Method for integrated treatment of secondary osteoarthrosis accompanying rheumatoid arthritis

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to a therapy of the patients suffering rheumatoid arthritis accompanied by secondary osteoarthrosis. The presented method for integrated treatment involves: Methotrexate 7-15 mg per os 1 time a week, non-steroid anti-inflammatory preparations, diacerein 50 mg - 2 times a day in a combination with the exposure to low-intensity laser light, including the exposure of knee joints to skin infrared pulse laser light along a projection of a joint space, and the exposure of blood to supravenous red laser light.

EFFECT: implementing the method ensures an evident analgesic, anti-inflammatory effect, a reduced length of morning stiffness, improved functional capacity and expanded range of motion in the injured joints, as well as lower consumption of non-steroid anti-inflammatory preparations thereby reducing a rate of related side effects.

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The invention relates to medicine, namely to internal medicine.

Rheumatoid arthritis is a chronic systemic inflammatory disease of connective tissue with lesions predominantly peripheral joints by type of progressive symmetrical erosive and destructive polyarthritis. Rheumatoid arthritis affects approximately 0.4-1% of the population, from 13 to 47%, according to different authors, ill after 50 years, having by this time in 82% of cases in addition to the main several concomitant diseases: osteoarthritis, osteoporosis, arterial hypertension, ischemic heart disease, atherosclerosis, etc.

Along with steadily progressive destructive lesions of the joints associated with rheumatoid arthritis comorbid conditions are one of the leading causes of reduced quality of life, increased risk of disability in patients with rheumatoid arthritis (Michaud K, Wolfe F., 2007). Secondary osteoarthritis is the most common concomitant disease in rheumatoid arthritis.

In a randomized trial of Jean - Pierre Valat "Study of the effectiveness of diacerein in the symptomatic treatment of osteoarthritis of the knee was evaluated dynamics of clinical indicators: index, WOMAC, pain in YOUR movement, the need for paracetamol, the global assessment of the patient, portable the path and the response of patients according to the OMERACT-OARSI criteria. In this study to evaluate the clinical effectiveness has been confirmed by modern laboratory indicators that reflect the main pathogenetic processes in these comorbid conditions. The exclusion criteria were patients from the study was the presence of diseases of the musculoskeletal system. Thus, patients with rheumatoid arthritis in combination with secondary osteoarthritis, which most often occurs in practice, physician rheumatologist, were not included in the present study (ClinicalTrials. gov Identifier: NCT00445276).

In a clinical study Pelletier JP et al."The efficacy and safety of diacerein in the treatment of osteoarthritis of the knee: a double-blind placebo controlled study"included in the research group of diacerein estimated dynamics of indicators of clinical efficacy, as well as selection of the most effective dosage. When this did not clarify the Genesis of osteoarthritis, idiopathic or secondary. Thus, the effect of the drug was not considered from the point of view of a single effective means not only for the treatment of osteoarthritis, but comorbid conditions, which is the cause of this disease. Did not search for the optimal adjuvant therapy, to enhance the clinical effect of drug therapy and to reduce the need nesteroidnykh anti-inflammatory medications (Arthritis Rheum. 2000 Oct; 43(10):2339-48. ID: 11037895 [PubMed - indexed for MEDLINE] Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group. Pelletier JP, Yaron M, Haraoui B, Cohen P, Nahir MA, Choquette D, Wigler I, Rosner IA, Beaulieu AD. Source Centre hospitalier de 1'Universite de Montréal, Hôpital Notre-Dame, Quebec, Canada.).

Conducted a large number of studies which proved positive clinical and pathogenetic influence of laser radiation in patients with rheumatoid arthritis and osteoarthritis. But in the course of the studies did not analyze the effectiveness of laser therapy in the presence of comorbid disease secondary osteoarthritis in patients with rheumatoid arthritis, has not been used for systemic treatment approaches, given a pathogenetic mechanisms of disease development.

In thesis Revazova A.A. "the Effectiveness of laser therapy in complex treatment of patients with rheumatoid arthritis does not take into account the presence of comorbidities and were not used modern anticytokine drugs (abstract. dis... Kida. the honey. Sciences: 14.00.05 / ATV; North.-Ossetians. the honey. Acad. - Vladikavkaz, 2002. - 22 S. Bibliogr.: s. - BC.).

