Medicinal agent based on 4-substituted 3(3-dialkylaminomethyl-indol-1-yl)maleimide derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to new 4-substituted 3-(3-dialkylaminomethyl-indol-1-yl)maleimide derivatives of general formula

and ,

where: X1-X4 denote C; Z denotes H; R1 denotes alkyl, H, -(CH2)3-N-(C2H5)2; R2 and R3 denote alkyl, or together with the nitrogen atom to which they are bonded form a C4-7-monocyclic ring containing 1 or 2 heteroatoms, selected from O and N, possibly substituted with an alkyl; R4 denotes H; Y denotes S, -N-(C2H5); where in formula I compounds R5 and R6 together with the nitrogen atom to which they are bonded form a C9-10 a condensed bicyclic ring containing an N heteroatom, possibly substituted with R, where R denotes -N-(R2)-R3; in formula II compounds R5 denotes phenyl, optionally substituted with OCH3.

EFFECT: obtaining new compounds which can be used as protein kinase inhibiting agents.

2 cl, 6 tbl, 6 ex

 

The invention relates to derivatives of 4-substituted 3-(3-dialkylaminomethyl-indol-1-yl)maleimide, methods of their production and use based on the identified activity as inhibitors of protein kinase C as a drug used for the treatment of pathological conditions in process mechanism involving protein kinase C, or on the basis of their cytotoxic activity as anticancer drugs.

The level of technology

Neoplastic diseases are one of the leading causes of death in Russia and around the world. For cancer cells is characterized by rapid division and invasiveness, i.e. the ability to migrate and metastasize. In tumor cells defective mechanisms of cell death (apoptosis), which otherwise could regulate their level, as well as proliferation and migration. In contrast, in tumor cells the mechanism of survival, protecting them from apoptosis. In some cases, to provide therapeutic effect with malignant diseases were successfully applied such inhibitors of protein kinases as derivatives indolocarbazole - staurosporin, rebeccamycin, UCN-01, NB-506 and others. One of the problems that occur when cancer chemotherapy is the development of the tumor cells multidrug resistance induced by chemotherapeutics the mi drugs. Multidrug resistance (MDR) of malignant tumors is one of the main reasons for the clinical progression of the disease, when the tumor becomes insensitive to chemotherapy regardless of the combination of drugs. MDR may occur in cells subjected to stress, especially under the action of chemotherapeutic drugs. To these influences, the protection mechanisms in these cells weakly expressed or absent; but surviving after treatment with one toxin, cells acquire resistance to many substances (Gottesman MM, Fojo T, Bates SE. Nature Rev. Cancer 2002; 2:48-58).

One of the major reasons MDR is reduced accumulation of toxins in the cell, due to their active excretion in the intercellular environment. Such transport is an integral protein of the plasma membrane P-glycoprotein (Pgp, weight 140-170 kDa). Human Pgp is encoded by gene MDR1 (multidrugresistance 1).

The cause of clinical MDR is the overexpression of MDR1 gene through induction of extracellular stimuli, in particular anticancer drugs (Gottesman MM, Fojo T, Bates SE. Nature Rev. Cancer 2002, 2, 48-58; Ambudkar SV et al. Annu. Rev. Pharmacol. Toxicol. 19996 39, 361-398.). Inducibility MDR1 gene involves the activation of the transmission signals to the cell nucleus. The obtained data about the participation of protein kinases (PKS) in urgent establishment of the LU; pharmacological inactivation of this mechanism abolished the increase in MDR1 mRNA induced by PKC antagonists and chemotherapy. Blocking PKC using pharmacological effects would prevent the development of MDR in the process of chemotherapy (Director P., Roninson I. Oncol. Res. 1992, 4, 281-290; Director P., Roninson I. J. Natl. Cancer Inst. 1993, 85, 632-639).

Known derivatives of bis(indol-3-yl)maleimide (BIS-I, BIS-II, BIS-IV. BIS-VI, BIS-VII and other), which are inhibitors of protein kinase C; investigated and methods for their production (Davis et al. J.Med.Chem. 1992, v.35, N.1, p.177-184, US 6133452, US 5545636, US 2005004201, EP 0657458 A1, WO 02/38561 A1). Known for the ability of bis(indol-3-yl)maleimide (for example, BIS-I) [3-(1-(3-dimethylaminopropyl)indol-3-yl)-4-(indol-3-yl)pyrrole-2,5-dione] to prevent the development of MDR in tumor cells through inhibition of PKC-alpha. (V.Gekeler et al., Br.J.Cancer 1996, 74, 897-905).

Protein kinase C (serine-threonine protein kinase) family of enzymes (more than 10 isoforms)involved in the regulation of processes such as apoptosis, gene expression, cell differentiation, angiogenesis, active transport of chemotherapeutic substances from cells and the emergence of multi-drug resistance, invasion and senescence (Hoffman, Curr. Cancer Drug Targets, 2004, 4, 2, 125-146). Thus, inhibitors of protein kinases With potential for use in cancer chemotherapy.

It is known that serine-threonine of proteini the basics of eukaryotic type may also play a role in the emergence of microbial resistance to antibiotics (Elizarov S.M., et al, J. Molecular Biology, 2005 Vol.35, Ns 2,226), including through the formation of biofilms (Hussain H, et al., J.Bacteriol, 2006, 188, №4, 1628). Known for the role of series - treoninove protein kinases in the development of virulence in Streptomyces pneumoniae (Eshenique J. et al, J. Infection and Immunity, 2004, Apr., 2434). Therefore, specific inhibitors of protein kinases can be used in the treatment of diseases caused by such microorganisms (Drews S.J.,et al, FEMS Environ Lett. 2001, 18, 205 (2), 369).

