16-(1,2,4-oxadiazol-3-yl)-15,16-epoxilabdanoids possessing cytotoxic activity on human tumour cells

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, specifically to 16-(1,2,4-oxadiazol-3-yl)-15,16-epoxilabdanoids of formula

wherein R=Me(Ia), Ph(1b), CH2Cl(lc) possessing an ability to inhibit human tumour cell growth. The compounds are produced of lambertianic acid contained in Siberian cedar gum and fir needles.

EFFECT: there are produced new compounds which possess considerable cytotoxic activity on human tumour cells.

1 cl, 1 tbl, 4 ex

 

The invention relates to organic chemistry, specifically to the new 16-(1,2,4-oxadiazol-3-yl)-15,16-epoxidation formula (Ia-in)

where R=Me (a), Ph (b), CH2Cl (),

with significant cytotoxicity to tumor cells.

These properties suggest the possibility of using the compounds in medicine as a pharmaceutical drug.

In recent years increasing attention to the study of cytotoxic lactones Larionova type. According To [I. Chinou. Labdanes of Natural Origin-Biological Activities (1981-2004) // Curr. Med. Chem., 2005, v.12, p.1295-1317]in this series found more than 20 compounds promising as anticancer agents. Active anticancer agents are natural labdanoids with modified furan cycle, for example, biosolid (II) and zuromin In (III).

These natural metabolites are analogous to the properties of the claimed compounds. Biosolid (II) is contained in the neutral part of the oleoresin of Pinus sibirica Pinus sibirica R. Mayr. In [Shults E.E., J. Velder, H.-G. Schmalz, Chernov S.V., T.V.Rubalova, Y.V. Gatilov, G. Henze, G.A. Tolstikov, A. Prokop. Gram-scale synthesis of pinusolide and evaluation of its antileukemic potential. // Bioorg. Med. Chem. Lett., 2006, v.16 (16), p.4228-4232] described how to obtain it from larionovo of diterpenoid lambertianic acid (IV).

And TraceMonkey and chemopreventive potential of biosolid was studied in vitro on cell lines lymphoma BJAB Burkitt. It was shown that biosolid not only reduces the proliferative activity of tumor cells at relatively low concentrations, but also specific induces apoptosis in 70% of cells at a concentration of 100 µM. Apoptosis in BJAB cells is mediated by loss of mitochondrial membrane potential. In essence, biosolid at a concentration of 100 µM leads to loss of mitochondrial membrane potential, indicating that this connection uses the mechanism of mitochondrial apoptosis in the corresponding signaling pathway cell death. A significant induction of apoptosis by pinacolada (100 µM) was also observed in the ex vivo experiment. Fragmentation of DNA was observed in the primary lymphoblastic cells, and leukemia. Biosolid ex vivo overcomes anthracycline resistance primary lymphoblasts derived from patients with high risk acute lymphoblastic leukemia (ALL) and poor response to chemotherapy [Shults E.E., J. Velder, H.-G. Schmalz, Chernov S.V., T.V. Rubalova, Y.V. Gatilov, G. Henze, G.A. Tolstikov, A. Prokop. // Bioorg. Med. Chem. Lett., 2006, v.16 (16), p.4228-4232; Koo K.A., Lee M.K., Kim S.H., Jeong E.J., Kim S.Y., Oh T.N., Kim Y.C. Pinusolide and 15-methoxypinusolidic acid attenuate the neurotoxic effect of staurosporine in primary cultures of rat cortical cells. // Br. J. Pharmacol., 2007, v.150 (1), p.65-71].

The authors of [B.H. Han, Yang, H.O., Kang Y.-H., Suh, D.-Y., Go H.J., Song, W.-J., Kim Y.Ch., Park, M.K. In Vitro Platelet-Activating Factor Receptor Binding Inhibitory Activity of Pinusolide Derivatives: A Structure-Activity Study. // J. Med. Chem. 1998, v.41 (14), p.2626-2630] described pinosol the d as the new antagonist of factor platelet aggregation. In experiments using rabbit platelets was obtained the value of the IC50for platelet aggregation caused PHAT (factor platelet aggregation) from 19 to 5 µM at lower concentrations VEILS from 500 to 5 nm. ED50in vivo amounted to 1.1 mg/kg for intravenous and 69.0 mg/kg per os.

Biosolid (2 mg/kg) also has local anti-inflammatory effect in the experiment on the ear of a mouse; the compound's potency comparable to hydrocortisone [CCW K.A., S.H. Sung, Kim Y.C. A New Neuroprotective Pinusolide Derivative from the Leaves of Biota orientalis // Chem. Pharm. Bull., 2002, v.50(6), p.834-836].

The main disadvantages of pharmacological action of biosolid (II) is its use in large doses (IC 100 µM), however, due to the selectivity of pharmacological (anti-proliferative and apoptosis inducing) effect associated with activation of caspase-3 indicated epoxyamine, obtaining its structural analogues is of considerable interest to create anti-tumor agents with directed action cycle of cell division.

For taromina In (III) was found cytotoxic activity in various tumor human cells with selectivity for tumor cells of the breast MCF-7 (IC50=0.59 μm). [F. Abas, N.H. Lajis, K. Shaari, D.A. Israf, J. Stanslas, U.K. Yusuf, S.M. Raof. A Labdane Diterpene Glucoside from the Rhizomes of Curcuma mangga // J. Nat. Prod. 2005, v.68 (7), p.1090-1093]. The compound (III) is inaccessible metabol the volume.

Similar in structure to the claimed compounds is aslacton 16-formylmethylene (V)with antioxidant, hepatoprotective and haemostimulating activity [Patent RU 2353620. Kharitonov Y., Schulz EE, Sorokina I.V., Tolstikova T.G., Baev DS., Zhukov N.A., Tolstikov G.A. (Z)-Methyl-16-(5-oxo-2-phenyloxazol-4-ylidenemethyl)-15,16-epoxy-8(17), 13(16),14-libdatrie-18-oat, possesses antioxidant, hepatoprotective and haemostimulating activity. Publ. 27.04.2009, bull. No. 12; S.A. 2009, 150, P495008k].