Closest to the claimed is a Method for the treatment of moderate and marked symptoms of articular syndrome in rheumatoid arthritis" (No. 2198004). In the present study along with the study of non-pharmacological treatment - phonophoresis not the residual attention is given to the correction and optimization of pharmacological therapy of rheumatoid arthritis. Temporary improvement of the clinical picture of the disease clouds the real condition of the patient and promotes uncontrolled progression of the disease. Currently widespread in the treatment of patients with rheumatoid arthritis given long-acting drugs that not only improve clinical symptoms of patients, but also to slow the progression of the disease, i.e. a disease-modifying effect. Thus, this method is not considered issues pharmacological correction with the use of modern disease-controlling drugs. In addition, given the high prevalence of secondary osteoarthritis in patients with rheumatoid arthritis, is not considered possible additional contribution to the clinical picture of articular syndrome is the presence of this comorbid conditions that need to be considered in the treatment of the underlying disease.

Achievable technical result is to optimize the treatment of secondary osteoarthritis (OA) rheumatoid arthritis (RA). This result occurs due to:

- simultaneous effect on inflamed knee joints and periarticular structures involved at the moment in the pathological process and, together with the impact on the system the mechanisms of pathogenesis of rheumatoid arthritis and the OST is artrose;

- comprehensive treatment reaches all the main goals of therapy in patients with RA with secondary osteoarthritis: pronounced analgesic, anti-inflammatory effects, reduce the duration of morning stiffness, improve functional capacity and increase range of motion in affected joints and virtually has no side effects;

- reduce the need for non-steroidal anti-inflammatory drugs, thereby reducing the frequency of side effects.

The destruction of cartilage in rheumatoid arthritis leads to the symptoms characteristic of osteoarthritis - degenerative changes in the bones, the growth of osteophytes, etc. Thus, in rheumatoid arthritis develops secondary osteoarthritis. Secondary osteoarthritis contributes to the deterioration of the underlying disease, accelerates the progression of rheumatoid arthritis that leads to premature disability patients.

Traditionally in the treatment of rheumatoid arthritis use of basic drugs (methotrexate - "gold standard"), which has immunosuppressive effects and symptomatic drugs fast action (NSAIDs).

Thus, in the treatment of rheumatoid arthritis is not considered the most frequent comorbid disease secondary osteoarthritis. We need to search n the o a method of treating rheumatoid arthritis with secondary osteoarthritis, slowing the progression of the cartilage destruction characteristic of osteoarthritis, with simultaneous effects on pathogenic mechanisms, both basic and additional diseases, enhancing the positive effect of baseline treatment.

In the proposed method used the combined use of traditional therapy of rheumatoid arthritis and the combined use of an inhibitor of interleukin-1 and NEELY, which has known anti-inflammatory, regenerative, slowing down the destruction of cartilage and analgesic action, thereby enhancing the effect of the drugs and reducing the need for non-steroidal anti-inflammatory means. This combination allows you to optimally affect the main pathogenetic processes that manifests positive clinical and laboratory dynamics in patients with rheumatoid arthritis with secondary osteoarthritis.

The method is as follows.

Sick is therapy, which consists of:

1) traditional drug therapy:

basic drug methotrexate from 7 to 15 mg per os 1 week long. The dose was selected on the basis of the activity of the underlying disease.

- nonsteroidal anti-inflammatory drugs (NSAIDs),

2) inhibitor of interleukin-1 (diacerein 50 mg 2 times per day)

3) laser Ter the FDI using low-intensity laser radiation.

Thus, all patients received basic treatment with methotrexate and NSAIDs, as well as diacerein and NEELY. Diacerein is registered for the treatment of primary and secondary osteoarthritis. Thus, by acting on the secondary osteoarthrosis, we achieve a positive effect on the course of the underlying disease is rheumatoid arthritis.

The drug diacerein belongs to the group of inhibitors of interleukin-1. Has inhibitory effect on secretion and activity of interleukin-1. The main pathogenetic action of diacerein and its active metabolite Reina in osteoarthritis is the inhibition of the synthesis of IL-1, suppressing the expression of receptors for IL-1 on the surface of chondrocytes, thereby reducing the sensitivity of the cells to the action of this cytokine.