It is known that drugs LY-333531, LY-379196, LY-317615, created on the basis of bis-(indol-3-yl)maleimide, are selective inhibitors of PKC-beta and can be used as tools against retinopathy and nephropathy in diabetes (Jirousek M.R., Gillig J.R., Gonzalez C.M., et al., J. Med. Chem. 1996 39 2664. Paul M., Krumrich C.A., J. Org. Chem. 2001, 66, 2024). It is known that inhibitors of protein kinases can be used in inflammatory and neurodegenerative processes (Goekjian P.G., Jirousek M.R., Curr. Med. Chem. 1999 6, 877, WO 02/38561 A1, WO 03/082859 A1).

Thus, bis-indolylmaleimide, their analogues and related structures are classes of compounds promising for the search and development of new drugs (inhibitors of protein kinases), having a high selectivity of action and with fewer side and General toxic effects, which is especially important in cancer chemotherapy.

The closest prototypes substances disclosed in the present invention are derivatives of bis(in the ol-3-yl)maleimide.

Disclosure of the invention.

The essence of the invention lies in the fact that the resulting new chemical compounds, derivatives of 4-substituted 3-(3-dialkylaminomethyl-1-yl)maleimide, generalized structural formula (formula I and formula II), which is presented in scheme 1.

Scheme 1.

where X1-X4can be C or N, Y Is S or O, Z is halogen, alkyl, aryl, including substituted, HE, alkoxy, NH2, NO2, COOH, CN or any other valid Deputy. R1is alkyl, aryl, including those containing various functional groups, as well as HE, alkoxy, NH2, COOH, CN or any other valid Deputy. R2and R3is alkyl, aryl, including substituted, or any other valid Deputy. R4is alkyl, aryl, including those containing various functional groups, such as HE, alkoxy, NH2, COOH, CN. In the formula I R5and R6can be alkyl, aryl substituents, which may contain various functional groups. NR5R6can be also derived indoline, tetrahydroquinoline or other saturated heterocycle, and indole, pyrrole. In formula II, R5is alkyl or aryl, which may contain various functional groups.

In contrast to the known bis-indolylmaleimide PR is deljennie connections have a number of structural features. Namely, both of the substituent in positions 3 and 4 maleimides fragment is connected by the link-heteroatom (C-N in the case of indole substituent in position 3 maleimides cycle or links of C-N, C-S or S-O in the case of the substituent in position 4 maleimides cycle). Further, in the known prototypes of inhibitors of protein kinase bis-indolylmaleimide type (drugs BIS) heteroatom in the side chain (in position 1 or 3 of the indole fragment) is separated from a heterocycle by a chain of three methylene groups. In contrast, the compounds presented in this application contain in position 3 of the indole fragment dialkylaminomethyl Deputy, thus, ekzoticeski heteroatom (nitrogen) is separated from the indole heterocycle one methylene group. Also disclosed methods of producing these compounds.

The implementation of the invention

The matter presented in this invention can be synthesized using known chemical transformations. For the synthesis of all compounds presented in the invention, suitable General methods outlined below.

The original 3-bromo-4-(indol-1-yl)maleimide was obtained as described previously (Lakatosh S.A., Luzikov Y.N., Preobrazhenskaya M.N., Org. Biomol. Chem. 2003 1 826). The bromine atom in the molecule easily replaced in the presence of bases of different nucleophilic reagents, such as amines (including 2,3-di is grondal (indocin), tetrahydroquinolin and other saturated nitrogen-containing heterocycles), thiols or phenols. Alkylation by maleimides the nitrogen atom is the appropriate alkylating agents in the presence of base (scheme 2). The substituent in position 1 maleimides cycle can also be introduced by transamination by heating the source materials with the corresponding primary amine.

Scheme 2.

4-Substituted 3-(indol-1-yl)maleimide were converted into the corresponding dialkylaminomethyl derived using the reaction of manniche (aminomethylpyridine) (scheme 2).

Examples of target compounds obtained according to this scheme can be presented below (scheme 3) structure:

Scheme 3.

3-(2,3-Dihydroindol-1-yl)-4-(indol-1-yl)maleimide easily converted into the corresponding bis-3,4 - (indol-1-yl)maleimide under the action of oxidizing agents (for example, by the action of dichlorodicyanoquinone or active Mno2in toluene or o-xylene). Dialkylaminomethyl such di(indol-1-yl)maleimides under the reaction conditions, manniche was given depending on the ratio of initial reagents mixture of mono - and disubstituted derivatives or only disubstituted derivatives. Monogame the military derivative was separated from the other reaction products chromatographic (figure 4.).

Scheme 4

Obtaining the claimed compounds is illustrated by the following examples.

Synthesis of indolylmaleimide of 3,4-dibromomalonamide when as nucleophiles are indolin or N-alkyl-N-aryl - or dialkylamide described previously (Lakatosh S.A., Luzikov Y.N., Preobrazhenskaya M.N., Org. Biomol. Chem. 2993 1 826). Other compounds can be obtained using other nucleophilic reagents by the same method.

Example 1.

1-(3-Bromopropyl)-3-(2,3-dihydroindol-1-yl)-4-(indol-1-yl)maleimide. To a solution of 3-(2,3-dihydroindol-1-yl)-4-(indol-1-yl)maleimide (1 g) in dioxane (30 ml) was added 5-fold excess of dibromopropane and K2CO3(10 g) and the mixture was heated with vigorous stirring for 12 h, filtered, the filtrate was evaporated. The residue was dissolved in EtOAc (100 ml), washed with saturated NaCl solution (50 ml), dried and evaporated.