Analogous to the properties of the claimed compounds [in addition to natural Radanovich of diterpenoids II, III] is a vegetable triterpenoid betulin acid (VI). Describes some of the biological effects of the agent (VI), including antiviral, antiparasitic, antibacterial activity and in particular the growth retardation of tumor cells [Eiznhamer D.A, Xu Z.Q. Betulinic acid: a promising anticancer candidate // I. Drugs. - 2004. - V.7(4). - P.359-373]. Antitumor activity was demonstrated in cell lines of melanoma [Liu W.., But J.., Cheung F.W., Liu V.R., Ye W.., Che .N. Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line // Eur. J. Pharmacol. - 2004. - V.498(1-3). - P.71-78], head and neck squamous cell carcinoma [Eder-Czembirek With, Czembirek C, Erovic BM, et al. Combination of betulinic acid with cisplatin-different cytotoxic effects in two head and neck cancer cell lines. // Oncol Rep - 2005 - V.14 - P.667-671], leukemia [H. Ehrhardt, Fulda, S., Fuhrer, M., Debatin K.M., Jeremias I. Betulini acid-induced apoptosis in leukemia cells // Leukemia. - 2004. - V.18(8). - P.1406-1412] and other tumor cell lines [Yun Y., Han, S., Park, E., Yim D., Lee, S. K. Immunomodulatory activity of betulinic acid by producing proinflammatory cytokines and activation of macrophages // Arch. Pharm. Res. - 2003. - V.26(12). - P.1087-1095].

In 2000, betulin acid (VI) was included in the programme RAID (Rapid Access to Intervention Development) of the National cancer Institute as a potential anticancer agent (http://dtp.nci.nih.gov/docs/small_mol/status_small_mol.html). Currently, the drug is based on Betulinol acid is undergoing clinical trials in the U.S. as a treatment for malignant melanoma (http://clinicaltrials.gov/show/NCT00346502).

Object of the invention is the creation of new tools, which are able to inhibit the growth of human tumor cells, based on the available plant metabolite lambertianic acid (IV).

The problem is solved with new chemical compounds 16-[(5-R)-1,2,4-oxadiazol-3-yl]-15,16-paxilabdominal, formula (Ia-in), with the ability to suppress the growth of human tumor cells, SEM-13, MT-4 and U-937.

where R=Me (a), Ph (b), CH2Cl (in)

The method of obtaining the compounds (Ia-in) is shown in figure 1 sequence of transformations lambertianic acid (IV). Methylation lambertianic acid (IV) gives methyl ester (IVa), formirovanie which conditions reacts is, Vilsmeier-khaak leads to methyl ether 16-formylamino acid (VII), which is easily detected by crystallization (yield ~50%) [Klock D.A., M. Shakirov, Grishko V.V., Raldugin VA Methyl ether lambertianic acid in the reaction of Vilsmeier-khaak and desencibilizirutaya photocyclization of product formed. "Izv. An. The series of chem., 1995, No. 12, s-2516]. Processing 16-formylmethylene (VII) with an aqueous solution of ammonia in the presence of iodine in tetrahydrofuran get 16-cyanomethylation (VIII) (yield 91%) [Kharitonov Y., Schulz EE, M. Shakirov, Bagryanskaya YOU, Tolstikov G.A. Synthetic transformation of higher terpenoids. XXII. Interaction derived lambertianic acid with tsinkorganicheskih reagents, obtained from ethylbromoacetate. // Ukr. body. chemistry. 2010, vol.46, 9, s-1348]. Interaction between the nitrile (VIII) with hydrochloric acid hydroxylamine in the presence of a base get amidoxime (IX) (yield 78%). When interacting amidoxime (IX) with acetyl chloride or benzoyl chloride in the presence of triethylamine get N-O-acyl derivatives of amidoximes (Ha,b) (yield 100% and 88%, respectively), boiling which in toluene synthesize 1,2,4-oxadiazole (Ia,b) (yield 63% and 74%). Interaction amidoxime (IX) with 2-chloroacetyl chloride in the presence of triethylamine leads to labdanoids oxadiazole (IB) (yield 39%).

The technical result of the invention is to provide new derivatives of labda is oidov (Ia-in), with the ability to suppress the growth of human tumor cells. The new compounds are obtained by chemical modification of available plant metabolite Pinus sibirica R. Mayr. - lambertianic acid (IV), which easily stands out from the timber product - cedar resin or needles of cedar, which is the tonnage of waste area [Tgolemanov, Iavarone, Mpoly., Uwharrie, Svernov, Eel, Gaellic. Neurotropic activity of adducts lambertianic acid with N-substituted maleinimide. Chemical and pharmaceutical journal. 2004, V. 38(10), s-15]. Physico-chemical constants of new, first obtained the compounds described in examples 1-3.

Biological activity of compounds (Ia-in) was studied by determining the ability to suppress the growth of tumor cells SEM-13, MT-4 and U-937. Cytotoxic activity was determined by determining the CCID50the dose inhibiting the viability of tumor cells by 50%. To determine CCID50used standard MTT test as described in the recommendations [Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. // J Immunol Methods 1983, v.16 (1), p.55-63; Wilson J. K., J.M. Sargent, Elgie A.W., Hill, J.G., Taylor, C.G. A feasibility study of the MTT assay for chemosensitivity testing in ovarian malignancy // Br. J. Cancer, 1990, v.62 (2), p.189-194]. The results of the study of the cytotoxic activity are shown in the table.

Cytotoxic activity of 1,2,4-oxadiazolidine(Ia-in)ConnectionTumor cells SEM-13, CCID50, (µm)Tumor cells U-937, CCID50, (µm)Tumor cells MT-4, CCID50, (µm)Ia1.1±0.124.4±2.123.5±1.2IB9.5±1.114.7±1.045.1±2.2IB0.08±0.036.7±0.50.76±0.2Betulin acid (VI)4.3±0.86.1±1.411.6±2.2Biosolid (II)9.2±0.0234.1±0.849.1±0.8Lambertianic acid (IV)69.143.292.1

From the table it is seen that the inventive compounds (Ia-in) have the ability to inhibit the growth of leukemia cells, the human is CA. Their cytotoxic dose of 0.08-9.5 μm for cells T-cell leukemia CEM-13, 6.7-24.4 μm for cells human monocytes U-937 and 0.76-23.5 μm - cell T-cell leukemia MT-4. The highest cytotoxic activity has a connection (Ie). This connection has appeared in 115 times more active inhibitor viability of tumor cells SEM-13, 5 times more active inhibitor viability of tumor cells U-937 and 65 times more active inhibitor viability of tumor cells MT-4 than biosolid (II). The compound is also 50 times more actively inhibits the growth of cells SEM-13 and 15 times more effective against tumor cells MT-4 than betulin acid (VI). The structure of compound (IB) is the presence of chlormethine Deputy in oxadiazine fragment labdanoids. It is possible that its cytotoxic effects associated with alkylation gurinovka DNA bases tumor cells by imidazole part, leading to the elimination of charismata and thus stopping the multiplication of cells.

