Method for creating biological model of moderate growth inhibition of tumour and metastases in lewis lung carcinoma with prolonged cyclophosphanine-induced leukopenia in mice
SUBSTANCE: what is involved is simulating moderate growth inhibition of tumour and metastases in Lewis lung carcinoma with prolonged cyclophosphanine-induced leukopenia in mice by intraperitoneal introduction of cyclophosphane in 1/3 ADR - 3 times, 83.3 mg/kg each on 6th, 12th and 18th post-transplantation days. On the 3rd day after each introduction, peripheral blood is analysed (total leukocyte count, leukogram) - the lowest WBC count is determined. The clinical effectiveness is assessed at the end of the experiment on the 21st post-transplantation day as shown by tumour weight, a percentage of growth inhibition, a metastasis rate, the number of lung metastases, a metastasis inhibition index.
EFFECT: new biological model of carcinoma with comorbid prolonged leukopenia enables weighing the contribution of substances of different nature to the anti-cancer clinical effectiveness and to the elimination of white blood cell toxicity when the above substances are included into the therapy.
1 ex, 1 tbl
The invention relates to medicine, specifically to Oncology, and can be used for preclinical studies of substances that enhance antitumor and antimetastatic effects of the action of drugs and reducing their toxicity on white blood cells.
In modern clinical Oncology chemotherapy is one of the main methods of treatment of patients with malignant neoplasms, particularly in the later stages of the development of tumor in the presence of extensive metastasis .
Most anticancer drugs drugs have side effects and affect not only cancer cells but also healthy with a high growth fraction, first of all, blood cells, causing the development of Hypo - and aplastic States. Such violations are a major limiting factor for chemotherapy. One of the widely used drugs in the Oncology clinic is cyclophosphamide, which along with the cytostatic effect on tumor has a number of toxic effects (impaired hematopoiesis, immune depression)that limits its continued use in high doses for the treatment of patients with tumors. Thus, increasing the antitumor and antimetastatic effects activity of cyclophosphamide by reducing the th toxicity is relevant.
In the literature there is evidence that after a single intraperitoneal administration to mice of cyclophosphamide at a dose of 125 mg/kg (1/2 of the maximum tolerated dose, MTD) significantly inhibited the growth of primary tumor and metastases of carcinoma of the lung Lewis. There leukopenia with minimum values of 3 and 4 days, and recovery of peripheral blood counts with 5 d after injection of cyclophosphamide .
It is known that 2-fold introduction of cyclophosphamide at a dose of 60 mg/kg to mice with Lewis lung carcinoma leads to a significant inhibition of tumor growth (63%) and metastases (index inhibiting metastasis equal to 82%) .
In these biological models, there is a pronounced inhibition of tumor growth and metastasis, in which it is impossible to assess the contribution to improving the efficiency of cytostatic therapy substances of different nature when they are in treatment.
Given the fact that in clinical practice cytotoxic therapy is applied courses (usually 3 times lower), arising from long-leukopenia is a barrier to full treatment.
Thus, our proposed model of moderate inhibition of growth of primary tumor and metastases in the development of carcinoma, Lewis lung in mice with concomitant prolonged leukopenia, you the bathroom 3x introduction of cyclophosphamide, can be used in the preclinical study of substances that increase the efficacy of chemotherapy and reduce the toxic effect of drugs on white blood cells.
In the analysed literature adequate prototype not found.
The objective of the invention is to provide a new biological model of moderate inhibition of tumor growth and metastasis associated with prolonged leukopenia.
The problem is solved by repeated introduction of animals of cyclophosphamide. What's new is that as a model course use of cytostatic agents used 3-fold intraperitoneal administration to mice C57B L/6 with inoculated intramuscularly with 4 million cells of Lewis lung carcinoma of cyclophosphamide at a dose of 83.3 mg/kg (1/3 MTD) at 6, 12 and 18 days after transplantation of the tumor. The first time the cyclophosphamide is administered at 6 days after inoculation of the tumor due to the fact that by this time already laid metastases of carcinoma of the lung Lewis and it is possible to evaluate the influence of cytostatic agents on their development . Further, the cyclophosphamide is administered at 12 and 18 days after transplantation of the tumor, in order to maintain a moderate inhibitory effect of cytostatic agents on the tumor growth during the experiment. In addition, the cyclophosphamide is administered three times with an interval of 6 days to reduced the cytotoxic effects of the amount of glue is OK white blood remained at the same level for a long time. With moderate impact of cytostatic to tumor development and concomitant prolonged leukopenia possible to assess the contribution in enhancing the effectiveness of cancer treatment and toxicity reduction in white blood cells included in the regimen substances of different nature.
