Pharmaceutical composition, methods for its preparing and applying

FIELD: organic chemistry, biochemistry, biology.

SUBSTANCE: invention relates to a pharmaceutical composition eliciting the inhibitory effect on activity of serine protease (caspase-3) in the form of tablet, capsule or injections placed into acceptable package, to a method for its preparing and a method for treatment of diseases associated with enhanced activation of apoptosis. The composition comprises compound 2,3-dihydro-1H-benzo[g]pteridine-4-one of the general formula (1) (1)

or its salt with pharmacologically acceptable acid as an active component taken in pharmaceutically effective amount wherein X means oxygen (O) or sulfur (S) atom; R1 and R2 represent independently of one another hydrogen atom, inert substitute taken among the group including low- or non-reactive and optionally substituted radical, such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, (C7-C12)-heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, heterocyclyl; optionally substituted hydroxy-(C1-C5)-alkyl group; R3, R4, R5 and R6 represent independently of one another hydrogen, halogen atom, -CF3, -CN, inert substitute taking among the group including low- or non-reactive and optionally substituted radical, optionally substituted hydroxyl group, optionally substituted hydroxy-(C1-C5)-alkyl group, optionally substituted amino-group, optionally substituted amino-(C1-C7)-alkyl group, optionally substituted carboxy-(C1-C7)-alkyl group, optionally substituted (C1-C6)-alkylcarboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group, optionally substituted (C1-C6)-alkylcarbamoyl group, optionally substituted sulfamoyl group. Also, invention relates to applying compounds of the formula (1) for preparing pharmaceutical composition and experimental study (in vitro and in vivo) processes associated with apoptosis.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of composition.

7 cl, 1 dwg, 2 tbl, 5 ex

 

This invention relates to a new chemotype compounds, namely 2,3-dihydro-1H-benzo[g]pteridine-4-ones possessing physiological activity. More specifically, the present invention relates to new pharmaceutical compositions containing these compounds as active substances; and also for obtaining these compositions and method of use of these compositions for the treatment and prevention of the development of various diseases associated with increased activation of apoptosis. (apoptosis-Apoptosis: Pharmacological Implications and Therapeutic Opportunities. Kaufmann, S.H., Ed.; Academic Press: San Diego, 1997). This wide range of diseases includes, in particular, cardiovascular (e.g., acute ischemic lesion stroke, myocardial infarction), neurodegenerative, for example, Parkinson's disease and Alzheimer's disease (Ryan C.; Salvesen G. Caspases and neuronal development. Biol. Chem. 2003, 384 (6), 855-861), viral diseases (such as hepatitis C and AIDS), etc. (Cryns, V.L.; Yuan, J. The cutting edge: Caspases in apoptosis and disease. In When Cells Die; Lockshin, R. A., Zakeri, Z., Tilly, J.L., Eds.; Wiley-Liss: New York, 1998, 177-210).

The basis of the pharmacological effect of 2,3-dihydro-1H-benzo[g]pteridine-4-ones lies efficient suppression of apoptosis, exercisable by inhibiting cysteine protease-caspase-3, which plays a key role in the development of apoptosis.

It is now known that the life of multicellular organisms is based on the balance sheet post the constantly flowing processes division and cell growth must be accompanied by an alternative process of removing old, damaged, mutated and other undesirable for the body cells. Managed form of programmed cell death with characteristic morphological and biochemical characteristics defined as apoptosis (Greek word corresponding to Russian "Listopad": Aro - branch, ptosis - falling) (Apoptosis: Pharmacological Implications and Therapeutic Opportunities. Kaufmann, S.H., Ed.; Academic Press: San Diego, 1997. When Cells Die; Lockshin, R.A.; Zakeri, Z.; Tilly, J.L.; Eds.; Wiley-Liss: New York, 1998). Today it is established that the violation of the control cell death leads to shifts of homeostasis and the development of various pathological conditions (Nicholson D.W. From bench to clinic with apoptosis-based therapeutic agents. Nature (London) 2000, 407, 810-816). In the case of increased activation of apoptosis occur most serious pathology related to cardiovascular, neurodegenerative, infectious, metabolic and theplane (V.L. Cryns; Yuan J. The cutting edge: Caspases in apoptosis and disease. In When Cells Die; Lockshin, R.A.; Zakeri, Z.; Tilly, J.L.; Eds.; Wiley-Liss: New York, 1998, 177-210). Thus it is shown that the course of AIDS and the number of severe diseases of the nervous system (Parkinson's disease, Alzheimer's disease) is characterized by increased activation of apoptosis (Hartmann, A.; Hunot S.; Michel, P.; Muriel M.P.; Vyas, S.; Faucheux Century; Mouatt-Prigent, P.; Tunnel H.; Srinivasan, A.; Ruberg M.; Evan G.; Agid Y.; Hirsch E. Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in PA's disease. PNAS 000, 97 (6), 2875-2880). During cerebral ischemia and stroke, a significant portion of the cells in the affected area dies it is by the mechanism of apoptosis. In relation to the cells of humans and animals apoptosis in most cases is associated with proteolytic activation cascade of caspases - family evolutionary conservative cysteine proteases that specifically break down proteins after aspartic acid residues. On the basis of structural homology caspase divided into subfamilies (a) caspase-1 (caspase 1, 4, 5), (b) caspase-2 (caspase-2), and C) caspase-3 (caspase 3, 6-10). (Nicholson, D.W.; Thomberry, N.A. Caspases: killer proteases. Trends Biochem. Sci. 1997, 22, 299-306); (Nicholson D.W. Caspase structure, proteolytic substrates, and function during apoptotic cell death [Review]. Cell. Death. Diff. 1999, 6, 1028-1042).