Compounds (Ia-in) have a selective action on tumor cells SEM-13, and compounds (Ia) and (IB) exceed 10 times and 100 times, respectively, the cytotoxic drug dose comparison of biosolid (II). Cytotoxic activity of compounds (IB) on all models is similar to what Ecotoxicity of biosolid (II). Lambertianic acid (IV) to a much greater dose blocked the growth of tumor cells SEM-13, MT-4 and U-937 (CCID50=43.2-92.1 μm).

The invention is illustrated by the following examples.

Example 1. Getting 16-(5-methyl-1,2,4-oxadiazol-3-yl)methylamphetamine (Ia).

1. (1S,4aR,5S,8aR)-Methyl 5-[2-(furan-3-yl)ethyl]-1,4A-dimethyl-6-methylundecane-naphthalene-1-carboxylate (methylarbutin) (IVa).

To a solution of 2.5 g lambertianic acid (IV) in 50 ml of ethanol is added 1.99 g dimethylsulfate and with good stirring for 15 min was added dropwise a solution of 2.2 g of potassium hydroxide in 22 ml of water. The temperature should not exceed 40°C. the Reaction mass is stirred for 2 h at room temperature, then add 100 ml of water, the product extrahiert methylene chloride (4×50 ml). The combined extract was washed with 1%aq. NaOH solution (2×25 ml), water (3×25 ml) and dried with magnesium sulfate. The solvent is evaporated, the residue to obtain 2.38 g (91%) of methyl ester lambertianic acid (IVa) in the form of butter.(1.3, chloroform). Data of NMR spectra1H and13To correspond to the one presented in [W.G. Dauben, German V.F. The structure of lambertianic acid. A new diterpenic acid. // Tetrahedron. 1966, v.22 (2), p.679-683].

2. (1S,4aR,5S,8aR)-Methyl 5-[2-(2-formylfuran-3-yl)ethyl]-1,4A-dimethyl-6-methylentetrahydrofolate-1-carboxylate(16-formalmathematical) (VII).

To mix the solution 8. g (26.7 mmol) of diterpenoid (IVa) in 40 ml of DMF is added dropwise 4.8 ml (52.5 mmol) POCl 3(20°C). The reaction mass leave at 20°C for 48 h, then poured onto 70 ml of ice water. To the resulting mixture are added 20 ml of a saturated aqueous solution of NaOAc, resulting organic layer is separated, the aqueous layer was extracted with ether. The combined extracts washed with 5%aqueous soda solution and dried over MgSO4. The solvent is evaporated in vacuo, the residue chromatographic on Al2O3(20:1, petroleum ether-ether, 4:1). The fractions containing the product crystallized from hexane, to obtain 4.9 g (51%) 16-formyl-methylamphetamine (VII). Data of NMR spectra1H and13To correspond to the one presented in [Klock D.A., M. Shakirov, Grishko V.V., Raldugin VA Methyl ether lambertianic acid in the reaction of Vilsmeier-khaak and desencibilizirutaya photocyclization of product formed. "Izv. An. The series of chem. 1995, No. 12, s-2516].

3. (1S,4aR,5S,8aR)-Methyl-5-[2-(2-cianfuran-3-yl)ethyl]-1,4A-dimethyl-6-methylindene-hydronephrosis-1-carboxylate (methyl ester of 16-cyano-15,16-epoxy-8(17),13(16),14-libdatrie-18-OIC acid) (VIII).

To a solution of 0.50 g (1.40 mmol) of 16-formylmethylene (VII) in 2 ml THF with vigorous stirring, 5 ml of aq. NH3(70 mmol) and 0.39 g (1.54 mmol) of I2. The reaction mixture is stirred for 5 h, diluted with 30 ml of water and extracted with chloroform (3 times 20 ml). Organic fraction thing in common is t, washed with water (3×20 ml) and dried MgSO4. The solvent is evaporated, the residue is crystallized from hexane. Obtain 0.45 g (91%) of the nitrile (VIII). TPL 72-75°C.(1.9, HLF). UV-spectrum, λmaxnm (lg ε): 201 (4.06), 241 (4.02), 279 (3.06). The infrared spectrum, cm-1: 788, 894, 1034, 1091, 1124, 1153, 1166, 1204, 1592, 1644, 1678, 1724, 2224, 3070, 3147. An NMR spectrum1N (δ, ppm, J, Hz) [in the description of NMR spectra1H and13With all connections made with the numbering of atoms diterpene skeleton, shown in structure (IV)]: 0.47 (3H, WITH20H3), 0.97 m (1H, H1), 1.00 m (1H, H3), 1.14 (3H, WITH19H3), 1.25 DD (1H, H5, J 11.7, 2.6), 1.49 m (1H, H2), 1.58 m (1H,H9), 1.63 m (1H, H11), 1.73 m, 1.77 m, 1.82 m (4H, H1,2,6,11), 1.87 m (1H, H7), 1.96 m (1H, H6), DM 2.12 (1H, H3I , Jheme12.3), 2.39 m (2N, N12,7), 2.69 m (1H, H12), 3.57 (3H, och3), 4.54, 4.90 (2H, N.17), 6.36 (1H, H14, J 1.8), 7.43 (1H, H15, J 1.8). An NMR spectrum13S, δ, ppm: 12.13 (With20), 19.45 t (2), 23.35 t (12), 23.48 t (11), 25.77 t (6), 28.32 (With19), 37.68 t (3), 38.16 t (7), At 38.63 t (1), 39.78 (With4), At 43.80 (With10), 50.69 (och3), 54.80 d (9), 55.73 (With5), 106.22 t (17), 111.13 (CN), 112.02 d (14), 123.12 (With13), 138.98 (With16), 146.63 d (15), 146.80 (With8), 177.15 (With18). Mass spectrum, m/z (IRel, %): 357 (0.39), 356(2), 355 (9), 340 (10), 296 (15), 249 13), 189 (26), 181 (12), 122 (11), 121 (100), 119 (11), 110 (37), 107 (22), 109 (19), 105 (14), 95 (11), 93 (17), 91 (15), 81 (27), 79 (15), 67.0 (12), 55.0 (14), 43.9 (19), 41.0 (14). Found [M]+355.2137. C22H29O3N. the Calculated M 355.2142.

4. (1S,4aR,5S,8aR)-Methyl 5-{2-(2-((Z)-N'-hydroxycarbonylmethyl)furan-3-yl]ethyl}-1,4A-dimethyl-6-methylene-decahydronaphthalene-1-carboxylate (IX).