Data essential features not identified from the medical-scientific and patent literature. They explicitly do not follow from the prior art for professionals. Offered as the invention of the model term use of cyclophosphamide can be used for pre-clinical study of substances that increase the efficacy of chemotherapy and reduce the toxic effect of cytostatics in respect of white blood cells.
Based on the foregoing, it should be considered the present invention with the relevant conditions of patentability: Novelty", "Inventive step", "Industrial applicability".
This model was experimental research in laboratories Oncohematology and pathological physiology and experimental therapy NII pharmacology" SB RAMS Tomsk.
The study was conducted on a three-month mice-female line C57B L/6 mass 19-20, as a model of malignant growth used hematogenous the metastatic Lewis lung carcinoma (3LL), perelevayuschimsya 4 million tumor cells in the mouse. For modeling course chemotherapy regimens used 3-fold intraperitoneal administration of cyclophosphamide (1/3 MTD - of 83.3 mg/kg at 6, 12, 18 days after inoculation of the tumor).
For detection of antitumor and antimetastatic actions, as well as toxic effects on the peripheral blood in animals (total leukocyte, neutrophil and eosinophil granulocytes, lymphocytes, monocytes) with 3-fold introduction of cyclophosphamide at a dose of 83.3 mg/kg was delivered the following experiment.
Animals were divided into following groups:
1. Background (n=10) healthy mouse.
2. "Control" (n=6) - untreated mice with Lewis lung carcinoma.
3. "Cyclophosphamide (n=6) mice with Lewis lung carcinoma treated with cyclophosphamide intraperitoneally at a dose of 83.3 mg/kg at 6, 12, 18 days of tumor development.
1 day before tumor inoculation and 3 days after 1, 2 and 3 injection of cyclophosphamide (9, 15, 21 days after transplantation of the tumor) from the tail vein of mice were collected peripheral blood was determined by its indicators (total number of leukocytes, leukocyte formula) standard hematological methods . The peripheral blood was determined at 3 days after each injection of cyclophosphamide in connection with the fact that this term is found as low as possible the number of white blood cells.
At the end of the experiment (21 days after Tran the plantations of the tumor) was determined by the mass of the tumor, the percentage inhibition of its growth, the frequency of metastasis, the number and size of lung metastases, the index of inhibition of metastasis [6, 7]. Processing of the obtained results was performed using non-parametric criterion of Wilcoxon-Mann-Whitney. The differences were considered significant at P<0,05 .
The experiment revealed that the 3-fold intraperitoneal administration of cyclophosphamide at a dose of 83.3 mg/kg had a moderate inhibitory effect on the growth of primary tumor and metastases. So, by the end of the experiment, the inhibition of tumor growth was 34%, the number of metastases decreased 4.7 times (P<0.01), and decreased the area of metastatic lung lesions compared with the control values, the frequency of metastasis was 100%, as in the control (table 1).
The study of peripheral blood in mice of the control group (with tumors) showed increased content of total number of cells at all time observations regarding this indicator in healthy animals (Background), mainly due to the increase in the number of neutrophilic granulocytes (table 2). The most pronounced leukocytosis was observed for 21 days of the experiment, when the total number of leukocytes increased 1.5 times (P<0.01), and by increasing the number of segmented neutrophils 4.3 times (P<0.01) compared with that in the background is ISA.
Depression of the white blade of blood, caused 3-fold by the introduction of cyclophosphamide, was reflected in the decrease in the total number of leukocytes in peripheral blood of mice throughout the study period: 3 days after 1, 2, 3 the introduction of cyclophosphamide - 3.4; 3,2; 5.9 times (P<0,01), respectively, relative to those in animal control. At the same time, surveillance observed a decrease in the number of segmented neutrophils (7.9; 2.5 and 5.8 times, P<0.01) and lymphocytes (3.0; 3.6 and 6.1-fold, P<0,01) against these indicators in the control (table 2).
