and above carry out metabolic therapy, including Metformin 1000 mg 2 times a day, a low-calorie diet with restriction of cellarage to 1500 kcal per day and increased physical activity in the form of intense walk, if the concentration of progesterone below 8.0 nmol/l additionally carry out the determination in serum by ELISA levels of leptin when it is below 57,18 ng/ml appoint carrying out the above metabolic therapy, when leptin levels are higher 57,18 ng/ml, patients receive a combination of metabolic and hormonal therapy which Metformin 1000 mg 2 times a day, Duphaston 10 mg 2 times a day with 16 for 25 day of the menstrual cycle, a low-calorie diet with restriction of cellarage to 1500 kcal per day and dosed physical load in the form of walking, starting with 10 minutes and gradually increasing to 40 min a day.



 

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30 cl, 4 dwg, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of formulae pharmaceutically acceptable salts or stereoisomers thereof, where R1 = -OR5, -NH-SO2R6; R2 = hydrogen; R3 = C1-6-alkyl; R4 = isoquinolinyl, possibly substituted; n equals 4 or 5; R5 = hydrogen; R6 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: novel compounds have hepatitis C virus replication inhibitory action and can be used in medicine.

6 cl, 32 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes a compound of general formula where A1 is selected from the following formula R1c denotes a hydrogen atom, a lower alkenyl group or a -Q3-A3(R1d)R1e group; A3 denotes a methane or lower alkyl group; Q3 denotes a single bond; R1d and R1e independently denote a hydrogen atom, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1 denotes a lower alkenyl group or a lower alkynyl group; R2 denotes a phenyl, pyridyl or thienyl group, which can contain a -Q4-A4(R1g)R1h group; A4 denotes a nitrogen atom, a lower alkyl group optionally substituted with a hydroxy-lower alkyl group, or a methane group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q denotes a single bond or a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1g and R1h independently denote a hydrogen atom, a lower alkyl group or a lower alkylsulphonyl group; R5 and R6 independently denote a hydrogen atom, a lower alkyl group or a hydroxyl-containing lower alkyl group, or a pharmaceutically acceptable salt thereof. The invention also describes a pharmaceutical composition based on compounds of formula I, having anti-cancer activity, an anticancer agent, a codrug, as well as an exposure sensitising agent containing the pharmaceutical composition.

EFFECT: novel compounds are obtained and described, having excellent Well-kinase inhibitory action and can therefore be used in medicine, especially when treating different malignant tumours.

13 cl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmacology and medicine and deals with application of 3,5-seco-4-norcholestan derivatives for obtaining medication-cytoprotector, which possesses high activity, except neuroprotector.

EFFECT: obtaining medication-cytoprotector, which possesses high activity.

18 cl, 2 tbl, 14 ex

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