A particularly important role, in fact, defines the life prospects of cells, plays the caspase-3 (Porter, A. G.; Janicke, R. U. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999, 6, 99-104). Therefore, the search for highly effective inhibitors of caspase-3, is able to block apoptosis, is a very promising approach to the creation of fundamentally new new cardioprotection (Chapman J.; Magee W.; Stukenbrok H.; Beckius G.; Milici, A.; Tracey W. A novel nonpeptidic caspase-3/7 inhibitor, (S)-(+)-5-[l-(2-methoxymethylpyrrolidinyl)-sulfonyl]isatin reduces myocardial ischemic injury. Eur. J. Pharmacol. 2002, 456{1-3), 59-68), neuroprotection (Scott C.; Sobotka-Briner, S.; Wilkins, D.; Jacobs, R.; J. Folmer; W. Frazee; br R.; Ghanekar, S.; D. Aharony Novel Small Molecule Inhibitors of Caspase-3 Block Cellular and Biochemical Features ofApoptosis. Pharmacol. Exp. Therp. 2003, 304 (1) 433-440), hepatic (Anseimo D.; Katori M.; M. Kaldas; Hoglen N.; Valentine, K.; Busuttil R.; Kupiec-Weglinski W.; Farmer, D. Apoptosis targeted therapy with the caspase inhibitor IDN-6556, ameliorates ex-vivo liver ischemia reperfusion injury. Am. J. Transplant.

2002, 2 (Suppl.3), 920) for the treatment and protection against a wide range of diseases, a key element of which is apoptosis.

Numerous studies conducted in recent years, led to the discovery of highly effective inhibitors of caspase-3 in a row peptide (Garcia-Calvo, M.; Peterson, E.; Leiting Century; Ruel, R.; Nicholson, D.; Thomberry, N. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 1998, 273, 32608-32613) and coworkers peptide compounds (Karanewsky, D.; Bai, X.; Linton S.; Krebs, J.; Wu J.; Pham Century; Tomaselli K. Conformationally constrained inhibitors ofcaspase-1 and of the human CED-3 homologue caspase-3. Bioorg. Med. Chem. Lett. 1998, 5, 2757-2762). An example of this type of compounds can be, for example, the following coworkers peptide derivatives developed by firms Idun Pharmaceuticals, Inc. (K.J. Tomaselli; Gladstone P.L.; Temansky R.J. Pat. PCT WO 0179162, 2001) and Vertex Pharmaceuticals Inc. (Golec, J.; Lang, P.; Diu-Hercend, A.; Knegtel, R.; Weber, P.; Miller, K.; Hercend, T.; Mortimore, M.; Miller, A. Pat. PCT WO 0285899, 2002).

However, such compounds have very limited clinical use because of their poor pharmacokinetic and physicochemical properties (Scott C.; Sobotka-Briner, S.; Wilkins, D.; Jacobs, R.; J. Folmer; W. Frazee; br R.; Ghanekar, S.; D. Aharony Novel Small Molecule Inhibitors of Caspase-3 Block Celluar and Biochemical Features of Apoptosis. Pharmacol. Exp. Therap. 2003, 304(1), 433-440). In this regard, continue to look for ones low-molecular kaspasky inhibitors. So, have been found quite effective inhibitors (IC50=5-40 PM) caspase-3 in a series of satinov, for example (Chapman J.; Magee W.; Stukenbrok H.; Beckius G.; Milici, A.; Tracey W. Anovel nonpeptidic caspase-3/7 inhibitor, (S)-(+)-5-[l-(2-methoxymethylpyrrolidinyl) sulfonyl]isatin reduces myocardial ischemic injury. Eur. J. Pharmacol. 2002, 456(1-3), 59-68) and (Lee, D.; Long, S.A.; Murray, J.H. et al. Potent and selective nonpeptide inhibitors of caspases 3 and 7. J. Med. Chem. 2001, 44(12), 2015-2026)

However, the low selectivity of the compounds of this class stimulates further the search for inhibitors of caspase-3. So, recently discovered caspase inhibitors in a number of hintline, substances possess moderate activity and selectivity (Scott C.; Sobotka-Briner, S.; Wilkins, D.; Jacobs, R.; J. Folmer; W. Frazee; br R.; Ghanekar, S.; D. Aharony Novel Small Molecule Inhibitors of Caspase-3 Block Cellular and Biochemical Features ofApoptosis. Pharmacol. Exp. Therap. 2003, 304(1), 433-440).

It should be noted that in the scientific and patent literature to date has no information about antiprotease activity of 2,3-dihydro-1H-benzo [g] pteridine-4-ones.

As a result of research aimed at finding new biologically active compounds selectively inhibit programmed cell death (apoptosis), the inventors have discovered a new gametip ones inhibitors of caspase-3, and they are the NGOs 12,3-dihydro-1H-benzo[g]pteridine-4-ones.

More specifically this invention relates to new pharmaceutical compositions containing 2,3-dihydro-1H-benzo[g]pteridine-4-ons in the form of active substances; as well as to its preparation and method of its use for the treatment and prevention of the development of various diseases associated with increased activation of apoptosis, e.g., acute ischemic lesions (eg, stroke, myocardial infarction), neurodegenerative (e.g., Parkinson's disease and Alzheimer's disease), viral diseases (such as hepatitis C and AIDS), etc.

Below are definitions of terms used in the description of this invention.

“Combinatorial library” means a collection of compounds obtained by parallel synthesis, designed to search for a leader or optimize the biological activity of lead compounds, with each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

“Focused library” means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, as a rule, CBE is an with directional search effectors (inhibitors, activators, agonists, antagonists, etc.) certain biological targets (enzymes, receptors, ion channels, and so on).

“Lead compound” means a compound with outstanding activity related to a particular disease.