Thus, 3-fold intraperitoneal administration of cyclophosphamide at a dose of 83.3 mg/kg to mice with Lewis lung carcinoma leads to moderate inhibition of tumor growth, metastasis and is accompanied by prolonged radiation throughout the study period. Moderate effect of cyclophosphamide on the tumor growth and prolonged leukopenia will identify the possibility of increasing the antitumor and antimetastatic effects of the action of cytostatics and correction of its toxic effects when introduced into the regimen of substances of different nature.
Proposed biological model will allow us to investigate the possibility of using drugs-correctors cytotoxic therapy for cancer clinic.
|Dynamics of the content of the total number of leukocytes and their individual forms (×109g/l) in the peripheral blood of mice with Lewis lung carcinoma in conditions 3 injections of cyclophosphamide at a dose of 83.3 mg/kg (X±m)|
|The monitoring group, dose × the number of introductions (number of animals)||The total number of leukocytes||Neutrophilic granulocytes||Lymphocytes||Eosinophils||Monocytes|
|The original background (1 day before inoculation 3LL)|
|A. Background (n=10)||8,75±0,7||0,03±0,02||1,2±0,22||7,34±0,55||0,09±0,02||0,08±0,02|
|3 days after 1 injection of cyclophosphamide, 83 mg/kg (9 days)|
|1. Control (n=6)||10,83±1,84||0,06±0,04||1,75±0,38||8,75±1,5||0,08±0,04||0,19±0,06|
|2. Cyclophosphamide, 83 mg/kg ×1 (n=6)||3,21±0,48||0,01±0,01||0,22±0,07||2,92±0,42||0±0||0,06±0,03|
|3 days after the 2nd injection of cyclophosphamide, 83 mg/kg (15 days)|
|1. Control (n=6)||9,00±1,23||0±0||2,05±0,21||6,70±1,2||0,06±0,03||0,17±0,03|
|2. Cyclophosphamide, 83 mg/kg ×2 (n=6)||2,79±0,32||0±0||0,81±0,15||1,86±0,2||0,02±0,01||0,10±0,03|
|3 days after 3 introduction the deposits of platinum, 83 mg/kg (21 day)|
|1. Control (n=6)||13,08±1,16||0,10±0,07||5,20±0,58||a 7.62±0,67||0,14±0,07||0,03±0,03|
|2. Cyclophosphamide, 83 mg/kg ×3 (n=6)||2,21±0,61||0,01±0,01||0,90±0,33||1,25±0,28||0,01±0,01||0,05±0,03|
1. Guidelines for chemotherapy of neoplastic diseases / edited Nieremontowany. - M.: Practical medicine, 2005. - P.26.
2. Abramova E.V. Influence of the extract of Scutellaria baicalensis on the regeneration of hematopoiesis in terms of chemotherapy: author. Diss.... Kida. the honey. Sciences., Tomsk, 1992. - P.10, 15.
3. Patent for invention No. 2270682 of the Russian Federation. Method of enhancing antitumor and antimetastatic activity of cyclophosphamide in the experiment / Kokorev O.V., Cherdyntseva NV, Zuikova O.V. Published: 27.02.2006, bull. No. 6.
4. the owner's manual on experimental (preclinical) study of new pharmacological substances / Under Rugarama. - M.: Medicine, 2005. - S.
5. Goldberg ED, Digi A.M., Shah V.P. Methods of tissue culture in Hematology. - Tomsk: Publishing house of Tomsk University, 1992. - S, 214.
6. Arkhipov S.A., Junker V.M., gruntenko EV change in the intensity of metastasis in the lungs of transplantable tumors in mice depending on the value Leno dose of tumor cells // Research on induction and metastasis of tumors in experimental animals. - Novosibirsk, 1984. - P.29.
7. Experimental evaluation of anticancer drugs in the USSR and the USA / edited Spoofing, Abberline (USSR), Agostina, Alaina (USA). - M.: Medicine, 1979. - P.131.
8. Gubler E.V. Computational methods of analysis and recognition of pathological processes. - L.: Medicine, 1978. - S.
The method of modeling a moderate inhibition of growth of primary tumor and metastases of carcinoma of the lung Lewis with prolonged leukopenia in mice, characterized in that the cyclophosphamide is administered intraperitoneally in 1/3 MTD - of 83.3 mg/kg 3 times at 6, 12, 18 days after inoculation.