To a stirred solution of 1.00 g (2.8 mmol) of the nitrile (VIII) in 10 ml of methanol successively added 0.59 g (8.4 mmol) of hydroxylamine hydrochloric acid and 2.13 ml (11.3 mmol) Et3N. the Reaction mixture was stirred at room temperature for 5 h, add 50 ml of water, the product extracted with chloroform (3×50 ml). The organic extracts washed with water (3×40 ml), dried with MgSO4and evaporated. The residue is crystallized from hexane. Obtain 0.85 g (78%) of compound (IX) in the form of a white precipitate. UV-spectrum, λmaxnm (lg ε): 256 (3.85). The infrared spectrum, cm-1: 893, 926, 1157, 1228, 1444, 1581, 1606, 1649, 1724, 2947, 3412, 3491. An NMR spectrum1N (δ, ppm, J, Hz): 0.47 (3H, WITH20H3), 0.99 dt (1H, H1, J 13.3, 4.1), 1.01 dt (1H, H3, J 13.5, 3.5), 1.14 (3H, WITH19H3), 1.26 DD (1H, H5, J 12.3, 2.6), DM 1.45 (1H, H2, J 11.3), 1.58 m (1H, H11), 1.62 USS (1H, H9), 1.77, 1.81 m (4N, N1,2,6,11), 1.87 DM (1H, H7J 12.2), 1.94 DD (1H. N6J 12.3, 2.6), DM 2.12 (1H, H3I , Jheme14.3), 2.39 m (1H, H7), 2.50 m (1H, H12), 2.73 m (1H, H12), 3.58 (3H, och3), 4.61, 4.87 (2H, N.17,17), 4.94 (2H, NH2, 6.32 (1H, H14, J 1.8), 7.32 (1H, H15, J 1.8), 7.87 USS (1H, HE). An NMR spectrum13S, δ. ppm: 12.35 (With20), 19.71 t (2), 23.51 t (12), 23.93 t (11), 26.03 t (6), 28.55 C (19), At 37.93 t (3), 38.47 t (7), At 38.67 t (1), 39.97 (With4), 44.02 (With10), 50.90 K (och3), 55.14 d (9), 55.97 d (5), 106.36 t (17), 113.25 d (14), 125.40 (With13), 140.20 (With16), 141.42 d (15), 146.25 (With8), 147.61 d (CH=), 177.57 (With18).

5. (1S,4aR,5S,8aR)-Methyl 5-{2-[2-((Z)-N'-acetoxymethyl)furan-3-yl]ethyl}-1,4A-dimethyl-6-methylene-decahydronaphthalene-1-carboxylate (Ha).

To a stirred solution of 1.00 g (2.57 mmol) amidoxime (IX) and 0.22 ml (3.09 mmol) of acetyl chloride in 10 ml methylene chloride in a stream of argon is added dropwise 0.71 ml (5.15 mmol) Et3N. the Reaction mixture was stirred at room temperature for 10 h, add 50 ml of water, the product extracted with chloroform (3×50 ml). The organic extracts washed with water (3×40 ml), dried with MgSO4and evaporated. The remainder chromatographic on silica gel (eluent - chloroform). Obtain 1.11 g (100%) of the compound (Ha) in the form of oil. UV-spectrum, λmaxnm (lg ε): 257 (3.96). The infrared spectrum, cm-1: 667, 755, 892, 947, 1005, 1155, 1228, 1366, 1435, 1504, 1603, 1638, 1721, 1756, 2847, 2946, 3370, 3505. An NMR spectrum1N (δ, ppm, J, Hz): 0.46 (3H, WITH20H3), 0.99 dt (2N, N1,3, J 13.5, 3.2), 1.13 (3H, WITH19H3), 1.25 DD (1H, H , J 12.4, 2.8), DM 1.45 (1H, H2, J 12.5), 1.57 m (1H, H11), 1.60 USS (1H, H9), 1.73 m 1.76 m 1.78 m (4N, N1,2,6,11), 1.85 m (1H, H7), 1.93 m (1H, H6), 2.10 DM (1H, H3I , Jheme13.9), 2.20 (3H, CH3), 2.37 m (1H, H7), 2.60 m (1H, H12), 2.80 m (1H, H12), 3.56 (3H, och3), 4.62, 4.85 (2H, N.17), 5.18 (2H, NH2), 6.34 (1H, H14, J 1.5), 7.35 (1H, H15, J 1.5). An NMR spectrum13S, δ, ppm: 11.89 (With20), 19.21 (CH3), 19.27 t (2), 23.27 tons, 23:71 t (11,12), At 25.56 t (6), 28.05 (With19), 37.46 t (3), At 37.96 t (7), 38.26 t (1), 39.51 (With4), 43.53 (With10), 50.38 K (och3), 54.83 d (9), 55.44 d (5), 106.08 t (17), 113.18 (With14), 127.53 (With13), 138.42 (With16), 144.14 d (15), 147.04 (With8), 149.08 with (=), 168.80 (CO), 176.98 (With18).

6. (1S,4aR,5S,8aR)-Methyl-1,4A-dimethyl-5-{2-[2-(5-methyl-1,2,4-oxadiazol-3-yl)furan-3-yl]ethyl}-6-methylentetrahydrofolate-1-carboxylate [16-(5-methyl-1,2,4-oxadiazol-3-yl)methylarbutin] (Ia).