“Scaffold” means the General structural formula or molecular CORCAS or invariant connections area common to all compounds included in the combinatorial library.

“Gametip” means a series of compounds having a common structural formula and with a certain common property, for example, in some kind of fiziologicheskii activity. We can say, for example, "new gametip activators of potassium channels" or "known gametip kinase inhibitors", etc. As a rule, the presence of common structural fragment of compounds within one chemotype is a necessary and sufficient condition for the existence of common properties.

“Deputy” means a chemical moiety that is attached to scaffold or semi-synthesis in the process of their synthesis. As the Deputy may serve as a halogen atom, a hydroxyl group, carboxialkilnuyu group, carboxyl group, carnemolla group or inert Deputy.

“Inert Deputy” ("Non-interfering substituent"means low or directionspanel radical, including, but not limited to C 1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted heterocyclyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred inert substituents are C1-C7alkyl, C2-C7alkenyl,1-C7quinil, C7-C12alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

“Substituted group, substituted radical or scaffold” means respectively the group, the radical or scaffold, which is meets Deputy, including but not limited to inert Deputy, halogen atom, nitro group, cyano group, sulfo group, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, carnemolla group. For example: substituted alkyl means alkyl with one or more substituents, such as hydroxyalkyl or methoxycarbonylethyl, amino-methoxycarbonyl-methyl, dimethylaminoethyl, 2-hydroxy-2-methoxycarbonyl-ethyl and others; substituted amino group means an amino group which has one or disamenities, for example, acylamino group, N,N-dialkylamino group, N-acyl-N-aryl-amino group, acetyl-methoxycarbonylmethyl-amino group and others; substituted phenyl means phenyl, which has one or more substituents, for example, 2-ethoxycarbonylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

“Optionally substituted group optionally substituted radical or scaffold” means a group, the radical or scaffold, including groups, radicals or scaffold with deputies and without deputies. For example, the concept of optional substituted amino group includes an unsubstituted amino group and amino group containing any, not inconsistent with chemistry substituents, including but not limited to acylamino group, N,N-dialkylamino groups, N-acyl-N-aryl-amino group, AC is l-methoxycarbonylmethyl-amino group and others

“Aryl” means one or more aromatic cycles, each of which includes 5 or 6 carbon atoms. “Aryl” may be condensed political, such as naphthalene or unfused, such as biphenyl. “Substituted aryl” has one or more “not interfering” deputies.

“Halogen” means fluorine atom, chlorine, bromine or iodine.

“Heterocycle” means one or more saturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. “Heterocycle” may be condensed political, such as benzimidazole, benzoxazole. benzthiazole, quinoline or unfused, for example, as bipyridyl.

“Azaheterocycle” means a heterocycle comprising at least one nitrogen atom, such as benzimidazole, benzoxazole. benzthiazole, quinoline.

“Substituted heterocycle” means a heterocycle having one or more “not interfering” deputies.

“Parallel synthesis” means a method for chemical synthesis of combinatorial libraries of individual connections.

The aim of the present invention is to provide new pharmaceutical compositions in the form of tablets, capsules or injections placed in pharmaceutically acceptable packing : the ku.

This goal is achieved by a pharmaceutical composition having inhibitory activity against serine proteases (Caspase-3), in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, containing as active substance pharmaceutically effective amount of 2,3-dihydro-1H-benzo[g]pteridine-4-it General formula 1 or salts thereof with farmacologicas acceptable acid

in which: X is O or S;

R1and R2independently from each other represent a hydrogen atom, an inert Deputy selected from the group comprising low-or directionspanel optionally substituted radical, such as C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, C7-C12geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, heterocyclyl, optionally substituted With hydroxy1-5alkyl group, optionally substituted amino With1-7alkyl group;

R3, R4, R5and R6independently from each other represent: a hydrogen atom, halogen atom, CF3CN, inert Deputy selected from the group comprising low - or erecciones is capable of optionally substituted radical, such as C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, C7-C12geterotsiklicheskikh, C7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, heterocyclyl, optionally substituted hydroxyl group, optionally substituted With hydroxy1-6alkyl group, optionally substituted amino group, optionally substituted amino1-6alkyl group, optionally substituted carboxy1-6alkyl group, optionally substituted C1-6-alkylcarboxylic1-6is an alkyl group, optionally substituted carbamino group, optionally substituted C1-6alkylcarboxylic group, optionally substituted sulfamoyl group.

According to the invention preferred pharmaceutical composition for treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis is a composition containing as active substance pharmaceutically effective amount of substituted 8-amino-2-thioxo-2,3-dihydro-1H-benzo[g]pteridine-4-it General formula 1.1 and/or substituted 8-amino-2,3-dihydro-1H-benzo[g]pteridine-2,4-dione of General formula 1.2 or their salts with Farmak is logicheskie acceptable acid

in which:

R1, R2, R3, R5R6have the above meaning;

R7and R8independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted hydraxis1-6alkyl group, optionally substituted amino1-6alkyl group, optionally substituted C1-6alkyl-carboxy1-6alkyl group, optionally substituted C1-6alkylcarboxylic group, optionally substituted formyl group, substituted sulfonyloxy group; or R7and R8together with the nitrogen atom to which they are attached represent optionally substituted and optionally including additional heteroatom, selected from the group oxygen, nitrogen or sulfur, 3-10-membered cycle; or R7and R8together with the nitrogen atom to which they are attached, represent a condensed heterocycle, optionally substituted and optionally including additional heteroatom, selected from the group oxygen, nitrogen or sulphur.