SUBSTANCE: midline laparotomy is performed in an anaesthetised experimental animal. The adhesions are formed by applying one-two stitches onto a parietal side of the abdominal wall be means of a sterile polypropylene filament 4/0-6/0.
EFFECT: method enables stimulating the controlled adhesion process accompanied by no excessive inflammatory process.
SUBSTANCE: invention refers to experimental medicine and may be used to study the stimulation of the reparative processes in tissues of an involved joint. That is ensured by simulating the intra-articular fracture of the cotyloid cavity. The stimulation involves the restoration of anatomic relationships in the joint, the stabilisation thereof with an external fixation apparatus. Later, starting from the second postoperative day, a solution or a mixture of solutions is introduced drop-by-drop into the joint cavity for 3-5 days. Differentiating in the osteoblastic direction and forming a preferential bone fusion requires a mixture of officinal solutions of 40% glucose, 5% ascorbic acid, autologous blood plasma, taken in a volume ratio of 1:2:7 to be introduced. For the purpose of the fibroblast differentiation and formation of a preferential connective tissue fusion, a mixture of officinal solutions of 5% glucose and 5% ascorbic acid in the volume ratio 1:1 is introduced. Differentiating in the chondroblastic direction and forming a preferential cartilage fusion are ensured by introducing officinal 0.9% sodium chloride solution.
EFFECT: method provides the targeted regulation of the reparative processes in tissues of the involved joint.
3 dwg, 3 ex
SUBSTANCE: invention relates to medicine and can be applied for restoration of innervations in denervated tissue of resected small intestine in case of gastrectomy. Anterior and posterior stem vagotomy at the place of vagus nerve branching and gastrectomy with further application of esophago-jejunoanastomosis are performed. Periendoneurolysis of bundles of nerve fibres along 5 mm is performed on distal end of vagus nerve stem. Inter-tissue canal is formed on small intestine wall in projection of formed anastomosis line to submucous layer. Implantation of both distal ends of stems of vagus nerves into wall of small intestine is started, for which purpose, submerging epineural sutures are passed through formed inter-tissue canal in such a way that puncture-in and puncture-out of needle took place from inside outside, after that, when sutures are tightened, distal stems of vagus nerve are in free way submerged into formed canal by means of epineural sutures to the depth10-15 mm with further fixation at the place of their implantation.
EFFECT: method makes it possible to reduce risk of motor-evacuative function impairment.
SUBSTANCE: carbon tetrachloride (CCl4) is introduced orally into male rats at 0.1 ml per 100 g of animal's body weight for 21 days.
EFFECT: method is simple, accessible and safe; it provides a short period of time to simulate subacute hepatic failure adequate to the real clinical conditions that enables the more complete study of the pathophysiological mechanisms of this disease.
SUBSTANCE: epigastric flap is cut out on the anterior abdominal wall of a white rat, and lifted. In this case, the caudal epigastric vein and superficial epigastric neurovascular bundle are kept intact. The superficial epigastric and femoral vessels and nerves are separated. The superficial epigastric cutaneous nerve is transected. Vascular clamps are applied on the femoral artery and vein in the proximal direction from an origin of the superficial epigastric vessels, and both vessels are transected in between. The venous bed of the flap is arterialised by creating a microvascular end-to-end anastomosis between the proximal end of the femoral artery and the distal end of the femoral vein. The venous drainage is provided by creating a microvascular end-to-end anastomosis between the proximal end of the femoral vein and the distal end of the femoral vein.
EFFECT: method enables creating a multi-functional experimental model of the arterialised venous graft combined with the arterialisation of the deep veins of the lower extremities with good replant engraftment and minimal postoperative complications.
1 ex, 3 dwg
SUBSTANCE: disclosed are versions of a method based on a specially designed algorithm for assessing the deprivation action of 1,4-butane diol, thiopental and sodium oxybutyrate. The algorithm comprises 5 steps: determining the average lethal dose for the substance, describing the clinical presentation of intoxication with evaluation of neurological parameters and vital functions during intoxication in a wide range of doses, creating an array of data obtained when evaluating neurological parameters and vital functions, conducting statistical processing and constructing a mathematical model. Based on that, a coma depth index is calculated for each specific case.