The residue was chromatographically (silica gel, the system n-hexane - EtOAc 5:1).

Received the product in the form of oil red.

1H-NMR (400 MHz, DMSO-d6) 0.96 (2H, t, J=7.14 NEt2), 2.17 (2H, t, J=6.59-CH2-), 3.08 (2H, t, J=8.05-CH2indolin), 3.61 (2H, t, J=6.73-CH2-), 3.67 (2H, t, J=6.63-CH2-), 4.23 (2H, t, J=8.01-CH2indolin), 6.08 (1H, d, J=8.02 indole), 6.49 (1H, t, J=7.58 indole), 6.60 (1H, d, J=3.3 indole), 6.64 (1H, t, J=7.32 indole), 6.95 (1H, t, J=7.04 indole), 7.00 (1H, t, J=7.04 indole), 7.04 (1H, d, J=7.29 indole), 7.20 (1H, d, J=8.10 indole), 7.37 (1H, d, J-3.29 indole), 7.46 (1H, d, J=7.65 indole);

Por what measures 2.

1-(3-Diethylaminopropyl)-3-(2,3-Dihydroindol-1-yl)-4-(indol-1-yl)maleimide. To a solution of 1-(3-bromopropyl)-3-(2,3-dihydroindol-1-yl)-4-(indol-1-yl)maleimide (500 mg) in DMF (5 ml) was added diethylamine (1 ml) and K2CO3(3 g). The mixture is left under stirring overnight, otpolirovala. The filtrate was diluted with EtOAc, washed with saturated NaCl solution (3×20 ml), dried and evaporated. The residue was chromatographically (silica gel, system l3-Meon-Et3N 6:1:0,1)

Received 1-(3-diethylaminopropyl)-3 -(2,3-dihydroindol-1-yl)-4-(indol-1-yl)maleimide in a solid orange color.

1H NMR (400 MHz, DMSO-d6) 0.96 (2H, t, J=7.14 NEt2), 1.76 (2H, t, J=7.14-CH2-), (2.44-2.50) (6H, m, NEt2, -CH2-), 3.07 (2H, t, J=7.88-CH2indolin), 3.60 (2H, t, J=6.95-CH2-), 4.26 (2H, t, J=7.92-CH2indolin), 6.04 (1H, d, J=8.02 indole), 6.48 (1H, t, J=7.83 indole), 6.62 (1H, t, J=3.34 indole), 6.64 (1H, t, J=7.50 indole), 6.96 (1H, t, J=7.18 indole), 7.00 (1H, t, J=8.02 indole), 7.03 (1H, d, J=7.36 indole), 7.19 (1H, d, J=8.05 indole), 7.37 (1H, d, J=3.3 indole), 7.48 (1H, d, J=7.33 indole);

Example 3 (Aminomethylpyridine)

1-Methyl-3-(2,3-Dihydroindol-1-yl)-4-(3-dimethylaminomethylene-1-yl)maleimide LCTA-1183. To a solution of the original indolylmaleimide 3 (R=Me, Nuc=indolin) (1.5 mmol) in CH3COOH (50 ml) was added paraform (500 mg) and NH(CH3)2(40% aqueous solution, 1 ml, 7.9 mmol). The mixture was stirred for 36 hours at 50°C, evaporated under reduced pressure, diluted. EtOAc (100 ml), washed us, is placed a solution of NaHCO 3. The organic layer was separated, the aqueous portion was re extracted with EtOAc (50 ml). The extracts were combined and washed with saturated solution of NaCl (50 ml), dried and evaporated. The residue was chromatographically (silica gel, system tO: isopropanol: water solution of ammonia(25%) 12:4:0,5) received the product LCTA-1183 (0.9 mmol), as a dark red crystalline powder. Yield 70%

Data1H NMR are given below in Table 1.

Other dialkylaminomethyl derivative of indolylmaleimide can be obtained from the appropriate intermediates and secondary amines in the described conditions with the release of 50-75%.

Table
Physico-chemical characteristics of some of the compounds obtained:
No.R=1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1183N(CH3)22.13 (6H, s, N (CH3)2), 3.01 (3H, s, N-CH3), 3.10 (2H, t, J=7.97-CH2indolin), 3.52 (4H, s, N-CH2), 4.29 (2H, t, J=7.91-CH, indolin), 6.05 (1H, d, J=8.09 indole), 6.44 (1H, t, J=7.37 indole), 6.62 (1H, t, J=7.37 indole), 6.93 (1H, t, J=7.47 indole), 6.99 (1H, t, J=7.88 indole), 7.03 (1H, d, J=04 indole), 7.14 1H, d, J=8.02 indole), 7.26 (1H, s, indole), 7.52 (1H, d, J=7.65 indole);
LCTA-12112.29 (4H, s, -CH2-Oh), 3.01 (3H, s, N-CH2), 3.10 (2H, t, J=7.97-CH2indolin), 3.54 (4H, s, N-CH2), 3.58 (2H, s, -CH2-N), 4.30 (2H, t, J=7.91-CH, indolin), 5.96 (1 H, d, J=8.01 indole), 6.39 (1H, t, J=7.69 indole), 6.62 (1H, t, J=7.32 indole), 6.96 (1H, t, J=7.69 indole), 7.02 (1H, t, J=7.46 indole), 7.04 (1H, d, J=6.92 indole), 7.18 (1H, d, J=8.06 indole), 7.22 (1 H, s, indole), 7.56 (1H, d, J=7.55 indole);
LCTA-12121.66 (4H, s, -CH2-), 2.39 (4H, s, N-CH2), 3.01 (3H, s, N-CH,), 3.09 (2H, t, J=8.02-CH2indolin), 3.69 (2H, s, -CH2-N), 4.27 (2H, t, J=8.05-CH2indolin), 6.02 (1H, d, J=8.05 indole), 6.42 (1H, t, J=7.55 indole), 6.63 (1H, t, J=7.32 indole), 6.94 (1H, t, J=7.51 indole), 6.99 (1H, t, J=6.96 indole), 7.03 (1H, d, J=7.29 indole), 7.14 (1 H, d, J=7.73 indole), 7.24 (1H, s, indole), 7.52 (1H, d, J=7.28 indole);
LCTA-1213*2.43 (4H, s, N-CH2), 2.51 (4H, s, N-CH2), 3.01 (3H, s, N-CH2), 3.10 (2H, t, J=7,88-CH2indolin), 3.69 (2H, s, -CH2-N), 4.30 (2H, t,.1=7.91-CH2indolin), 5.98 (1H, d, J=7.91 indole), 6.42 (1H, t, J=7.73 indole), 6.63 (1H, t, J=7.37 indole), 6.97 (1H, t, J=7.69 indole), 7.03 (1H, t, J=8.05 indole), 7.04 (1H, d, J=7.40 indole), 7.19 (1H, d, J=8.14 indole), 7.27 (1H, s, indole), 7.57 (1H, d, J=7.51 indole);
* Salt with fumaric acid