Intracellular metabolite blocks the activation and translocation of NFkB into the nucleus, reducing the expression of NFkB-dependent genes, including who is responsible for the production of inflammatory cytokines: TNF-α, IL-1, IL-6, nitric oxide and MP, contributing to increased destruction of components of cartilage matrix.

The technique of laser therapy involves cutaneous laser irradiation of the knee joints on the projection of the joint space and venous laser blood irradiation with exposure through the skin and the wall of venules vascular bundle in the cubital fossa. For however, the aqueous exposure using an infrared pulsed laser radiation with a wavelength of 0.89 μm. The frequency of the pulse 80-1500 Hz, the pulse power of 5 W, the duration of exposure to the field 1-2 min per session total time of radiation does not exceed 10-15 minutes

For venous laser irradiation of blood used red laser power of 2.5 mW, a wavelength of 0.63 µm, frequency 80 Hz. The procedure duration is 1 min left and right.

Laser therapy was performed by a semiconductor laser optical apparatus "Mustang 2000" with radiating heads MLOC, CLO.

Before the first procedure and upon completion of the course of inpatient treatment in patients determined the levels necrosis factor swollen alpha, interleukin - 1,6, high-sensitivity C-reactive protein. Evaluation of the effectiveness of the combined therapy was performed before and after 10-14 days after the start of treatment, based on the dynamics of clinical and laboratory parameters.

We treated 33 patients with secondary osteoarthritis in the background of rheumatoid arthritis.

The selected method of complex treatment with the inhibitor of interleukin-1 and low-intensity laser radiation has increased the effectiveness of treatment of patients with secondary osteoarthritis with rheumatoid arthritis, exerting a positive influence on the course of the underlying disease on the background of basic therapy. Selected treatment regimen reduces the incidence of side effects for MF is t reduce the need for non-steroidal anti-inflammatory drugs. All patients were divided into 2 groups.

In the 1st group consisted of 17 people, which in addition to traditional therapy, including methotrexate and NSAIDs, got inhibitor of interleukin-1 in combination with low-intensity laser radiation, in the 2nd group patients (n=16) received only conventional drug therapy.

The dynamics of clinical and laboratory parameters in patients with secondary osteoarthritis with rheumatoid arthritis under the influence of treatment with the inhibitor of interleukin-1 and the combination of the drug with laser therapy (M±m) are shown in the table below.

IndicatorsPatients of RA in combination with secondary OA n=33 receiving
group 1group 2
(n=17)(n=16)
YOUR at rest (mm)1-3 day40,6±1,8239,8±1,86
10-14 day24,3±1,33*28,2±1,72
When YOUR movement (mm)1-3 day 58,7±1,8260,2±1,67
10-14 day37,9±1,76*45,8±1,82*
YOUR palpation (mm)1-3 day59,7±2,160,2±1,4
10-14 day32,8±1,5*47,4±1,3*
Overall assessment of the health of YOUR patient (mm)1-3 dayan 80.2±1,6778,1±1,53
10-14 day50,4±1,7760,2±1,33
WOMAC1-3 day125,2±2,66126,2±2,42
10-14 day75,2±1,44*109,4±2,32*
Lequesne1-3 day12,7±0,3213,1±0,41
10-14 day9,1±0,42*10,2±0,24*
The number of swollen joints1-3 day 5,2±0,326,1±0,42
10-14 day1,1±0,42*3,1±0,24*
The number of painful joints1-3 day10,2±0,3211,2±0,33
10-14 day3,2±0,45*6,5±0,31*
SLO1-3 day18,36±2,1619,5±2,19
10-14 day12,24±1,95*13,22±1,32*
DAS281-3 day4,7±,0455,4±0,35
10-14 day2,6±0,54*2,9±0,32*
Erythrocyte sedimentation rate1-3 day45,22±1,8640,7±1,95*
10-14 day32,62±1,7536,5±1,97*
IL -1 (PG/ml)1-3 day24,6±1,623,2±1,4
10-14 day19,1±1,8**18,6±1,2**
IL-6 (PG/ml)1-3 day28,6±1,526,6±1,6
10-14 day15,7±0,8**19,2±1,2**
TNF-α (PG/ml)1-3 day26,8±1,825,2±1,3
10-14 day17,8±1,2**19, 22 the±1,4**
P*<0,001**<0,05