According to the invention preferred pharmaceutical composition for treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis, is a composition containing as AK is active substance pharmaceutically effective amount of substituted N-(4-oxo-2-thioxo-1,2,3,4-tetrahydro-(benzo[g]pteridine-8-yl)-formamidine General formula 1.3 and/or substituted N-(2,4-dioxo-1,2,3,4-tetrahydro-(benzo[g]pteridine-8-yl)-formamidine the General formula 1.4, or their salts with pharmacologically acceptable acid

in which: R1, R2, R3, R5and R6have the above meaning; R9and R10independently from each other represent a hydrogen atom or an inert Deputy.

According to the invention preferred pharmaceutical composition for treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis, is a composition containing as active substance pharmaceutically effective amount of substituted 5-[(4-oxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-dihydro-pyrimidine-4,6-dione of General formula 1.5 or its salt with a pharmacologically acceptable acid, in which:

X, R1, R2, R3, R5and R6have the above meaning;

R11and R12independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted hydraxis1-5alkyl group, optionally substituted amino1-7alkyl group.

The aim of the present invention is also a method of obtaining a pharmaceutical composition.

This goal is achieved by a method of obtaining pharmaceutical com is osili, which consists in mixing the active substance with an inert filler and/or solvent, the distinctive feature of which is that as the active substance is used pharmacologically effective amount of a substance of General formulas 1, 1.1, 1.2, 1.3, 1.4 or 1.5 or its salt with a pharmacologically acceptable acid.

The aim of the present invention is also a method of treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis.

This goal is achieved by a method of treating and preventing various diseases of warm-blooded animals and humans associated with increased activation of apoptosis, by introducing a warm-blooded animal or human pharmaceutical compositions containing as active substance pharmaceutically effective amount of 2,3-dihydro-1H-benzo[g]pteridine-4-it General formulas 1, 1.1, 1.2, 1.3, 1.4 or 1.5 or its salt with a pharmacologically acceptable acid.

The aim of the present invention is the creation of new pharmacological tools for investigating the processes of apoptosis.

This goal is achieved by the application of physiologically active compounds of General formula 1 or their salts with pharmacologically priemlimymi acids, which is the main inhibitors of caspase-3, to obtain drugs or experimental (in vitro or in vivo) studies of apoptosis as pharmacological tools.

2,3-Dihydro-1H-benzo[g]pteridine-4-ones of General formula 1 is produced by interaction between the pyrimidine-2,4,5,6-tetragon 5-oximo 2 or 2-thioxo-dihydro-pyrimidine-4,5,6-Trion 5-oximo 3 meta phenylenediamine 4 on the diagram below:

Another way of obtaining substituted 2,3-dihydro-1H-benzo[g]pteridine-4-ones [Krasnov, K.A. J. Org. Chem. 1998, 34 (1), 129-133] provided on the following scheme:

The table below shows some of 2,3-dihydro-1H-benzo[g]pteridine-4-ones of General formula 1 obtained according to the above diagram.

During the synthesis of 2,3-dihydro-1H-benzo[g]pteridine-4-ones of General formula 1 have been used commercially available source reagents.

Below the invention is described using specific examples of the preparation of specific compounds and combinatorial libraries. The structure of the obtained compounds was confirmed by the data of chemical, chromatographic and spectral analysis. Liquid-phase concurrent sites new compounds and combinatorial libraries was carried out using a special synths "CombiSyn-012-3000" [Mbar, Aevidence, Patent of Russia 2180609, 2002; PCT WO 02/087740 A1, 2002] and equipment [Technology Platform. In Custom Chemistry; Chemical Diversity Labs, Inc.; San Diego, CA, 2002; p.5].

Biological (antiprotease) activity of the compounds was determined on the serine protease (Caspase 3), which are involved in the regulation programmirovanie cell death (apoptosis). The activity of Caspase 3 was determined by the rate of cleavage of the peptide substrate containing fluorescent molecule (methylcoumarin) in accordance with the Protocol described in Technical Bulletin company Sigma-Aldrich [www.sigmaaldrich.com/sigma/bulletin/casp3fbul.pdf].

All solvents and reagents that were used in the synthesis of compounds of General formula 1, were obtained from commercial sources, such as ACROS (Acros) (Belgium), Sigma-Aldrich (Sigma-Aldrich) (United States), Lancaster (Lancaster) (UK) and Chemdiv (ChemDiv) (USA). The melting point (TPL) were obtained on the instrument company Buchi (Buchi) (Switzerland) model-520.1H and13The NMR spectra were obtained on a spectrometer Gemini-300 (300 and 75 MHz, respectively) firm Varian (Varian) (USA) in CDCl3or dimethyl sulfoxide-d6. Chemical shifts are given in the scale(RRT). The internal standard tetramethylsilane was.

The content of the basic substance was controlled by HPLC on the device Shimadzu (Shimadzu) 10-AV (column Luna-CIS, Phenomenex, 25 cm 4.6 mm, UV detection at 215 and 254 nm) and LC-MS (VGH-MS) instrument Applied Biosytems (Shimadzu 10-AV LC, automatic sample Gilson-215, mass spectrometer API EH, UV (215 and 254 nm) and ELS detectors, column Luna C18, Phenomenex, 5 cm·2 mm).

Analytical TLC was performed on silica gel on aluminium plates Silufol UV254(5 cm (15 cm) (K-avalier, Czech Republic) or on glass slides with a 0.25-mm layer of silica gel 60 F254(Merck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For chromatographic purification of used silica gel 5-40 μm (Chemapol, Czech Republic) and 63 μm (EM Science, USA). In accordance with these LC/MS all the synthesized compounds had a basic substance content above 95% (unless otherwise specified).

The invention is illustrated by, but is not limited to the following examples.