No.R1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1313NEt2(0.86-0.99) (6H, m, NEt2), (1.18-1.21) (3H, m, NEt), (2.40-2.45) (4H, m, NEt2), 3.24 (2H, t, J=8.04-CH2indolin), (3.57-3.59) (2H, m, NEt), 3.65 (2H, s, N-CH2), 4.30 (2H, t, J=8.06-CH2indolin), 6.00 (1H, d, J=8.01 indole), 6.42 (1H, t, J=7.65 indole), 6.63 (1H, t, J=7.50 indole), 6.94 (1H, t, J=7.14 indole), 6.99 (1H, t, J=6.95 indole), 7.03 (1H, d, J=7.28 indole), 7.14 (1H, d, J=8.01 indole), 7.23 (1H, s, indole), 7.56 (1H, d, J=7.55 indole);
No.R1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1286NEt20.96 (2H, t, J=7.14 NEt2), 1.76 (2H, t, J=7.14-CH2-), (2.44-2.50) (6H, m, NEt2, -CH2-), 3.07 (2H, t, J=7.88-CH2indolin), 3.60 (2H, t, J=6.95-CH2-), 4.26 (2H, t, J=7.92-CH2indolin), 6.04 (1H, d, J=8.02 indole), 6.48 (1H, t, J=7.83 indole), 6.62 (1H, t, J=3.34 indole), 6.64 (1 H, t, J=7.50 indole), 6.96 (1H, t, J=7.18 indole), 7.00 (1H, t, J=8.02 in the ol), 7.03 (1H, d, J=7.36 indole), 7.19 (1H, d, J=8.05 indole), 7.37 (1H, d, J=3.3 indole), 7.48 (1H, d, J=7.33 indole);

No.R=1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1237NEt2(0.97-1.01) (6H, m, NEt2), (2.40-2.46) (4H, m, NEt2), 3.08 (2H, t, J=8.05-CH2indolin), 3.66 (2H, s, N-CH2), 4.27 (2H, t, J=8.05-CH2indolin), 6.01 (1H, d, J=7.87 indole), 6.41 (1H, t, J=7.10 indole), 6.61 (1H, t, J=7.42 indole), 6.93 (1H, t, J=6.85 indole), 6.99 (1H, t, J=6.92 indole), 7.02 (1H, d, J=8.28 indole), 7.14 (1H, d, J=7.92 indole), 7.24 (1H, s, indole), 7.55 (1H, d, J=7.23 percent indole), 10.8 (1H, s, NH);
LCTA-12301.83 (4H, t, J=2.11-CH2pyrrolidin), 2.90 (4H, t, J=3.95-CH2pyrrolidin) 3.09 (2H, t, J=7.14-CH2indolin) 4.23 (2H, s, N-CH2), the 4.29 (2H, t, J=8.01-CH2indolin), 6.02 (1H, d, J=8.05 indole), 6.47 (1H, t, J=7.51 indole), 6.63 (1H, t, J=7.37 indole), (6.99-7.07) (3H, m, indole), 7.21 (1H, d, J=7.51 indole), 7.51 (1H, s, indole), 7.64 (1H, d, J=7.23 indole), 10.5 (1H, s, NH);