1) Index WOMAC (Western Ontario and McMAster Universities Osteoarthritis Index), developed by N. Bellamy et al. - use to assess the effectiveness of therapy of osteoarthritis of the knee, is a questionnaire for self-completion of his patients and contains 24 items describing the pain, stiffness and functional activity for 48 h before evaluation using YOUR (visual analogue scale).

2) Lequesne Index (questionnaire) - algo-functional index in gonarthrosis characterizes not only pain, but the patient's condition.

3) DAS28 - display the spruce quantitative assessment of disease activity rheumatoid arthritis, is calculated by the formula.

Example No. 1.

Patient L., 60 years old, suffering from seropositive RA for 12 years. In the course of the disease have been conducted on treatment in specialized hospital, where he applied modern pathogenetic treatment methods, including the introduction of parenteral corticosteroids, intra-articular, in combination with NSAIDs, disease control drugs (methotrexate) and traditional physiotherapy.

Outpatient constantly taking maintenance doses of NSAIDs and drug methotrexate. Despite ongoing therapy, visible improvement was not noted.

During the inspection it was noted swelling, sudden tenderness (pain on YOUR alone - 7 cm, the motion - 6 cm) and a significant limitation of movements in the proximal interphalangeal joints 2-4 fingers of both hands and wrist, elbow, knee and ankle joints. Limited function and considerably painful to palpation and motion of the knee joints.

According to the results of clinical and laboratory data diagnosed with Rheumatoid arthritis, seropositivity arthritis, activity 3, stage 3 (erosive), secondary gonarthrosis (R 2), synovitis of the right knee joint, RR.

Ill addition to traditional therapy methotrexate at a dose of 10 mg/week long and NSAIDs (who diclofenac 50 mg/d) administered a course of laser therapy in combination with taking an inhibitor of interleukin-1 diacerein (artrocker 50 mg × 2/day) by the above method. Treatment using NEELY was 14 sessions.

After completion of the treatment the patient's condition improved markedly decreased the number of painful and number of swollen joints, joint pain almost completely disappeared, which allowed to cancel receiving NSAIDs.

Data biochemical and laboratory methods of treatment was characterized by a significant positive dynamics (shown in the table below).

Index1-3 day10-14 day
YOUR at rest (mm)7020
When YOUR movement (mm)6030
YOUR palpation (mm)7040
Overall assessment of the health of YOUR patient (mm)6030
Morning stiffness (min)12040
WOMAC12470
Lequesne12,8 7
DAS 285,22,3
CRP (mg/l)208
ESR mm/h4524
TNF-α (PG/ml)25,217,1
IL-1 (PG/ml)23,817,1
IL-6 (PG/ml)27,218,6
The need for NSAIDs (diclofenac)50 mg/dayno

Example No. 2.

Patient A., aged 52 suffered from rheumatoid arthritis for 10 years. The last 4 years was constantly taken weekly methotrexate at a dose of 16 mg

Clinical diagnosis: rheumatoid arthritis seropositive, act II, Art. VI, secondary poliosteoartroz, 2-sided gonarthrosis (R - Art. III) FN II Art.

On the background of basic pathogenetic therapy methotrexate 15 mg × 1 p/week long-term with NSAIDs (Nise 100 mg × 1 p/day) conducted a course of laser therapy according to the proposed method in combination with the reception of diacerein 50 mg/2 times a day for 14 days. The results of treatment are presented the table below.

Dynamics of indicators of the clinical course of the disease

Index1-3 day10-14 day
YOUR at rest (mm)6030
When YOUR movement (mm)7040
YOUR palpation (mm)7050
Overall assessment of the health of YOUR patient (mm)7040
Morning stiffness (min)18080
WOMAC13586
Lequesne18,710,2
DAS 286,23,1
CRP (mg/l)2314
ESR mm/h5428
TNF-α (PG/ml) 28,620,4
IL-1 (PG/ml)26,918,6
IL-6 (PG/ml)26,520,8
The need for NSAID nimesulide100 mg/dayno

Based on the results presented in the table, the positive dynamics of the disease was confirmed not only clinical parameters and laboratory markers of disease.