Example 1. Parallel synthesis of combinatorial libraries of 2,3-dihydro-1H-benzo[g]pteridine-4-Onna General formula 1. Was heated in an atmosphere of nitrogen 0.01 mole of aniline 7 and 0.01 mol of 6-florouracil (thiouracil) at 100-170°C for 1-3 h, the Reaction mass was cooled to room temperature, was added 30 ml of 10% hydrochloric acid and stirred. Sediment hoteltravel, washed with 3% hydrochloric acid, then with 1% sodium bicarbonate solution and water. If necessary, recrystallized from alcohol. Received connection 8 with the release of 30-80%. Was dissolved in 0.01 mol of compound 8 by heating in 20 ml of acetic acid, then cooled to 10°and probabl is whether under stirring a solution of 0.015 mole of sodium nitrite in 5 ml of water. The reaction mixture was stirred 1 h) at room temper temperature, and then heated until complete dissolution of the precipitate, which is a mixture of substances 1 and 9, and were added with stirring, 0.05 mol of zinc dust. Was stirred 0.5 h at 100°, followed by decantation of the solution to precipitate metal, diluted with water and ohlidal 5-10°C for 1 h the Precipitate was filtered, washed with water then with alcohol and dried. Received 2,3-dihydro-1H-benzo[g]pteridine-4-ones 1 with the release of 40-90%, including:

8-Amino-3-benzyl-7-methyl-1H-benzo[g]pteridine-2,4-dione 1 {1};

8-Amino-1H-benzo[g]pteridine-2,4-dione 1 {2};

8-Dimethylamino-1H-benzo[g]pteridine-N-(2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide-2,4-dione 1 {3};

N-(2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {4};

Heptane acid (2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {5};

8-Amino-7-methyl-1H-benzo[g]pteridine-2,4-dione 1 {6};

N-(7-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {7};

N-(7-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {8};

Heptane acid (7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {9};

Nonanalog acid (7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {10}

N-(7-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-succineidae acid 1 {11};

2,2,2-Cryptor-N-(7-methyl-2,4-dio is co-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {12};

1-Benzyl-5-[(7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-pyrimidine-2,4,6-Trion 1 {13};

8-Amino-9-methyl-1 H-benzo[g]pteridine-2,4-dione 1 {14};

2,2,2-Cryptor-N-(9-methyl-2,4-Dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {15};

8-Amino-1,3-dimethyl-1 H-benzo[g]pteridine-2,4-dione 1 {16};

8-Dimethylamino-1,3-dimethyl-1H-benzo[g]pteridine-2,4-dione 1 {17};

8 Diethylamino-1,3-dimethyl-1 H-benzo[g]pteridine-2,4-dione 1 {18};

N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {19};

N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {20};

Heptane acid (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {21};

Nonanalog acid (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {22};

N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-benzamid 1 {23};

N-(1,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-N,N-dimethyl-formamidine 1 {24};

N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-succineidae acid 1 {25};

3-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-ylcarbonyl)-acrylic acid 1 {26};

N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {27};

5-[(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-pyrimidine-2,4,6-Trion 1 {28};

5-[(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo [g] pteridine-8 ylamino)-methylene]-1,-dimethyl-pyrimidine-2,4,6-Trion 1 {29};

1-Benzyl-5-[(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-pyrimidine-2,4,6-Trion 1 {30};

1-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-3-phenyl-urea 1 {31};

8-Amino-1,3,7-trimethyl-1H-benzo[g]pteridine-2,4-dione 1 {32};

N-(1,3,7-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {33};

N-(1,3,7-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {34};

Heptane acid (1,3,7-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {35};

Nonanalog acid (1,3,7-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {36};

N-(1,3,7-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-benzamid 1 {37};

N,N-Dimethyl-N’-(l,3,7-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-formamidine 1 {38};

2,2,2-Cryptor-N-(1,3,7-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-acetamide 1 {39};

5-[(1,3,7-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-pyrimidine-2,4,6-Trion 1 {40};

1-Methyl-5-[(1,3,7-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-pyrimidine-2,4,6-Trion 1 {41};

N-(1,3,9-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {42};

N-(1,3,9-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {43};

Heptane acid (1,3,9-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amine 1 {44}

Nonanalog acid (1,3,9-trimethyl-2,4-dioxo-1,2,3,4-t is trihydro-benzo[g]pteridine-8-yl)-amide 1 {45};

2,2,2-Cryptor-N-(1,3,9-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {46};

8-Amino-1,3-dimethyl-9-nitro-1H-benzo[g]pteridine-2,4-dione 1 {47};

8-Ammo-3,7-dimethyl-1H-benzo[g]pteridine-2,4-dione 1 {48};

N-(3,7-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {49};

N-(3,7-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {50};

Heptane acid (3,7-dimethyl -2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {51};

N’-(3,7-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-N,N-dimethyl-formamidine 1 {52};

N-(3,7-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {53};

3-Allyl-8-amino-1 H-benzo[g]pteridine-2,4-dione 1 {54};

N-(3-Allyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {55};

N-(3-allyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {56};

Heptane acid (3-allyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {57};

N’-(3-Allyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-N,N-dimethyl-formamidine 1 {58};

N-(3-Allyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {59};

N-(3-Allyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {60};

N-(3-Allyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {61};

Heptane acid (3-allyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g] pteridine-8-yl)-amide 1 {62};

N-(3-allyl-7methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {63};

8-Amino-3-butyl-1H-benzo[g]pteridine-2,4-dione 1 {64};

3-Butyl-8-dimethylamino-1H-benzo [g] pteridine-2,4-dione 1 {65};

N-(3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {66};

N-(3-Butyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {67};

Heptane acid (3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {68};

Nonanalog acid (3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {69};

N’-(3-Butyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-N,N-dimethyl-formamidine 1 {70};

N-(3-Butyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {71};

5-[(3-Butyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-methylene]-1,3-dimethyl-pyrimidine-2,4,6-Trion 1 {72};