R
No.1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1121N(CH3)22.11 (6H, s, -N(CH3)2), 3.02 (3H, s, N-CH3), 3.39 (2H, s, -CH2), 3.54 (3H, s, -och3), 6.38 (2H, d, J=8.82 benzene), 6.96 (2H, d, J=8.83 benzene), 7.07 (1H, s, indole), 7.07 (1H, t, J=6.51 indole), 7.19 (1H, t, J=7,14 indole), 7.29 (1H, J=8.24 indole), 7.49 (1H, d, J=7.73 indole);
LCTA-1222*N(C2H5)21.13 (6H, m, -CH3, -N(C2H5)2), 2.54 (4H, m, -CH2, -N(C2H5)2), 3.02 (3H, s, N-CH3), 3.55 (3H, s, -O-CH3), 3.93 (2H, s, -CH2), 6.39 (2H, d, J=8.93 benzene), 6.57, 6.98 (2H, d, J=8.79 benzene), 7.11 (1H, t, J=7.14 indole), 7.22 (1H, t, J=7.24 indole), 7.29 (1H, s, indole), 7.33 (1H, d, J=8.20 indole), 7.57 (1H, d, J=7.88 indole);
LCTA-11232.32 (4H, s, -CH2, morpholine), 3.02 (3H, s, N-CH3), 3.48 (2H, s, -CH2), 3.54 (3H, s, -O-CH3), 3.57 (2H, s, -CH2Oh, morpholine), 6.37 (2H, d, J=8.97 benzene), 6.96 (2H, d, J=8.95 benzene), 7.08 (1H, t, J=6.96 indole), 7.09 (1H, s, indole), 7.19 (1H, t, J=7.14 indole), 7.29 (1H, d, J=8.13 indole), 7.54 (1H, d, J=7.84 indole);
LCTA-1224*1.83 (4H, s, -CH2, piroliden), 2.84 (4H, s, pirolidene), 3.02 (3H, s, N-CH3), 3.55 (3H, s, -och3), 4.02 (2H, s, -CH2), 6.39 (2H, d, J=8.93 benzene), 6.97 (2H, t, J=8.89 benzene), 7.11 (1H, t, J=6.94 indole), 7.22 (1H, t, J=7.10 indole), 7.31 (1H, d, J=8.20 indole), 7.58 (1H, d, J=7.88 indole);
LCTA-12251H NMR (400 MHz, DMSO-d6) 2.27 (3H, s, O-CH2), 2.43-2.51 (8H, m, piperazine), 3.02 (3H, s, N-CH3), 3.51 (2H, s, -CH2-N), 3.56 (8H, m, NCH3, piperazine), 6.38 (2H, d, J=8.93 benzene), 6.97 (2H, t, J=8.76 benzene), 7.07 (2H, t, J=7.76 indole), 7.09 (1H, s, indole), 7.19 (1H, t, J=7.14 indole), 7.29 (1H, d, J=8.25 indole), 7.53 (1H, d, J=7.68 indole);
* Salt with fumaric acid

roomR1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1229*N(CH3)21.08 (3H, t, J=0.88, -N2CH3, aniline), 2.46 (6H, s, N(CH3)2), 2.98 (3H, s, N-CH3), 4.00-4.06 (4H, m, -CH2, -NCH2CH3, aniline), 6.74 (1H, t, J=7.32 benzene), 6.85 (2H, t, J=8.16 benzene) 6.98 (2H, d, J=8.65 benzene), 7.03 (1H, t, J=7.83 indole), 7.12 (1H, t, J=7.10 indole), 7.19 (1H, s, indole), 7.23 (1H, d, J=8.23 indole), 7.55 (1H, d, J=7.84 ndol);
LCTA-1276N(C2H5)2of 0.98 (6H, t, J=7.12, N(CH2CH3)2) 1.04 (3H, t, J=0.88, -N(CH3)2), aniline), 2.39 (4H, q, J=7.16, 7.00, NCH2CH3)2). 2.97 (3H, s, N-CH3), 3.52 (2H, s, -CH2), 3.89 (2H, q, J=6.60, 6.50-NCH2CH3, aniline), 6.78 (1H, t, J=7.33 benzene), 6.88 (2H, t, J=8.06 benzene) 6.94 (1H, s, indole),), 6.96-7.01 (3H, m, benzene, indole), 7.07 (1H, t, J=7.10 indole), 7.17 (1H, t, J=8.06 indole), 7.49 (1H, d, J=7.83 indole);
LCTA-13661.10 (3H, t, J=6.88, -NCH2CH3, aniline), 2.29 (4H, s, CH2-O morpholine), 3.00 (3H, s, N-CH3), 3.48 (2H, s, -CH2), 3.58 (4H, s, -N-CH3morpholine), 3.97 (2H, q, J=6.88, 6.80-NCH2CH3, aniline), 6.78 (1H, t, J=7.39 benzene), 6.74 (1H, t, J=7.32 benzene), 6.84 (2H, t, J=7.50, indole), 6.94 (1H, s, indole), 6.97-7.02 (3H, m, benzene, indole), 7.10 (1H, t, J=7.88 indole), 7.53 (1H, d, J=7.84 indole);
LCTA-13651.04 (3H, t, J=6.31, -NCH2CH3, aniline), 1.67 (4H, s, CH2pyrrolidin), 2.37 (4H, s, AR pyrrolidin) 2.97 (3H, s, N-CH3), 3.42 (4H, s, -CH2pyrrolidin), 3.58 (2H, s, -CH2),), 3.89 (2H, q, J=6.30,6.31-NCH2CH3, aniline), 6.78 (1H, t, J=7,39 benzene), 6.88 (2H, t, J=7.51 benzene), 6.95 (1H, s, indole), 6.97-7.00 (3H, m, Ben is ol, indole), 7.07 (1H, t, J=7.10 indole), 7.17 (1H, d, J=8.24 indole), 7.47 (1H, d, J=7.84 indole);
LCTA-13671.06 (3H, t, J=6.31, -NCH2CH3, aniline), 2.16 (3H, s, NCH3, piperazine), 2.31 (4H, s, CH2piperazine) 2.97 (3H, s, N-CH3), 3.45 (6H, s, -CH2), 3.94 (2H, q, J=6.30,6.31-NCH2CH3, aniline), 6.75 (1H, t, J=7.28 benzene), 6.85 (2H, t, J=8.24 benzene), 6.91 (1H, s, indole), 6.96-6.99 (3H, m, benzene, indole), 7.07 (1H, t, J=7.10 indole), 7.17 (1H, d, J=8.09 indole), 7.48 (1H, d, J=7.83 indole);
*Salt with fumaric acid

Oxidation of 3-(2,3-dihydroindol-1-yl)-4-(indol-1-yl)maleimides into the corresponding di(indol-1-yl)maleimide described previously (Lakatosh S.A., Luzhikov Y.N., Preobrazhenskaya M.N., Org. Biomol. Chem. 2003 1 826).