EFFECT: method provides high accuracy of determining severity of damage and extent of deprivation action of chemical substances with simple and highly reliable prediction of the result of intoxication, which can be used to optimise search for pathogenetic intoxication therapy agents.
3 cl, 3 ex
SUBSTANCE: eyeball is enucleated in autopsy, washed with an alcohol solution and Hank's solution with antibiotics. An anterior segment of the eyeball is removed along a dentate line. A vitreous body and neural retina are separated from a retinal pigment epithelium (RPE). That is followed by the devitalising treatment of the separated retina for creating a cell-free retinal frame. This frame is washed in a nutrient medium with antibiotics. Then, the frame is transferred into a slide chamber, and colonised with the RPE cells. For producing an RPE cell culture, an eyecup is filled with Hank's solution with EDTL. Then, the native RPE cells are collected. A part of the RPE cells is transferred into a sterile medium for recovery, and centrifuged. Then, the recovered cells are resuspended in a growth medium, pipetted, bottled and cultured with the medium changed to form a primary culture. Then, the primary culture cells are passaged. These cells are cultured in culture flasks. The passage 1-5 cultured cells are removed as monolayer cultures from the culture surface, and the cultured RPE cells are directed as a suspension for colonisation pf the cell-free retinal frame. In this case, retinal inspection and devitalising treatment control are conducted by microscopy. Monitoring the cell cultures is ensured by immune histochemical test, PCR and microscopy.
EFFECT: method provides creating a three-dimensional PRE cell culture model with the specified parameters of number, density and tissue differentiation due to phased controlling the modelling process.
14 cl, 2 ex, 3 tbl, 28 dwg
SUBSTANCE: simulating a severe craniocerebral injury in rats with a gross persistent neurologic impairment is ensured by a single impact applied to the intact dura through a burr hole in the frontal-parietal-temporal region at an impact energy between 0.06 J to 0.09 J. Applying the exact-force impact enables quickly forming uniform groups of the above laboratory animals with the most similar focal brain substance injury.
EFFECT: obtaining more reliable results in developing and evaluating the new methods of treating a severe craniocerebral injury in humans.
SUBSTANCE: method involves tooth preparation in 3% sodium hypochlorite, further exposure in 9% nitric acid for two days, in 100% alcohol - for one day, in methyl salicylate - for two days.
EFFECT: long-term tooth translucence protection both in further storage in methyl salicylate, and in air storage with the method being easy-to-use and requiring no toxic substances to be used.
SUBSTANCE: 20 minutes before radiation in the UV chamber, an infusion of nettle, birch, plantain and oak leaves, tansy blossom taken in 1:1:1:1:1 are introduced orally into laboratory animals daily at a rate of 5 ml/kg of body weight.
EFFECT: method enables providing a manifested actoprotective and antioxidant effect on the exposed animals that gives reason to recommend the above agent to increase the non-specific body resistance with underlying pro-oxidant factors.
FIELD: medicine, pharmaceutics.
SUBSTANCE: there are described new tetracyclic compounds of general formula (I), wherein is a single or double bond; no bonds or a single bond; or V means N; T and X as shown in structure fragments above; U and W independently mean C or N with one of them shall be N; R3, R4, R5 and R6 - H; Rv is absent; Ru and Rw are independently absent or mean (C1-12)alkyl; Y =N-OR1 or NP'1, wherein R1 - H, (C1-12)alkyl optionally substituted by phenyl, phenyloxy, carboxy, (C1-12)alkoxy, (C1-12)alkoxycarbonyl, or (C2-12)alkenyl; R'1 is phenyl, or pharmaceutically acceptable salts thereof, or diastereomers thereof, or regioisomers thereof, or: mixtures thereof, a pharmaceutical composition containing them, and specific compounds for cysteine protease inhibition.
EFFECT: compounds may be used in medicine in treating cancer, neurodegenerative diseases, inflammatory disorders, cardiovascular diseases, etc.