8-Amino-3-butyl-7-methyl-1H-benzo[g]pteridine-2,4-dione 1 {73};

N-(3-Butyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {74};

N-(3-Butyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {75};

Heptane acid (3-butyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {76};

N’-(3-Butyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-N,N-dimethyl-formamide 1 {77};

N-(3-Butyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {78};

8-Amino-3-butyl-9-nitro-1H-benzo[g]pteridine-2,4-dione 1 {79};

8-Amino-3-hexyl-1H-benzo [g] pteridine-2,4-dione 1 {80};

N-(3-Hexyl-2,4-dioxo-1,2,3,4-tetrahed the on-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {81};

N-(3-Hexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {82};

Heptane acid (3-hexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {83};

Nonanalog acid (2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {84};

N-(3-Hexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-benzamid 1 {85};

2,2,2-Cryptor-N-(3-hexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {86};

5-[(3-Hexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-pyrimidine-2,4,6-Trion 1 {87};

5-[(3-Hexyl-2,4-Dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-1,3-dimethyl-pyrimidine-2,4,6-Trion 1 {88};

1-Benzyl-5-[(3-hexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-mthylene]-pyrimidine-2,4,6-Trion 1 {89};

8-Amino-3-hexyl-7-methyl-1H-benzo[g]pteridine-2,4-dione 1 {90};

N-(3-Hexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {91};

Heptane acid (3-hexyl-7-methyl-1-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {92};

2,2,2-Cryptor-N-(3-hexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {93};

5-[(3-Hexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-1-methylpyrimidine-2,4,6-Trion 1 {94};

8-Amino-3-cyclohexyl-1H-benzo [g] pteridine-2,4-dione 1 {95};

N-(3-Cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {96};

Heptane acid (3-cyclohexyl-2-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {97};

Nonanalog acid (3-cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {98};

N-(3-Cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-benzamid 1 {99};

N-(3-Cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-succineidae acid 1 {100};

N-(3-Cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {101};

5-[(3-Cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-methylene]-1,3-dimethyl-pyrimidine-2,4,6-Trion 1 {102};

N-(3-Cyclohexyl-7-methyl-2,4-dioxo-l,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {103};

N-(3-Cyclohexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {104};

Heptane acid (3-cyclohexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {105};

Nonanalog acid (3-cyclohexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {106};

N-(3-Cyclohexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-benzamid 1 {]07};

N’-(3-Cyclohexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-N,N-dimethyl-formamide 1 {108};

N-(3-Cyclohexyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {109};

8-Amino-3-benzyl-1H-benzo[g]pteridine-2,4-dione 1 {110};

3-Benzyl-8-dimethylamino-1 H-benzo[g]pteridine-2,4-dione 1 {111};

N-(3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {112};

N-(3-Benzyl-2,4-dioxo-1,2,3,4-tet is ahydro-benzo[g]pteridine-8-yl)-propionic 1 {113};

Heptane acid (3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {114};

N-(3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-succineidae acid 1 {115};

N-(3-Benzyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {116};

Heptane acid (3-benzyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {117};

Nonanalog acid (3-benzyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {118};

N-(3-Benzyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {119}

N-(3-Benzyl-9-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {120};

8-Amino-3-phenethyl-1 H-benzo[g]pteridine-2,4-dione 1 {121};

8-Dimethylamino-3-phenethyl-1H-benzo[g]pteridine-2,4-dione 1 {122};

N-(2,4-Dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {123};

N-(2,4-Dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {124};

Heptane acid (2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {125};

Nonanalog acid (2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {126};

N’-(2,4-Dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-N,N-dimethyl-formamide 1 {127};

N-(2,4-Dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-2,2,2-Cryptor-ndimethylacetamide 1 {128};

8-Amino-7-methyl-3-phenethyl-1H-benzo[g]pteridine-2,4-dione 1 {129};

N-(7-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {130};

Heptane CIS is the notes (7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {131};

Nonanalog acid (7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {132};

N,N-Dimethyl-N’-(7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-formamidine 1 {133};

2,2,2-Cryptor-N-(7-methyl-2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {134};

8-Amino-9-methyl-3-phenethyl-1H-benzo[g]pteridine-2,4-dione 1 {135};

8-Amino-2-thioxo-2,3-dihydro-1H-benzo[g]pteridine-4-one 1 {136};

8-Dimethylamino-2-thioxo-2,3-dihydro-1H-benzo[g]pteridine-4-one 1 {137};

N-(4-Oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {138};

N-(4-Oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-propionic 1 {139};

Heptane acid (4-oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-amide 1 {140};

8-Amino-7-methyl-2-thioxo-2,3-dihydro-1H-benzo[g]pteridine-4-one 1 {141};

N-(7-Methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {142};

2,2,2-Cryptor-N-(7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {143}.

Example 2. Was focused library, including 10240 compounds, including 143 2,3-dihydro-1H-benzo[g]pteridine-4-Onna 1 {1-143} and tried it on antiprotease activity. Antiproteaznaya activity was determined by the serine protease (Caspase 3), which are involved in the regulation of programmed cell death (apoptosis). The activity of Caspase 3 was determined by the rate of cleavage of the peptide substrate containing free is tnou molecule (methylcoumarin). Removal methylcoumarin from the peptide molecules in the proteolytic reaction of the enzyme is accompanied by increased fluorescence intensity measurements which were performed with fluorescent parallel reader VICTOR2V (PerkinElmer, USA) at a wavelength of excitation of 355 nm and the wavelength of emission of 460 nm. For carrying out reactions used an optical 96-hole of the blade. In our experiments we used the caspase 3 and the fluorescent substrate of the company Sigma (USA). The reaction conditions and the composition of the medium used in accordance with the recommendation of the manufacturer. The starting solutions of test compounds were prepared by dissolution in DMSO (dimethyl sulfoxide) to a concentration of 10 mm. The original solutions of compounds were added to the enzyme solution in such an amount to obtain a final concentration of 10 μm. After a 10 minute incubation of the enzyme with the test compound to the solution was added an enzyme substrate and measurement of fluorescence was performed after 1 hour after addition of the substrate (F