Example 4.

3-(3-Dimethylaminomethylene-1-yl)-4-(indol-1-yl)-1-methylmaleimide and 3,4-bis-(3-dimethylaminomethylene-1-yl)-1-methylmaleimide. To a solution of the original 1-methyl-3,4-bis(indol-1-yl)maleimide (1 g, 2.9 mmol) in CH3COOH (50 ml) was added paraform (1 g) and NH(CH3)2(40% aqueous solution, 6 ml, 46 mmol). The mixture was stirred for 36 hours at 80°C, evaporated, diluted with EtOAc (100 ml) and washed with saturated solution of Na2CO3. The organic layer was separated and washed with saturated solution of NaCl (2×40 ml), dried and evaporated. The residue was subjected to khromatografichnogo division (specification of the gel, n-heptane: EtOAc: Asón 5:5:1) received an individual connection.

Data of NMR for compounds obtained according to this scheme, are given in the Table 2

Table 2.
No.R1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1122N(CH3)22.16 (6H, s, N-(CH3)2), 3.12 (3H, s, N-CH3), 3.55 (2H, s, -CH2-O), 6.57 (2H, t, J=9.41 indole), 6.67 (1H, t, J=7.23 indole), 6.73 (1H, d, J=7.28 indole), 6.79 (1H, t, J=3.43 indole), 6.90 (2H, d, J=5.49 indole), 7.46 (1H, d, J=10.11 indole), 7.47 (1H, s, indole), 7.52 (1H, d, J=7.77 indole), 7.65 (1H, d, J=3.48 indole);
LCTA 1251N(C2H5)21.00 (6H, m, -CH3), 2.46 (4H, m, -CH2-), 3.12 (3H, s, N-CH3), 3.69 (2H, s, -CH2N), 6.55 (1H, d, J=8.38 indole), 6.65 (1 H, d, J=6.22 indole), 6.67 (1H, t, J=7.74 indole), 6.75 (1H, d, J=8.32 indole), 6.78 (1H, d, J=4.08 indole), 6.91 (1H, t, J=3.96 indole), 6.93 (1 H, t, J=3.97 indole), 7.44 (1H, s, indole), 7.47 (1H, d, J=7.84 indole), 7.56 (1H, d, J=7.73 indole), 7.64 (1H, d, J=3.44 indole);
LCTA 12192.32 (4H, s, N-CH2), 3.12 (3H, s, N-CH3), 3.56 (2H, s, -CH 2-Oh), 3.62 (2H, s, -CH2-N), 6.52 (1H, d, J=7.55 indole), 6.64 (1H, t, J=6.98 indole), 6.71 (1H, d, J=8.23 indole), 6.78 (1H, t, J=3.34 indole), 6.80 (1H, d, J=5.45 indole), 6.91 (1H, t, J=8.06 indole), 6.95 (1H, t, J=7.05 indole), 7.39 (1H, s, indole), 7.46 (1H, d, J=7.84 indole), 7.58 (1H, d, J=7.88 indole), 7.64 (1H, d, J=3.46 indole);
LCTA-12521.69 (4H, s, N-CH2), 2.44 (4H, s, -CH3-), 3.10 (3H, s, N-CH3), 3.75 (2H, s, -CH2-N), 6.50 (1H, d, J=7.55 indole), 6.59 (1H, d, J=8.42 indole), 6.62 (1H, t, J=7.18 indole), 6.72 (1H, t,.1=8.28 indole), 6.74 (1H, d,.1=3.50 indole), 6.88 (1H, t, J=6.98 indole), 6.91 (1H, t, J=7.90 indole), 7.42 (1H, d, J=6.92 indole), 7.43 (1H, s, indole), 7.51 (1H, d,.1=7.83 indole), 7.60 (1H, d, J=3.48 indole);
LCTA-12202.16 (3H, s, N-CH3), 2.52 (4H, s, N-CH2), 2.56 (4H, s, N-CH2), 3.12 (3H, s, N-CH3), 3.61 (2H, s, -CH2-N), 6.53 (1H, d, J=8.24 indole), 6.65 (1H, d, J=7.36 indole), 6.69 (1H, d, J=7.85 indole), 6.77 (1H, t, J=7.36 indole), 6.78 (1H, t, J=3.84 indole), 6.91 (1H, t, J=7.50 indole), 6.94 (1H, t, J=7.69 indole), 7.39 (1H, s, indole), 7.46 (1H, d, J=7.73 indole), 7.55 (1H, d, J=7.73 indole), 7.64 (1H, d, J=3.36 indole);