A solution of 1.00 g (2.32 mmol) of the compound (Ha) in 10 ml of toluene is boiled for 50 hours, the Solvent evaporated, the residue chromatographic on silica gel (eluent - chloroform). Obtain 0.60 g (63%) of the compound (Ia) in the form of oil. [α]580+30.83° (2.72, CHCl3). UV-spectrum, λmaxnm (lg ε): 262(3.96). The infrared spectrum, cm-1: 665, 758, 888, 986, 1031. 1092, 1154, 1185, 1229, 1268, 1347, 1423, 1448, 1460, 1523, 1585, 1626, 1722, 2846, 2946. An NMR spectrum1N (δ, ppm, J, Hz):0.44 (3H, With20H3), 0.97 dt (2N, N1,3, J 13.5, 3.9), 1.11 (3H, WITH19H3), 1.23 DD (1H, H5, J 12.2, 2.7), 1.42 DM (1H, H2, J 14.2), 1.60 m (1H, H11), 1.62 USS (1H, H9), 1.72-1.77 m (4N, N1,2,6,11), 1.82 m (1H, H7), 1.93 m (1H, H6), 2.09 DM (1H, H3I , Jheme13.2), 2.36 etc (1H, H7, J 12.0, 2.7), 2.57 (3H, CH3), 2.62 m (1H, H12), 2.88 m (1H, H12), 3.54 (3H, och3), 4.64, 4.85 (2H, N.17), 6.38 (1H, H14, J 1.5), 7.45 (1H, H15, J 1.5). An NMR spectrum13S, δ, ppm: 12.09 (With20), 12.44 (CH3), 19.81 t (2), 24.04 t, 24.07 t (11,12), 26.11 t (6), 28.65 (With19), 38.06 t (3), 38.57 t (7), 38.89 t (1), 40.12 (With4), 44.14 (With10), 50.97 K (och3), 55.44 d (9), 56.12 d (5), 106.44 t (17), 113.52 (With14), 130.56 (With13), 137.36 (With16), 144.08 d (15), 147.60 (With8), 161.73 (With3'), 175.89 (With5'), 177.55 (With18). Mass spectrum, m/z (IRel, %): 412 (13), 411 (10), 397 (13), 369 (10), 353 (15), 245 (12), 231 (13), 203 (10), 189 (24), 177 (29), 166 (15), 164 (14), 163 (15), 133 (10), 122 (11), 121 (100), 119 (11), 109 (12), 107 (21), 105 (14), 95 (11), 93 (17), 91 (15), 81 (27), 79 (16), 67 (11), 55 (15), 43 (25), 41 (13), 18 (12). Found [M]+412.2338. C24H32O4N2. Calculated M 412.2357.

Example 2. Getting 16-(5-phenyl-1,2,4-oxadiazol-3-yl)methylamphetamine (IB).

Stages 1-4 are performed according to procedures described in example 1.

5. (1S,4aR,5S,8aR)-Methyl-5-(2-{2-[(Z)-N'-(benzoyloxy)carbamido is]furan-3-yl}ethyl)-1,4A-dimethyl-6-methylentetrahydrofolate-1-carboxylate (HB).

To a stirred solution of 1.00 g (2.57 mmol) amidoxime (IX) and 0.36 ml (3.09 mmol) of benzoyl chloride in 10 ml methylene chloride in a stream of argon is added dropwise 0.71 ml (5.15 mmol) Et3N. the Reaction mixture was stirred at room temperature for 10 h, add 50 ml of water, the product extracted with chloroform (3 times 50 ml). The organic extracts washed with water (3×40 ml), dried with MgSO4and evaporated. The remainder chromatographic on silica gel (eluent - petroleum ether-ether, 4:1). Obtain 1.12 g (88%) of compound (HB) in the form of oil. UV-spectrum, λmaxnm (lg ε): 229 (4.21), 267 (4.11). The infrared spectrum, cm-1: 708, 757, 892, 1025, 1066, 1089, 1154, 1261, 1316, 1450, 1603, 1634, 1724, 2847, 2947, 3380, 3501. An NMR spectrum1N (δ, ppm, J, Hz): 0.50 (3H, WITH20H3), 1.01 dt (2H, H1,3, J 13.2, 4.2), 1.15 (3H, WITH19H3), 1.30 DD (1H, H5J 12.6, 2.3), 1.46 DM (1H, H2, J 14.2), 1.65 m (1H, H11), 1.70 USS (1H, H9), 1.78-1.84 (m 4H, H6,1,2,11), 1.90 m (1H, H7), 1.97 m (1H, H6), DM 2.12 (1H, H3I , Jheme13.2), 2.39 m (1H, H7), 2.70 m (1H, H12), 2.91 m (1H, H12), 3.59 (3H, och3), 4.70, 4.90 (2H, N.17), 5.20 (2H, NH2), 6.40 (1H, H14, J 1.5), 7.40 (1H, H15, J 1.5), 7.47 t (2N, H3',5', J 7.6), 7.57 m (1H, H4'), 8.07 DD (2N, N2',6', J 7.6, 1.2). An NMR spectrum13S, δ, ppm: 12.50 (With20), 19.85 t (2), At 23.91 t (12), At 24.48 t (17), 26.16 t (6), 28.69 C (19), 38.07 t (3), 38.57 t (sup> 7), 38.83 t (1), 40.16 (With4), 44.18 (With10), 51.02 K (och3), 55.50 (With9), 56.06 d (5), 106.73 t (17), 113.90 d (14), 128.37 (With3',5'), 128.84 (With13), 129.33 (With2',6'), 129.54 (With1'), 132.82 d (4'), 138.87 (With16), 142.74 d (15), 147.66 (With8), 150.70 with (=), 163.65 (FR)177.80 (With18). Mass spectrum, m/z (IRel, %): 492 (0.53), 474 (15), 371 (10), 239 (18), 225 (10), 122 (44), 121 (26), 105 (100), 77 (43), 51 (13). Found[M]+492.2630. C29H36O5N2. Calculated M 492.2619.

6. (1S,4aR,5S,8aR)-Methyl-1,4A-dimethyl-6-methylene-5-{2-[2-(5-phenyl-1,2,4-oxadiazol-3-yl)furan-3-yl]ethyl}-6-methylene-decahydronaphthalene-1-carboxylate (IB).

A solution of 1.00 g (2.03 mmol) of the compound (HB) in 10 ml of toluene is boiled for 12 hours, the Solvent evaporated, the residue chromatographic on silica gel (eluent-chloroform). Obtain 0.71 g (74%) of compound (IB) in the form of oil, [α]580+12.39° (8.47, CHCl3). UV-spectrum, λmaxnm (lg ε): 260 (4.50). The infrared spectrum, cm-1: 704, 757, 888, 1154, 1185, 1228, 1350, 1415, 1450, 1521, 1561, 1609, 1722, 2846, 2946. An NMR spectrum1N (δ, ppm, J, Hz): 0.49 (3H, WITH20H3), 1.01 m (2N, N1,3), 1.15 (3H, WITH19H3), 1.28 DD (1H, H5J 12.1, 2.8), 1.45 m (1H, H2), 1.68 m (1H, H11), 1.69 USS (1H, H9), 1.73-1.84 m (4N, N1,2,6,11), 1.87 m (1H, H7), 1.97 m (1H, H6), 2.13 DM (1H, H3I , Jheme14.2), etc 2.40 (1H, H7J 11.0, 2.8), 2.78 m (1H, H12), 3.00 m (1H, H12), 3.58 (3H, och3), .74, 4.94 (2H, N.17), 6.45 (1H, H14, J 1.7), 7.53 m (3N, N3”,5”,15), 7.59 m (1H, H4”), 8.20 (2H, N.2”,6”, J 7.1). An NMR spectrum13S, δ, ppm: 12.39 (With20), 19.76 t (2), 24.13 t (12), 24.20 t (11,12), 26.02 t (6), Gained 28.53 C (19), At 37.96 t (3), 38.52 t (7), 38.86 t (1), 40.02 (With4), 43.99 (With10), 50.82 (och3), 55.41 (With9), 56.01 (With5), 106.44 t (17), 113.54 d (14), 123.78 (With13), 127.92 (With3”,5”), 128.79 (With2”,6”), 130.84 (With1”), At 132.54 d (4”), 137.46 (With16), 144.10 d (15), 147.55 (With8), 162.13 (With3'), 174.89 (With5'), 177.23 (With18). Mass spectrum, m/z (IRel, %): 474 (8), 355 (17), 340 (10), 296 (27), 239 (19), 189 (22), 188 (11), 186 (12), 181 (16), 173 (12), 172 (13), 122 (12), 121 (100), 119 (11), 109 (22), 107 (21), 105 (59), 95 (11), 93 (17), 91 (16), 83 (16), 81 (27), 79 (15), 77 (21), 67 (12), 55 (16), 41 (14), 28 (11), 18 (10). Found [M]+474.2440. C29H34O4N2. Calculated M 474.2435.