e
i
). For the correction on its own fluorescence of the tested compounds fluorescence measurement (F
0
i
) was performed in a separate circuit boards that do not contain enzyme reagents (enzyme plus substrate). Full enzyme activity was measured by fluorescence in reaction wells containing all reaction components except the tested compounds (F100) and zero activity was determined by the fluorescence of the wells containing the appropriate test connection and all the reaction reagents except the enzyme (F0). Calculation of inhibition was produced by the following formula:

where, subscript corresponds to the test compound, in the presence of which is measured fluorescence, and the superscripts (e) and (0) means the presence or absence of enzymatic reagents, respectively, 2,3-dihydro-1H-benzo[g]pteridine-4-Onna.

In the following table 2 shows the activity of one of the tested compounds of General formula 1, namely, 2,2,2-Cryptor-N-(7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {15}, and the drawing shows the concentration dependence of inhibition caspase 3 this soedinenii 1 {15}.

Table 2

Proteasa activity 2,2,2-Cryptor-N-(7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)ndimethylacetamide 1 {15}
IDThe structure of connectionsIC50, nMActivity
1 {15}265Inhibition

The drawing shows the concentration dependence of inhibition of caspase 3 2,2,2-Cryptor-N-(7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {15}

Example 3. An example illustrating the preparation of tablets containing 100 mg of active ingredient. Mix 1600 mg of starch, 1600 mg of powdered lactose 400 mg of talc and 1000 mg of 2,2,2-Cryptor-N-(7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-ndimethylacetamide 1 {15} and spracovavat in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each. According to the invention likewise receive pharmaceutical composition in the form of tablets containing as active ingredient other compounds of General formula 1.

Example 4. Capsules containing 200 mg of compound 1 {15}, according to the invention can be obtained tweeling by mixing compound 1 {15} with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Primer. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with suitable solubility, for example, hydrochloride of compound 1 {15}, 300 mg chlorbutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed and sterilized in an autoclave.

1. Pharmaceutical composition having inhibitory activity against serine proteases(Caspase-3), in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, containing as active substance pharmaceutically effective amount of 2,3-dihydro-1H-benzo[g]pteridine-4-it General formula 1 or salts thereof with pharmacologically acceptable acid

in which

X is O or S;

R1and R2independently from each other represent a hydrogen atom, an inert Deputy selected from the group comprising low - or directionspanel optionally substituted radical, such as C1-C7alkyl,C2-C7alkenyl,2-C7quinil,C1-C7alkoxy,C7-C12aralkyl,7-C12geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl, -10cycloalkenyl, phenyl, aryl, heterocyclyl, optionally substituted hydraxis1-5alkyl group, optionally substituted amino1-7alkyl group;

R3, R4, R5and R6independently from each other represent: a hydrogen atom, halogen atom, CF3CN, inert Deputy selected from the group comprising low - or directionspanel optionally substituted radical, such as C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,

With7-C12geterotsiklicheskikh,7-C12alkaryl,

With3-C10cycloalkyl,3-C10cycloalkenyl, phenyl,aryl, heterocyclyl, optionally substituted hydroxyl group, optionally substituted hydroxy-C1-6alkyl group, optionally substituted by an amino group, optionally substituted amino1-6alkyl group, optionally substituted carboxy1-7alkyl group, optionally substituted C1-6alkylcarboxylic1-6alkyl group, optionally substituted karbamoilnuyu group, optionally substituted C1-6alkylcarboxylic group, optionally substituted sulfamoyl group.

2. The pharmaceutical composition according to claim 1, containing in quality is the firmness of the active substance pharmaceutically effective amount of substituted 8-amino-2-thioxo-2,3-dihydro-1H-benzo[g]pteridine-4-it General formula 1.1 and/or substituted 8-amino-2,3-dihydro-1H-benzo[g]pteridine-2,4-dione of General formula 1.2 or their salts with pharmacologically acceptable acid

in which

R1, R2, R3, R5and R6have the above meaning;

R7and R8independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted hydroxy-C1-6alkyl group, optionally substituted amino-C1-6alkyl group, optionally substituted C1-6alkylcarboxylic-C1-6alkyl group, optionally substituted C1-6alkylcarboxylic group, optionally substituted formyl group, substituted sulfonyloxy group;

or

R7and R8together with the nitrogen atom to which they are attached represent optionally substituted and optionally including additional heteroatom, selected from the group oxygen, nitrogen or sulfur, 3-10-membered cycle;

or

R7and R8together with the nitrogen atom to which they are attached, represent a condensed heterocycle, optionally substituted and optionally including additional heteroatom, selected from the group oxygen, nitrogen or sulphur.

3. The pharmaceutical composition according to claim 1, containing as active substance pharmaceutically effective amount of substituted N-(4-oxo-2-thioxo-1,2,3,4-is tetrahydro-benzo[g]pteridine-8-yl)-formamidine General formula 1.3 and/or substituted N-(2,4-dioxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8-yl)-formamidine General formula 1.4, or their salts with pharmacologically acceptable acid

in which

R1, R2, R3, R5and R6have the above meaning;

R9and R10independently from each other represent a hydrogen atom or an inert Deputy.