1. The method of complex treatment of secondary osteoarthritis with rheumatoid arthritis, including taking the medicine and physical impact factor, characterized in that as the drugs take methotrexate 7-15 mg per os 1 time per week, non-steroidal anti-inflammatory drugs, diacerein 50 mg 2 times a day, and as a physical factor is used, the effect of low-intensity laser radiation, including cutaneous infrared pulsed laser irradiation of the knee joints on the projection of the joint space and venous blood irradiation with red laser radiation.

2. The method of complex treatment of secondary osteoarthritis with rheumatoid arthritis according to claim 1, ex is different, however, that cutaneous irradiation is carried out with the pulse frequency 80-1500 Hz, a pulse power of 5 W, the exposure time on the field for 1-2 minutes, total time of radiation in a single session, no more than 10-15 minutes

3. The method of complex treatment of secondary osteoarthritis with rheumatoid arthritis according to claim 1, characterized in that the venous blood irradiation is carried out with an exposure time of 1 minute, with a capacity of 2.5 mW and a frequency of 80 Hz.



 

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15 cl, 11 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gastroenterology, and may be used for treating the patients with gastroesophageal reflux disease. That is ensured by the simultaneous complex introduction of drug preparations, namely a proton pump inhibitor, a prokinetic, an antacid and the intravenous blood laser exposure. The proton pump inhibitor is presented by Ultop 20 mg 2 times a day. The prokinetic is presented by Ganaton 250 mg 3 times a day. The antacid is Gaviscon 10 ml 3 times a day. The intravenous blood laser exposure is performed at wave length 0.405 mcm at output power in a disposable light guide end 1-1.5 mWt at pulse frequency 80 Hz in an continuous emission mode for 15 minutes. The 5-6 daily procedures of the intravenous blood laser exposure are required for mild gastroesophageal reflux disease, the prostaglandin E2 level equal to 1025±112 pg/ml and more, the catalase level equal to 380±21 mcat/l and more, the ceruloplasmin level equal to 3.9±0.7 mcmole/l and more, the malonic dialdehyde level 12.6±1.5 mcmole/l and less. The 9-10 daily procedures of the intravenous blood laser exposure are required for medium and severe gastroesophageal reflux disease, the prostaglandin E2 level equal to 1025±112 pg/ml and more, the catalase level equal to 380±21 mcat/l and more, the ceruloplasmin level equal to 3.9±0.7 mcmole/l and more, the malonic dialdehyde level 12.6±1.5 mcmole/l and less.

EFFECT: method provides higher clinical effectiveness of the drug-induced therapy, earlier reduction of the symptoms, reduced length of treatment and rate of aggravations, lower drug load on the patient's body ensured by normalised lipid peroxidation, higher level of anti-inflammatory prostaglandins, normalised microcirculatory system, balanced vegetative nervous system.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely to ophthalmology, in particular to methods and devices for treatment of eyes with application of laser and is intended for performing impact on soft drusen by sub-threshold micropulse infrared laser. Laser coagulation with individual selection of power is performed. Sub-threshold micropulse impact with infrared diode 810 nm laser is applied. Coagulants with diameter 1.8 mcm in quantity from 8 to 10 are located in projection of soft drusen around foveolar zone and continuous circular spot is created by their superposition on each other. Each following coagulant overlaps the previous one on 1/8, after which last coagulant is applied in the centre of fovea area.

EFFECT: method makes it possible to perform single impact on macular zone, achieve even distribution of energy in it, reduce treatment terms, reduce number of drusen, increase vision acuity and prevent disease recurrences.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely to ophthalmology, and can be used for treatment of central serous chorioretinopathy with localisation of filtration point in avascular zone of retina. In case of localisation of filtration point in avascular zone of retina, impact is performed by yellow solid-state laser with wavelength 577 nm with the following parameters: micropulse duration 50 mcs, relative pulse duration 1.2%, power 1.5 W, spot diameter 100 mcm, interval between pulses in packet 4000 mcs, duration of pulse packet 100 mcs; laser applications are applied in chessboard order at the distance of one diameter of laser applicate from each other on entire area of affection - in filtration point, in the area of decompensation and detachment of pigment and neuroepithelium.