Example 3. Getting 16-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]methyl-lambertiana (Ie).

Stages 1-4 are performed according to procedures described in example 1.

5. (1S,4aR,5S,8aR)-Methyl-5-(2-{2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-furan-3-yl}ethyl)-1,4A-dimethyl-6-methylentetrahydrofolate-1-carboxylate (Ie).

To a stirred solution of 1.00 g (2.57 mmol) amidoxime (IX) and 0.23 ml (3.09 mmol) of 2-chloroacetyl chloride in 10 ml methylene chloride in a stream of argon is added dropwise 0.71 ml (5.15 mmol who) Et 3N. the Reaction mixture was stirred at room temperature for 10 h, add 50 ml of water, the product extracted with chloroform (3×50 ml). The organic extracts washed with water (3×40 ml), dried with MgSO4and evaporated. The remainder chromatographic on silica gel (eluent - chloroform). Obtain 0.45 g (39%) of compound (IB) in the form of oil. UV-spectrum, λmaxnm (lg ε): 206 (3.60), 245 (3.89), 266 (3.96). The infrared spectrum, cm-1: 757, 888, 1155, 1229, 1464, 1521, 1625, 1644, 1722, 2846, 2947. An NMR spectrum1N (δ, ppm, J, Hz): 0.47 (3H, WITH20H3), Dt 1.00 (2N, N1,3J 13.5, 3.9), 1.14 c (3H, C19H3), 1.26 DD (1H, H5, J 12.5, 2.7), 1.46 DM (1H,H2, J 14.4), 1.63 m (1H, H11), 1.64 m (1H, H9), 1.74-1.81 m (4N, N1,2,6,11), DD 1.85 (1H, H, J 12.3, 3.8), 1.96 DD (1H, H6, J 12.5, 3.2), DM 2.12 (1H, H3I , Jheme13.0), 2.39 etc (1H, H, J 12.0, 2.9), 2.66 m (1H, H12), 2.92 m (1H, H12), 3.58 (3H, och3), 4.66 (1H, H17), 4.70 (2H, CH2Cl), 4.89 (1H, H17), 6.43 (1H, H14, J 1.7), 7.50 (1H, H15, J 1.7). An NMR spectrum13S, δ, ppm: 12.19 (With20), 19.56 t (2), At 23.83 t (11), 23.87 t (11,12), At 25.86 t (6), 28.39 (With19), 32.91 t (CH2Cl), 37.79 t (3), 38.32 t (7), 38.64 t (1), 39.87 (With4), At 43.86 (With10), 50.73 K (och3), 55.21 (With9), 55.83 (With5), 106.27 t (17), 113.44 d (14), 131.32 (With13), 136.47 (With16), 144.32 (With15), 147.29 (With8), 161.75 (With3'), 173.57 (With5', 177.23 (With18).

Example 4. Research activity 16-(1,2,4-oxadiazol-5-yl)-15,16-epoxyamine formula (Ia-in)

In this work, we used lines of human tumor cells, MT-4, CEM-13 (cells T-cell leukemia, human) and U-937 cells human monocytes). Cells were cultured in medium RPMI-1.640 containing 10% serum of cattle embryos, 2 mmol/l L-glutamine, 80 μg/ml gentamicin and 30 mg/ml lincomycin, at a temperature of 37°C in CO2the incubator. Tested compounds were dissolved in DMSO and added to the cell culture at the required concentrations. Used on 3 wells for each concentration. For the experiment used cells at 3 days of culture after the evaluation of the morphology, count, concentration and cell viability. Cells SEM-13, U-937 or MT-4 were placed in wells of 96-hole tablet ("Cel-Cult", England) 100 ál in a hole in the seed concentration of 0.5×106cells in ml analyte was added to the cells, obtaining a final concentration of 0.01-1000 μm, using 3 wells for each concentration. Cells inkubirovanie in the same conditions without the addition of drugs, was control. Cells were cultured for 72 hours. An aqueous solution of MTT (5 mg/ml) was filtered through 0.22 μm filter (Flow laboratories, UK) was added to each of the studied culture at a ratio of 1:10 by volume mixture Incubus is believed 3-4 hours at 37°C in CO 3the incubator. After incubation, the supernatant was carefully removed, and then each analyzed well was added 100 μl of DMSO. Sediment resuspendable and 30 min were incubated in the dark at room temperature until complete dissolution of the crystals formazan.

The optical density (OD) of the samples was measured on multilauncher spectrophotometer BioRad 680 (USA) at a wavelength of equal to 490 nm. The percentage inhibition of cell growth was determined by the formula 100 - (mean OD experience/average OD in control)×100. The value obtained for control triplet (the first three holes without adding connections, parallel for each of the investigated experimental agent) was taken as 100%. Expected mean value and the error of the mean for each concentration of the analyzed compounds. The results created a chart based cell viability (%) concentration of the investigated cytotoxic substances was determined by the dose, 50% inhibitory cell viability (CCID50)and standard error (SE) indicator CD50.

The compound (Ia) inhibits growth of human tumor cells, SEM-13, U-937 and MT-4 at concentrations of 1.1, and 24.4 23.5 μm, respectively. The cytotoxic activity of this compound is manifested in lower doses compared with the cytotoxicity of similar properties of pinosol is and (II). The dose inhibiting the viability of tumor cells by 50% for compound (II) in the same conditions, is 9.2, and 34.1 49.1 ám.