4. The pharmaceutical composition according to claim 1, containing as active substance pharmaceutically effective amount of 5-[(4-oxo-1,2,3,4-tetrahydro-benzo[g]pteridine-8 ylamino)-methylene]-dihydropyrimidin-4,6-dione of General formula 1.5 or its salts with pharmacologically acceptable acid

in which

X, R1, R2, R3,R5and R6have the above meaning;

R11and R12independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted hydroxy-C1-5alkyl group, optionally substituted amino-C1-7alkyl group.

5. A method of obtaining a pharmaceutical composition according to any one of claims 1, 2, 3 or 4 by mixing the active substance with an inert filler and/or diluent, wherein said active substance is used pharmacologically effective amount of a substance of General formulas 1, 1.1, 1.2, 1.3, 1.4 and/or 1.5 of these in any one of claims 1 to 4, or its salt with a pharmacologically acceptable acid.

6. The method of treatment and prevention is ahead of the development of various diseases of warm-blooded animals and humans, associated with increased activation of apoptosis, by introducing a warm-blooded animal or human pharmaceutical composition according to any one of claims 1, 2, C, 4.

7. The application of physiologically active compounds of General formula 1 or their salts with pharmacologically acceptable acids specified in claim 1 , having the properties of inhibitors of caspase-3, to obtain drugs or experimental (in vitro or in vivo) studies of apoptosis as pharmacological tools.



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: one should apply glycosaminoglycanes at average molecular weight being 2400 D to prepare pharmaceutical composition for treating senile feeble-mindedness and neurological cerebral lesions induced due to sudden attack or trauma. The innovation suggested increases the number of medicinal preparations of necessary indication.

EFFECT: higher efficiency of application.

7 cl, 2 dwg, 8 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to nootropic, cerebroprotective medicinal agents as tablets. Tablet of a medicinal agent comprises thiotriazoline and piracetam as active components and accessory components used for formation of core and applying an envelope on it. Invention provides elevating rate and power of a medicinal agent effect on the brain blood supply, expanding spectrum of its pharmacological effect and excludes negative adverse effects.

EFFECT: improved and valuable medicinal properties of agent.

6 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to medicine, namely to pharmacology and psychiatry

The invention relates to the field of medicine and for the application of cyclic ether (R)-3-hydroxybutyrate of formula (1) for the treatment of disease conditions mediated by free radicals, toxic agents, such as peptides and proteins, and genetic defects, harmful to the cell metabolism, insulin resistance or other defects in glucose metabolism or conditions that cause the defect, ischemia, head injury, and/or improve the efficiency of cells

The invention relates to the field of medicine for a stimulator of expression of MAG (myelin-associated glycoprotein) containing the compound of formula (I):

The connection is suitable for the treatment of diseases, representing hypomyelination, demyelinization or demyelination

The invention relates to the field of pharmaceutical industry and relates to the establishment of the pharmaceutical composition of fenotropil with nootropic activity

The invention relates to the field of medicine and relates to a spontaneously dispersible pharmaceutical composition for oral administration comprising (2R,4S)-N-(1 -(3,5-bis(trifluoromethyl)benzoyl)-2-(4-Chlorobenzyl)-4-piperidinyl)quinoline-4-carboxamide as an antagonist of substance P and the carrier medium containing a hydrophilic component and a surfactant, and methods of treatment using the composition of CNS disorders, including depression and fear of society, and respiratory diseases, such as asthma and chronic bronchitis

The invention relates to new compounds of General formula

which have the properties of receptor antagonists neirokinina-1(NK-1)

The invention relates to new highly efficient ligands (agonists, antagonists, modulators, etc.) nicotinic receptors - new substituted 1,2-dihydro[2,7]naphthirydines General formula 1 in the form of single stereoisomers, racemic or additive mixtures, or their pharmaceutically acceptable salts, N-oxides or hydrates

in which: R1and R2independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, or R1and R2together represent polymethene chain, including 2-5 optionally substituted methylene group; R3and R4independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, optionally substituted C1-6allyloxycarbonyl group, optionally substituted karbamoilnuyu group; R5located at the carbon atoms of the pyridine fragment represents: a hydrogen atom, an inert Deputy, optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl is the function group; or R5if it is at the nitrogen atom of the pyridine fragment, form a pyridinium salt with a pharmacologically acceptable anion and is inert Deputy

The invention relates to the field of medicine and relates to a pharmaceutical composition having anticonvulsant and psychotropic action

The invention relates to pharmaceutical

The invention relates to pharmaceutical industry and AA derivatives of N-(aryloxyalkyl)-heteroarylboronic and-heteroarylboronic General formula (I) used to obtain drugs with antipsychotic or analgesic activity, and a method of treating psychoses by using these derivatives

The invention relates to medicine and can be used to obtain biologically active substances from the blood serum of animals and birds, are useful for the treatment or correction of a hearing impairment, sexual activity, spatial memory; and to increase physical endurance, stimulate proliferation of embryonic brain cells; useful in Parkinson's disease

The invention relates to sulfonylacetanilide General formula I

in which R1and R2each independently of the other denotes H, A, -(CH2)n-Ar or R1and R2both together are a single rich heterocycle with the nitrogen atom, Z represents H, A, CF3Hal or OA, a is alkyl with 1-6 carbon atoms, Ar denotes a one - or disubstituted by Deputy Z is phenyl, provided that Z cannot be a hydrogen atom, Hal represents F, Cl, Br or I, n is 1 or 2, or a physiologically acceptable salt or solvate

The invention relates to medicine, namely to pharmacology and psychiatry

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

FIELD: pharmacology.

SUBSTANCE: one should apply glycosaminoglycanes at average molecular weight being 2400 D to prepare pharmaceutical composition for treating senile feeble-mindedness and neurological cerebral lesions induced due to sudden attack or trauma. The innovation suggested increases the number of medicinal preparations of necessary indication.

EFFECT: higher efficiency of application.

7 cl, 2 dwg, 8 tbl

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