No.R=1H NMR (400 MHz, DMSO-d6) Himsley (ppm) Instrument Varian VXR-400
LCTA-1123N(CH3)22.16 (12H, s, N-CH3), 3.11 (3H, s, N-CH3), 3.56 (4H, s, CH2-), 6.56 (2H, d, J=8.24 indole), 6.67 (2H, t, J=8.16 indole), 6.893 (2H, t, J=7.87 indole), 7.49 (2H, s, indole), 7.51 (2H, d, J=7.87 indole);
LCTA-11842.34 (8H, s, N-CH2), 3.11 (3H, s, N-CH3), 3.56 (8H, s, CH3-Oh), 3.63 (4H, s, -CH2-N), 6.65 (2H, d, J=8.24 indole), 6.70 (2H, d, J=7.77 indole), 6.93 (2H, t, J=7.36 indole), 7.42 (2H, s, indole), 7.56 (2H, d, J=7.83 indole);
LCTA-12141.69 (8H, s, N-CH2), 2.43 (8H, s, CH2-N), 3.10 (3H, s, N-CH3), 3.73 (4H, s, -CH2-N), 6.60 (2H, d, J=8.28 indole), 6.69 (2H, d, J=7.65 indole), 6.92 (2H, t, J=6.94 indole), 7.45 (2H, s, indole), 7.52 (2H, d, J=7.98 indole);
LCTA-1232*2.46 (6N, s, N-CH3), 2.54 (8H, s, N-CH2), 2.77 (8H, s, CH2-N), 3.11 (3H, s, N-CH3), 3.72 (4H, s, -CH2-N), 6.62 (2H, d, J=8.20 indole), 6.72 (2H, t, J=7.83 indole), 6.94 (2H, t, J=7.32 indole), 7.47 (2H, s, indole), 7.55 (1 H, d, J=7.77 indole);
* Salt with fumaric acid

Compounds disclosed in the present invention, showed activity against protein kinase C α person. They can apply the camping for the prevention and treatment of pathological conditions, in the Genesis involving protein kinase C. in Addition, the proposed connection inhibitors of protein kinases can be used in the treatment of infectious diseases caused by microorganisms in the formation of virulence and resistance to antibiotics which play an important role in bacterial analogues of protein kinase C.

Compounds disclosed in the present invention, can be used as an active ingredient of pharmaceutical compositions or in combination with other active ingredients, known at the time of disclosure of the invention, which can be one of the currently known methods (for example, orally, intravenously, intramuscularly, etc) in the appropriate dosage form.

Compounds disclosed in the present invention, can be used as free bases or in the form of pharmacologically acceptable salts (for example, the sulfate, hydrochloride, methanesulfonate, fumarate, and others).

Study of the biological activity is illustrated by the following examples.

Example 5.

Study of the inhibition of the alpha-isoform of PKC.

Alpha-PKC incubated in optimized proteinkinases system in the presence of activators (phosphatidylserine, diacylglycerol, and CA2+with [γ-32P]ATP and protein substrate (histone H1), and then determined to teleserve kinase enable 32P-phosphate into histone H1 without and in the presence of increasing concentrations of inhibitors (minus background sorption). IC50determined graphically on the obtained curves of inhibition. The obtained data for some substances group LHTA are shown in table 3.

Structural formulas of the compounds are given in tables 1 and 2.

Table 3.
Concentrations of substances needed to reduce the activity of PKC-alpha by 50% (IC50)
SubstanceIC50(nm)
Bis-1103±12
LHTA-1276250±29
LHTA-1212140±15
LHTA-1286133±15
LHTA-131387±11
Bis-V at concentrations of 750 nm and 1000 nm lowers the activity α respectively 11% and 19%.

Example 6.

Suppression of MDR was defined by the absence of mRNA in cells MDR1 gene by the method of reverse transcription and polymerase chain reaction (PCR). When studies used meth is d, described previously (Director P., Roninson I. J. Natl. Cancer Inst. 85,632-639; this song honoured A.A., Azare J. Int. Rev. Cytol., 2005, 246, 1-29.)

The main effect studied in this section, the overexpression of MDR1 in H9 cells in response to exposure to antineoplastic drugs. In a series of experiments H9 cells were treated with Cytosar (Aga) is a drug used in cancer chemotherapy breast cancer and leukemia. The concentration of Cytosar determined in preliminary experiments on the survival of H9 cells in the presence of this agent. It is established that the minimum dose that causes the death of 100% of the cells within 48 hours, is about 10 μm. Expression of MDR1 in untreated cells H9 is not detected after 25 cycles of PCR, whereas in the treated 10 μm of Cytosar cells an increase in MDR1 mRNA was observed within 3-6 hours after exposure of Cytosar - concentration comparable to the clinic.

The single treatment of H9 cells by doxorubicin and Cytosar led to the induction of MDR1 gene. The same effect was caused phorbol myristate acetate (TN), used as a control agent is an agonist of the PCB. Specific inhibitors of PKC - chelerythrine, calphostin With and biondolillo I - prevent activation of the MDR1 gene. Similar results were obtained in K562 cells treated with Cytosar, doxorubicin or turbolover ether in the presence of each of these PKC inhibitors. So about what atom, pharmacological blocking of PKC prevents activation of the MDR1 gene anticancer drugs.

The obtained results allow to separate substances into three groups:

1. Nezatocheny connection, with a pronounced effect of suppressing the development of MDR (table 4).

2. Cytotoxic compounds, with a pronounced effect of suppressing the development of MDR (table 5).

3. Moderately cytotoxic compounds with a pronounced effect of suppressing the development of MDR (table 6).

Structural formulas of the compounds are given in tables 1 and 2.