The compound (1B) exerts its cytotoxic effect at concentrations 9.5, 14.7 and 45.1 μm, respectively, the effective dose of this compound to cells SEM-13 and MT-4 are almost identical with the effective concentrations of biosolid (II). When this compound (1B) inhibits cell growth of human monocytes U-937 2.3 times lower dose than biosolid (II).

16-[(5-Chloromethyl)-1,2,4-oxadiazol-3-yl]methylarbutin (IB) inhibits the growth of human tumor cells, SEM-13, U-937 and MT-4 at concentrations of 0.08, 6.7 and 0.76 mm, respectively, which corresponds to a reduction inhibitory concentration of the compound in 115, 5 and 65 times, respectively, compared with pinacolada (II). The compound (Ie) is the most active cytotoxic agent.

Thus, the claimed invention has the following advantages, namely:

- new 16-(1,2,4-oxadiazol-5-yl)-15,16-epoxyamine formula (Ia-in) have the ability to inhibit the growth of human tumor cells at micromolar concentrations;

- the claimed compounds (Ia-in) have a selective action on tumor cells SEM-13;

- the claimed compounds (Ia-in) are synthesized from available plant materials - pine needles or resin Siberian cedar.

16-(1,2,4-Oxadiazol-3-yl)-15,16-epoxyamine formula (Ia-in)

where R is Me (Ia), Ph (IB), CH2Cl (IB),
possessing cytotoxic activity towards tumor cells.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of compounds of formula (wherein R1, R2, X, Y and n have the values specified in the patent claim) or their pharmaceutically acceptable salts for treating the diseases related to the biological function of the trace amine associated receptors, namely depression, anxiety disorders, bipolar disorders, attention deficit/hyperactivity disorder, stress-induced disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, addictions, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy consumption and assimilation disorders, thermal homeostasis disorders and disturbances, sleeping and circadian rhythm disorders, and cardiovascular diseases. Besides, the invention refers to compounds of formulas I-A, I-B, I-C, I-D, l-E, l-F, I-G, I-H (structural formulas of which are presented in the patent claim) and to a pharmaceutical composition based on the compounds of formula (I) for treating the diseases related to the biological function of the trace amine associated receptors.

EFFECT: use of the compounds of formula 1 in preparing the drugs for treating the diseases related to the biological function of the trace amine associated receptors.

45 cl, 9 dwg, 1 tbl, 379 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

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26 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: invention relates to condensed bicyclic compounds, having affinity with mineralocorticoid receptor (VR) of formula [I] and formula [ii], as well as to pharmaceutical compositions on their basis. In general formula [I[ and [ii] ring A represents benzene ring, which has substituent R1, condensed with adjacent 6-membered heterocyclic ring, and said benzene ring additionally optionally is substituted with one or two substituent(s), selected from halogen atom and C1-8-alkyl group, R1 represents C1-8-alkylsulfonyl amino group or C1-8-alkyl aminosulfonyl group, R2 and R3 (a) are similar or different and represent group, selected from hydrogen atom, C1-8-alkyl group, and from 6- to 10-membered monocyclic or bicyclic aryl group (said aryl group is optionally substituted with halogen atom), (b) are combined with each other with formation of oxogroup or (c) are combined with each other on their ends together with adjacent carbon atom with formation of C3-10-cycloalkyl group, X represents the following group =N-, =C(R4)- or -CH(R4)-, R4 represents hydrogen atom, cyanogroup, halogen atom, C1-6-alkyl group, C2-6-alkenyl group, C3-10-dicloalkyl group, C1-7-alkanoyl group, carbamoyl group or C3-8cycloalkenyl group, Ar represents from 6- to 10-membered monocyclic or bicyclic aryl group, optionally containing one or several heteroatom(s), selected from sulphur atom, oxygen atom and nitrogen atom (said aryl group is optionally substituted with similar or different, one or two substituent(s), selected from halogen atom, cyanogroup, C1-8-alkyl group, trihalogen- C1-8-alkyl group and C1-8alkoxygroup), and dotted line represents presence or absence of double bond, Xa represents the following group =N- or =C(CN)-, RZ represents hydrogen atom or halogen atom, R25 and R35 represent alkyl group, and Ar3 represents phenyl group, optionally substituted with one or two group(s), which is(are) selected from halogen atom and trihalogenalkyl group.

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I), its optical isomer or pharmaceutically acceptable salt, R is specified in cl.1 of the patent claim. The compounds may be presented both as an optical isomer, and as a racemic substance, and may be used for mental disorders, such as schizophrenia.

EFFECT: higher efficacy of using the compounds.

8 cl, 4 tbl, 3 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention offers compounds presented by general formula (I): or their pharmaceutically acceptable salts wherein R1, R2, R3 and R4 are presented in the description and exhibit substantial COMT inhobotory activity. Besides, the present invention described pharmaceutical compositions inhibiting catechol-O-transferase activity which contain the compound or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

EFFECT: there are declared pharmaceutical combinations for treatment or prevention of Parkinson's disease which contain (1) the pharmaceutical composition containing the compound under any cl 1-8 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier, and (2) at least one compound specified in L-dope or carbidole.

10 cl, 9 ex, 17 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a mTOR kinase inhibitor. In formula (I): A represents a 6-8-member mono- or bicyclic heterocyclic ring containing 1 to 2 heteroatoms optionally specified in N and O as apexes of the ring and having 0-2 double bonds; and wherein the ring A is additionally substituted by 0 to 2 substitutes RA specified in a group consisting of -ORa, -Rc and -(CH2)1-4-ORa wherein Ra is optionally specified in hydrogen and C1-6alkyl; Rc represents C1-6alkyl; G is specified in a group consisting of -C(O)-, -OC(O)-, -NHC(O)- and -S(O)0-2-; B is specified in a group consisting of phenylene and 5-6-member heteroarylene consisting 1-2 nitrogen heteroatom as apexes of the ring, and substituted by 0 to 1 substitutes RB specified in F, Cl, Br, I and Rp; wherein Rp represents C1-6 alkyl; D is specified in a group consisting of -NR3C(O)NR4R5, -NR4R5, C(O)NR4R5, -NR3C(=N-CN)NR4R5, -NR3C(O)R4, -NR3C(O)OR4 and -NR3S(O)2R4, and wherein the group D and a substitute placed on an adjoining atom in the ring B, optionally combined to form a 5-6-member heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms specified in N, O and S, as apexes of the ring and substituted by the substitute 0-1 RD. The R1-R5 radical values are presented in the patent claim.