8 cl, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to biotechnology and molecular genetics. There are disclosed the versions of disintegrin and their use in pharmacology. The version of disintegrin involves the recovered polypeptide which possesses αvβ3 receptor antagonist activity and substantially lower ability to block αIIbβ3 and/or α5β1 integrin receptor than wild-type disintegrin. The polypeptide is coded by a modified nucleotide sequence of disintegrin possessing lower ability to bind to αIIbβ3 and/or α5β1 integrin than wild-type disintegrin.
EFFECT: invention may be used for treating and/or preventing the αvβ3 integrin-associated diseases in a mammal, which include without limitation osteoporosis, bone tumor or cancer growth, angiogenesis-related tumor growth and metastasis, tumor metastasis in bone, malignancy-induced hypercalcemia, angiogenesis-related eye diseases, Paget's disease, rheumatoid arthritis, and osteoarthritis.
23 cl, 16 dwg, 1 tbl, 25 ex
SUBSTANCE: invention refers to medicine, namely oncology, and may be used in integrated treatment of liver metastases of colon cancer. That is ensured by pre-operative blood sampling 200 ml followed by preparing autothrombotic mass by centrifugation. Autothrombotic mass 5 ml and chemopreparations are placed into a first flask; the remained blood corpuscles, plasma and chemopreparations are placed into a second flask. The flasks are separately incubated for 40 minutes at 37°C. A colonic laparoscopic operation follows. The operation begins with the drop-by-drop intravenous introduction of the incubated blood corpuscles and chemopreparations from the second flask. It is followed by laparoscopic extraction of liver metastases; thereafter incubated autothrombotic mass with chemopreparations from the first flask are introduced through a laparoscopic puncture needle into a bed of the extracted metastasis.
EFFECT: method enables reducing rate of tumour progression, as well as improving haemostasis within a liver resection region due to local intratissual chemotherapeutic action.
SUBSTANCE: invention refers to medicine, namely oncology, and may be used in integrated treatment of liver metastases of stomach and colon cancer. That is ensured by pre-operative blood sampling 200 ml followed by preparing autoplasma by centrifugation. Autoplasma 5 ml and chemopreparations are placed into a first flask; the remained blood corpuscles, plasma and chemopreparations are placed into a second flask. The flasks are separately incubated for 40 minutes at 37°C. A colonic surgery follows. The surgery begins with the drop-by-drop intravenous introduction of the incubated blood corpuscles and chemopreparations from the second flasks. It is followed by ultrasound-aided radio frequency thermal ablation of liver metastases. Upon completion, incubated autoplasma and chemopreparations from the first flask are introduced through an infusion pump in an electric surgical device in a bed of thermally destructed metastasis.
EFFECT: method enables reducing tumour progression rate and providing higher survival rate ensured by the combined effect of surgical procedure and intratissual chemotherapy.
SUBSTANCE: invention relates to medicine, namely, to oncology, and can be used in complex treatment of metastases in liver, in particular of large intestine cancer. For this purpose, performed is sampling of 200 ml of blood with its further centrifuging and separation of autoleukomass. 5 ml of autoleukomass and chemical preparations are placed into the first vial, the remaining formed elements of blood, plasma and chemical preparations are placed into the second vial. Vials are incubated separately for 40 minutes at 37°C. After that transcutaneous radio-frequency thermal ablation of metastases into liver is performed under ultrasound control. When thermal ablation is finished, incubated autoleukomass with chemical preparations from the first vial is introduced into the bed of metastasis subjected to thermal destruction by means of infusion pump in electrosurgical device. Simultaneously incubated formed elements of blood, plasma with chemical preparations from the second vial are introduced intravenously by drop infusion.
EFFECT: method makes it possible to reduce frequency of tumour progressing and increase survival of patients due to combination of surgery, local intra-tissue chemical therapy and autohemochemotherapy.
SUBSTANCE: invention refers to medicine, namely oncology, and may be used in conducting the regional infusion chemotherapy of hepatic metastases. That is ensured by introducing a chemopreparation into an artery feeding a metastatic centre that is followed by occlusion of arterial branches. Before introducing the chemopreparation in areas of the hepatic parenchyma adjoining the metastatic centres, 15% sodium fumarate 200-300 ml is introduced at 0.5-1.0 ml/sec.
EFFECT: use of the given method enables reducing or eliminating side reactions of the chemotherapy.