Table 4.*
Nezatocheny connection with a pronounced effect of suppressing the development of MDR. IC50- the concentration of a substance causing death of 50% of the cells (μm), EU50an effective concentration of a substance that inhibits the development of MDR-TB by 50% (μm).
SubstanceIC50(µm)EU50(µm)
LCTA-12113,3
LCTA-1232of 5.4
LCTA-1212>501,9
LCTA-12132,2
LCTA11835,2
LCTA 12144,6
LCTA 122516±34,6

Table 5*.
Cytotoxic compounds, with a pronounced effect of suppressing the development of MDR. IC50- the concentration of a substance causing death of 50% of the cells (μm), EU50an effective concentration of a substance that inhibits the development of MDR-TB by 50% (μm).
SubstanceIC50(ΜM)EU50(µm)
LCTA-11227±3of 5.4
LCTA11235±33,3

Table 6.*
Moderately cytotoxic compounds with a pronounced effect of suppression of the MDR. IC50- the concentration of a substance in the binding death of 50% of the cells (μm), EU50an effective concentration of a substance that inhibits the development of MDR-TB by 50% (μm).
SubstanceIC50(µm)EU50(µm)
LCTA-122316±36,6
LCTA118412±36,6
LCTA 122412±47,3
LCTA 127612±33,7
*Note to tables 4-6: Cytotoxicity determined by IC50in the MTT test on cultures of leukemia K and colon cancer NST. Toxic thought connection, IC50which was not more than 10 μm. For both cultures in General, the data match. Inhibition of MDR is defined by IC50suppression of activation of the MDR1 gene in leukemia cell C by treatment with Cytosar at a concentration of 10 μm. Active inhibitor of the considered connection, IC50which did not exceed ~5 µm (a measure for the control of substances bis I).

1. Compounds described by the General formulas I and II:

where X1-X4Osnach shall comply With; Z denotes H; R1means alkyl, H, -(CH2)3-N-(C2H5)2; R2and R3mean alkyl, or together with the nitrogen atom to which they are bound, form a4-7- monocyclic ring containing 1 or 2 heteroatoms selected from O or N, possibly substituted by alkyl;
R4means N; Y means S, -N-(C2H5)-; where in the compound of the formula I R5and R6together with the nitrogen atom to which they are bound, form a9-10condensed bicyclic ring containing as the heteroatom N, possibly substituted by R, where R is-N(R2)-R3;
and the connection formula II, R5means phenyl, optionally substituted och3.

2. The use of the compounds of formula I and II according to claim 1 as a means of inhibiting a protein kinase.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

Chemical method // 2386636

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.

EFFECT: design of an efficient method of obtaining the said compound.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3,3'-bis-(3,4-dihydro-3-phenyl-2H-1,3-benzoxazin-6-yl)-1(3H)-isobenzofuranone and analogues based on phenolphthalein, formaldehyde and a primary amine of formula 1: , in which R independently represents allyl or phenyl, and to a method of synthesising the said compounds. The invention also pertains to a method of making a refractory cast or layered material based on the said compounds and laminating compositions since through thermal hardening, these compounds form a net which does not catch fire easily and is resistant to high temperatures. The said compounds can be particularly useful in making printed circuit boards.

EFFECT: obtaining fire-resistant compounds.

5 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a group of novel chemical compounds pharmacologically acceptable salts thereof having formula , where A represents COOH; B represents H; n equals 0; V represents -CH2-, a single bond; W represents a 5-7-member heteroaromatic group with one heteroatom selected from N, O, S which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, when V represents a -CH2-group, where if V represents a single bond, W represents a bicyclic condensed a ring -member heterocyclic group with one heteroatom selected from O, S, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; X represents a 5-7-member heteroaromatic group with one O atom and one or two N atoms, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Y represents C6-C10 aryl which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, a 5-7-member heteroatomatic group with one S atom which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Z represents C1-C8 alkyl, C3-C7 cycloalkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryloxy which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A, or C1-C12 aralkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; group of substitutes A represents halogen, C1-C6 alkyl, halogen C1-C6 alkyl, C1-C6 alkoxy.

EFFECT: compounds exhibit inhibitory activity towards HvGR which enables their use to prepare a pharmaceutical composition used in therapy for autoimmune diseases.

33 cl, 6 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel tri-indolylmethane derivatives of general formulae I and II. The compounds can be used during bacterial or fungal infection and for protecting different products from harmful effect of bacteria or fungi, particulary as antiseptics or for disinfection. In general formulae

I

or II , where R1; R7; R13 independently represent hydrogen, alkyl, substituted alkyl, R2; R8; R14 independently represent hydrogen, alkyl, substituted alkyl, -OH, -OR, C1-C4acyl, where R is alkyl or substituted alkyl, R3-R6; R9-R12; R15-R18 independently represent hydrogen, alkyl, substituted alkyl, -OH, -OR, C1-C4acyl, where R represents alkyl or substituted alkyl, Y is an anion of a pharmacologically acceptable organic or inorganic acid; R19 is hydrogen, alkyl, substituted alkyl acyl, metal ion. The invention also relates to methods of obtaining compounds of formulae I and II, a pharmaceutical composition and use. The invention relates to a method for synthesis of tri-indolylmethane of formula III mono-substituted in the methane group which is an intermediate compound.

EFFECT: obtaining tri-indolylmethanes of general formulae I or II having antibacterial and antifungal activity.

17 cl, 4 dwg, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula , where X, R1, R2, R3, R4 and R5 assume values given in the description and paragraphs of the formula of invention, and their pharmaceutically acceptable salts.

EFFECT: compounds have antagonistic activity on histamine receptor 3 (H3).

25 cl, 3 tbl, 215 ex

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives with formula I , where: Ra is H; C1-C4alkyl; one of Rb, Rc, Rd and Re is C1-C4alkyl, and the others are H; or Rb, Re, Rd and Re are all H; and R is a radical with formula (a), (b) and (c), presented in the claim.

EFFECT: compounds inhibit protein kinase C (PKC), which allows for their use in making a medicinal agent for treating or preventing diseases or disorders mediated by T lymphocytes and/or PKC, particularly during transplantation.

8 cl, 11 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

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