EFFECT: invention also refers to a pharmaceutical composition containing said compounds, and to the use of the compounds for preparing a drug for treating a malignant tumour mediated by mTOR kinase activity.

33 cl, 13 dwg, 4 tbl, 498 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely a therapeutic preparation of male larval bees having immunomodulatory action. The therapeutic preparation of male larval bees having immunomodulatory action possessing a yellow powder prepared by grinding male larval bees to a homogenous biomass added with an aqueous-alcohol propolis extract and fine pollen; it is followed by freezing the paste and sublimation drying in a vacuum chamber in the certain environment.

EFFECT: preparation described above shows evident immunomodulatory action.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a composition for preventing or treating cancer containing egg albumen combined with copper vitriol in an effective amount as an agent, as well as to a method for preventing or treating by administering said composition. The invention also refers to a functional health-improving foodstuff for preventing cancer or improving the cancer-associated condition, containing egg albumen and copper vitriol. What is also declared is a method for preparing the composition of egg albumen and copper vitriol wherein the method involves heating and dehydration of copper vitriol until the entire volume of copper vitriol becomes grey, cooling of dehydrated copper vitriol, powdering and mixing with egg albumen.

EFFECT: invention provides preparing the composition with evident anti-cancer activity which induces cancer cell apoptosis and inhibits their growth.

14 cl, 11 tbl, 14 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: present invention refers to pharmaceutics and medicine, and concerns the use of 40-O-(2-hydroxyethyl)rapamycin for treating renal angiomyolipoma, lymphangioleiomyomatosis, subependimal astrocytoma and/or giant cell astrocytoma and a based pharmaceutical composition.

EFFECT: invention provides higher clinical effectiveness.

3 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention includes compositions and methods for obtaining activated polymer nanoparticles for targeted delivery of medication. Nanoparticle includes biocompatible polymer and amphiphilic stabilising agent, non-covalently bound with linker, which includes, at least, one elecrophile, selectively reacting with any nucleophile on targeting substance, and places targeting substance on external surface of biodegradable nanoenvelope, active substance being loaded into nanoenvelope. Biocompatible po;ymer includes one or several polyesters, selected from group, containing polylactic acid, polyglycolic acid, copolymer of lactic and glycolic acids and their combinations. Amphiphilic stabilising agent includes polyol. Active substance represents anti-cancer medication, preferably, curcumin.

EFFECT: invention ensures delivery of therapeutic substance to the place of its action.

27 cl, 11 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to acids which are suitable for use in medicine, having links of formulae (I) and (II) where n equals 1 or 2; A1 is selected from O or NR5, R5 is H or C1-4alkyl; A2 is O; R3 and R4 are selected from H, NH4 or an alkali metal; R1 and R2 are selected from C1-10alkyl, C6-20aryl, NH4, an alkali metal and an agent: taxane, camptothecin, doxorubicin, an acridine, coumarine, rhodamine, xanthene, cyanine or pyrene dye, a magnetic resonance imaging agent, a polydentate ligand or precursor thereof of formulae where R7 is selected from H, NH4 or an alkali metal, provided that one of R1 and R2 is said agent, conjugated with a polymer directly or through a linker group, and the ratio of the agent to the polymer conjugate ranges from 1 to 50% (wt/wt).

EFFECT: compared to a polyglutamic acid conjugate, the novel biodegradable conjugate has high solubility and provides the solution with high optical transparency in a wide pH range.

53 cl, 29 dwg, 38 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of formula (I) and pharmaceutically acceptable salts and solvates thereof, having IGF-IR and IR inhibiting properties, which can be used to treat proliferative cancerous diseases such as breast cancer, sarcoma, lung cancer and prostate cancer. In the compound of formula (I): R1 is selected from H and C1-C3alkyl; R2 is selected from H, C1-C3alkyl and halogen; R3 is selected from H, OH, C1-C6alkyl, groups -C1-C6alkylene-OH, -C1-C6alkylene-phenyl (optionally substituted with a halogen) and -C1-C6alkylene-C(O)NH2; R4 is selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl; or R3 and R4, together with atoms with which they are bonded, form a 5- or 6-member lactam; each of R5 and R6 is independently selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl, or R5 and R6 together with an aryl with which they are bonded form naphthalene; R7 is selected from C1-C6alkyl, -O-C1-C6alkyl, halogen, -N-R19R19 and -O-C1-C6alkylene-halogen; R8 is selected from H, halogen and C1-C6alkyl; one of R9 and R10 is selected from -C1-C6alkylene-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O- C0-C6alkylene(optionally substituted with -OH)-NR22R23, and etc, given in the claim and the other of R9 and R10 is selected from H, C1-C6alkyl, -O- C1-C6alkyl and halogen.

EFFECT: improved method.

41 cl, 12 dwg, 263 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof: where: each of R1, R2, R3, R4 is independently selected from a group consisting of a hydrogen atom, a halogen atom, an aryl, a C5-6 heteroaryl having 1-3 heteroatoms in the ring which are selected from O, S and N, -OR5, -NR5R6, and -NR5COR6, where said aryl or C5-6 heteroaryl, having 1-3 heteroatoms in the ring selected from O, S and N, is unsubstituted or additionally substituted with one or more groups selected from a group consisting of alkyl, alkoxyl and halogen, each of R5 and R6 is independently selected from a group consisting of a hydrogen atom or an alkyl, where said alkyl is unsubstituted or additionally substituted with one or more groups selected from a group consisting of an aryl, haloaryl, hydroxyl and alkoxyl. The invention also relates to a pharmaceutical composition which inhibits protein kinase and contains a compound of formula I, a method of producing the compound of formula I, use of said compounds to produce a medicinal agent for treating disorders associated with protein kinase, and a method of modulating catalytic activity of protein kinase.

EFFECT: improved method.

10 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating burns containing oxidised dextran of molecular weight 35-65 kDa as an active ingredient; as excipients for symptomatic therapy of burns it contains anaesthesine, polyethylene oxide of molecular weight 1.5-6.0 kDa, metronidazole, phosphatidylcholine and a pharmaceutically acceptable carrier in the following proportions, wt %: oxidized dextran - 0.5-5.0; anaesthesine - 0.5-2.5; polyethylene oxide - 0.5-5.0; metronidazole - 0.1-0.2; phosphatidylcholine - 1.0-2.0; pharmaceutically acceptable carrier - the rest. As a pharmaceutically acceptable carrier, the composition may contain purified water or physiologic saline or 10 mM phosphate buffer with pH 7.4.

EFFECT: invention provides higher clinical effectiveness in burns.

2 cl, 1 tbl, 3 ex

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