EFFECT: method makes it possible to close filtration point in avascular zone of retina with reduction of height and area of pigment and neuroepithelium detachment, which is accompanied by recovery of maximally correctible vision acuity in patient.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely traumatology, orthopaedics and rehabilitation, and may be used for treating inflammatory-degenerative arthropathies. The therapy is three-staged. The first stage involves at least one course of the integrated therapy aiming at inflammatory response suppression and pain syndrome arrest. The second stage involves at least one session of focused extracorporeal shock wave therapy to create microcavities buried in a interarticular cartilage. At the third stage, the created microcavities buried in the interarticular cartilage are filled with a modelling compound by interarticular electrophoresis followed by stabilising the modelling compound. The modelling compound is represented by a mixture of 15 portions of fine biopolymer gel, 65 portions of hyaluronic acid, 15 portions of animal's articular cartilage extracts and 5 portions of Dimexidum solution. The modelling compound is stabilised by non-invasive exposure to pulse high-power IR laser at wave length 785 nm and heated to 44 Celsius degree.

EFFECT: method provides high clinical effectiveness to be implemented in outpatient care that enables avoiding a surgical intervention, including joint replacement, and ensuring complete removal ensured by possibility of recovery of shape, volume and normal consistence of the interarticular cartilage.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

,

where X1 denotes a bond, NR8 or S; Y1 denotes O or NR ; R1 denotes C1-10alkyl, C6-10aryl or a 5-10-member heteroaryl containing 1-3 heteroatoms which are independently selected from N or S; where said R1 is optionally substituted with 0-2 J1; R2 denotes H or C1-10alkyl; each of R3, R4, R5 and R6 independently denotes H or C1-10alkyl; and R7 denotes C1-10alkyl, C3-10cycloalkyl, phenyl, 5-6-member heterocyclyl containing 1-3 heteroatoms independently selected from O and N, - (C1-6alkyl) -(C3-10cycloalkyl), - (C1-6alkyl) - (phenyl) or -(C1-6alkyl)-(6-member heterocyclyl containing 2 heteroatoms selected from O and N); where said R7 is optionally substituted with 0-5 J7; or R3 and R4, together with a carbon atom with which they are bonded, optionally form a 3-4-member saturated or partially unsaturated monocyclic fragment; R3 and R5, together with carbon atoms with which they are bonded, optionally form a 5-member monocyclic fragment; R8 denotes H; R9 denotes H or unsubstituted C1-6alkyl; or R2 and R9, together with atoms with which they are bonded, optionally form a 5-member aromatic monocyclic fragment containing 3 nitrogen atoms; each J1 independently denotes C1-6halogenalkyl, halogen, NO2, CN, Q or -Z-Q; or two J1 together can optionally form =O; Z denotes C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -NR-, -O-, -C(O)- or -SO2-; wherein each Z is optionally substituted with 0-2 J2; Q denotes H; C1-6alkyl; 3-8-member aromatic or non-aromatic monocyclic fragment containing 0-3 heteroatoms independently selected from O, N and S; or an 8-10-member aromatic bicyclic system; each Q is optionally substituted with 0-2 JQ; each J7 independently denotes C1-6alkyl or halogen(C1-4alkyl); each of JQ and J7 independently denotes M or -Y-M; each Y independently denotes an unsubstituted C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -O-, -C(O)- or -SO2-; each M independently denotes H, C1-6alkyl, C3-6cycloalkyl; halogen (C1-6alkyl), phenyl, halogen, CN, OH, OR1; or two M together can optionally form =O; R denotes H or an unsubstituted C1-6alkyl; R' denotes an unsubstituted C1-6alkyl. The invention also relates to methods of producing said compounds and a pharmaceutical composition for inhibiting PLK based on said compounds.

EFFECT: novel compounds which can be used in medicine as inhibitors of protein kinase are obtained.

34 cl, 1 tbl, 279 ex

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