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to compounds of formula (l) and their pharmaceutically acceptable salts wherein X represents CH or N; one of R1 and R2 represents H and the other one is specified in OR6, SR6, Me, Et and SOR8; R3 is specified in tert-butylmethyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl; R4 cyclopentyl C1-8alkyl optionally substituted by one C1-6alkoxy group; or C3-8cycloalkyl optionally substituted by one C1-6alkoxy group; R6 represents C1-8alkyl; and R8 represents C1-8alkyl, as well as to based pharmaceutical compositions and applying them as cathepsin K inhibitors and for analysing the cathepsin K inhibitors specified above.
EFFECT: there are presented new biologically active compounds and using them in medicine and pharmaceutics.
12 cl, 79 ex, 2 tbl
SUBSTANCE: invention relates to stable metastin derivatives, having excellent biological activity. The disclosed metastin derivatives improve stability, gelation tendency is reduced, pharmacokinetics are also improved, and an excellent cancer metastasis suppressing activity or a cancer growth suppressing activity is exhibited.
EFFECT: metastin derivatives of the present invention also have a gonadotropic hormone secretion suppressing activity and sex hormone secretion suppressing activity.
5 cl, 4 tbl, 18 ex
SUBSTANCE: invention relates to compounds of formula: where X is selected from a group consisting of hydrogen, halogen, cyano, nitro, ethenyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl; Y denotes hydrogen or fluorine; R4 and R5 denote hydrogen or lower alkyl; one of R1 and R8 is selected from a group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl, and the other denotes hydrogen; one of R6 and R7 is selected from a group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl, and the other denotes hydrogen, cyano group or lower alkyl; R2 is selected from a group consisting of hydrogen, lower alkyl and substituted lower alkyl; R3 is selected from a group consisting of oxygen, sulphur and NNH(C=O)OR9; R9 denotes lower alkyl or substituted lower alkyl; where the term "substituted" denotes substitution with 1-5 substitutes independently selected from a group consisting of lower alkyl, lower alkenyl, lower alkynyl, dioxo-lower alkenyl, halogen, hydroxy, -CN, -CF3, -NH2, -N(H, lower alkyl), N(lower alkyl)2, aminocarbonyl, carboxy, -NO2, lower alkoxy, thio-lower alkoxy, lower alkylsulphonyl, aminosulphonyl, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, lower alkylcarbonyl-NH, fluoro-lower alkyl, fluoro-lower alkoxy, lower alkoxy-carbonyl-lower alkoxy, carboxy-lower alkoxy, carbamoyl-lower alkoxy, hydroxy-lower alkoxy, -NH2-lower alkoxy, -N(H, lower alkyl)-lower alkoxy, -N(lower alkyl)2-lower alkoxy, benzyloxy-lower alkoxy, mono or di-lower alkyl, substituted with aminosulphonyl or lower alkyl, which can optionally be substituted with a halogen, hydroxy, -NH2, -N(H, lower alkyl) or -N(lower alkyl)2; the term "heteroaryl" denotes an aromatic heterocyclic ring system containing up to two rings; and the term "heterocycle" denotes a substituted or unsubstituted 5-8-member mono- or bicyclic, aromatic or non-aromatic hydrocarbon, where 1-3 carbon atoms are replaced with a heteroatom selected from a nitrogen, oxygen or sulphur atom; and pharmaceutically acceptable salts thereof or esters. The invention also relates to a pharmaceutical composition, use of compounds in claims 1-31, as well as to methods of producing compounds of formulae II and III.
EFFECT: obtaining novel biologically active compounds which inhibit interaction of MDM2 protein with a p53-like peptide.
38 cl, 186 ex
SUBSTANCE: invention refers to creation of peptides derived from area 32-51 of LALF proteins, deprived of LPS and heparin binding capability, and intensifying antineoplastic and immunomodulatory effect.
EFFECT: peptides and their combinations can be applied in cancer treatment, and also in a combination with the other standard therapies.
6 cl, 13 dwg, 1 tbl, 10 ex
SUBSTANCE: single-thread RNA is described with common formula G1XmGn or C1XmCn, which is modified with lipid. The single-thread RNA may act as immunogen, inducing the inherent immune response. The pharmaceutical composition is described. The invention may be used to treat infectitious diseases, allergies or cancer diseases.
EFFECT: improved composition properties.
22 cl, 15 dwg, 24 ex