Substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines and combinatory library

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of the general formula (1): or (2): or their pharmaceutically acceptable salts, N-oxides or hydrate possessing physiologically active properties, in particular, eliciting ability to induce apoptosis in tumor cells causing their death. In the general formula (1) or (2) X represents sulfur or oxygen atom; Y represents sulfur atom, group -SO, group -SO2, group -NH or group -NR6; R1 represents aryl, substituted aryl, heteroaryl; R2 and R5 represent hydrogen atom, alkyl, allyl, substituted benzyl, group -CH2-C(O)R3, group -CH2-C(O)NR3R4 wherein R3, R4 and R6 represent inert substitute. Also, invention relates to new combinatory libraries for search compound-leaders and candidates for medicinal compounds preparing by screening the combinatory libraries.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 9 ex

 

This invention relates to the search for new chemical substances and new physiologically active substances, compounds leaders (leader) and candidates in medicine (drug-candidates)that can be derived from the screening of combinatorial libraries, as well as to new combinatorial libraries.

More specifically the present invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines and combinatorial library consisting of new pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines.

Substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines have high potential physiological activity. Despite the absence in the patent and scientific literature, examples of structures containing pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine fragment should anticipate high biological activity of these compounds by analogy with the structures that contain the specified cycles or isostere in any other combinations. So, the connection1containing in its structure pyridine, peranovic and pyrimidine cycles, shows pronounced antibacterial properties [Al-Thebeiti, M. Heterocycles. 1999, 51 (11): 2765-2774]. Substance2in which instead of the pyridine ring is isostere him benzene, is not only antibacterial, and antifungal activity [Bedair, A., Emam, H., El-Hady, N., El-Agrody, A. Farmaco, 2001, 56 (12): 965-974].

Substance3where instead Pyrenophora ring is related furan, exhibits anti-allergic properties [Wagner, G., Prantz, J. Pharmazie, 1993, 48 (4): 250-253].

Given the high potential physiological activity of pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine, it is important to develop new classes of heterocyclic compounds of this type and combinatorial libraries pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine to search for biologically active compounds leaders.

To search for new biologically active compounds leaders inventors synthesized previously unknown pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines and developed a new combinatorial library comprising these compounds.

Substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines has not been studied.

The present invention relates to novel pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines and combinatorial library of new pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines.

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

"Combinatorial library" means a group of compounds obtained by parallel synthesis, designed to search for connections-hit or connection-leader, as well as to optimize the physiological activity of the compounds is hit or connection-leader, and each connection the library has the General structural formula scaffold, and the library is a collection of related homologues or analogues.

"Connection-hit" ("hit") means a compound expressed during primary screening high desired physiological activity.

"Connection-leader" ("leader") means the connection is significant (maximum) physiological activity, manifested by its interaction with specific biomechani.

"Parallel synthesis" means a method of doing combinatorial chemical synthesis library, which consists in simultaneously conducted in the same conditions a large number of similar reactions.

"Scaffold" means the General structural formula or molecular skeleton or invariant region of the compounds of the combinatorial library.

"Deputy" means a chemical moiety that is attached to scaffold or semi-synthesis in the process of their synthesis.

"Nucleophilic" means elektronoizbytochnye reagent.

"Electrophilic" means electron reagent.

"Leaving group" means a group, which is substituted by a nucleophile.

"Inert Deputy" (or "not interfering", "Non-interfering substituent"means low or directionspanel radical, including, but not limited to C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C 7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl, C2-C10alkylsulfonyl, C2-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 are1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, 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.

"Nucleophilic Deputy" means a chemical moiety that is attached to scaffold in the reaction with the nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophene the RC. "Electrophilic Deputy" means a chemical moiety that is attached to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic halides, organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothioscyanates.

"Aryl" means one or more aromatic cycles, each of which contains 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, unsaturated 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 unfused, for example, azoles (1,3,4-thiadiazole, 1,3,4-oxadiazol), etc. or condensed politicla, for example, as bentazone (benzimidazole, benzoxazole, benzthiazole), isoleucine (Bicycle, including azole cycle, for example, oxazoline, thiazole is hydrated, imidazole and others, and Zinovy cycle, for example, pyridine, pyridazinyl, pyrimidine, pyrazinoic and others), khinazolinov, thienopyrimidine, 1,2,3,5-tetrahydro-8-thia-5,7-diaza-cyclopent[a]inden-4-ones, 5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-ones, 7,8-dihydro-3H,5H-6-oxa-9-thia-1,3-diaza-fluoren-4-ones, 5,6,7,8-tetrahydro-3H-9-thia-1,3,6-triaza-fluoren-4-about, 2H-benzo[1,2,4]thiadiazine and other

"Azaheterocycle" means a heterocycle comprising at least one nitrogen atom, such as piperidine, morpholine, pyrrole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, benzimidazole, benzoxazole, benzthiazole, quinoline, isoleucine (Bicycle, including azole cycle, for example, oxazoline, thiazole, imidazole, etc. and Zinovy cycle, for example, pyridine, pyridazinyl, pyrimidine, pyrazinoic and others), khinazolinov, thienopyrimidine, 1,2,3,5-tetrahydro-8-thia-5,7-diaza-cyclopent[a]inden-4-ons, 5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-ones, 7,8-dihydro-3H,5H-6-oxa-9-thia-1,3-diaza-fluoren-4-ones, 5,6,7,8-tetrahydro-3H-9-thia-1,3,6-triaza-fluoren-4-about, 2H-benzo[1,2,4]thiadiazine.

"Substituted azaheterocycle" means azaheterocycle having one or more "not interfering" deputies.

The aim of the present invention is a new substituted 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula (1):

W is:

X represents a sulfur atom or oxygen;

R' is aryl, substituted aryl, hetaryl;

R2represents a hydrogen atom, alkyl, allyl, substituted benzyl, CH2-C(O)R3, CH2-C(O)NR3R4;

R3, R4are inert Deputy,

new substituted 5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula (2):

in which:

Y represents a sulfur atom, a group SO that the group of SO2, a NH group or a group NR6;

R1is aryl, substituted aryl, hetaryl;

R5represents a hydrogen atom, alkyl, allyl, substituted benzyl, CH2-C(O)R3, CH2-C(O)NR3R4;

R3, R4, R6represent inert substituent.

The aim of the present invention is also a new combinatorial library of new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula (1) and (2).

The preferred option of the invention are new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula (1) and (2) and a combinatorial library of new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula (1) and (2) or their pharmaceutically acceptable salt, N-oxide or hydrate.

Particularly preferred new compounds are:

2-substituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ones of General formula 1.1:

in which R1is aryl, substituted aryl, hetaryl;

2,3-disubstituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ones of General formula 1.2:

in which R1is aryl, substituted aryl, hetaryl;

R2represents a hydrogen atom, alkyl, allyl, substituted benzyl, CH2-C(O)R3CH2-C(O)NR3R4;

R3, R4are inert Deputy;

2-substituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-thiones General formula 1.3:

in which R1has the above meaning;

4-sulfanilamides 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.1:

in which R1and R5have the above meaning;

4-sulfonylamine 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.2:

in which R1and R5have the above meaning;

4-sulfonylamine 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.3:

in which R1and R5have the above meaning;

4-aminotoluene 6-hydroxymethyl-9-methyln-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.4:

in which R1is aryl, substituted aryl, hetaryl;

R9represents a hydrogen atom or an inert Deputy;

R5has the above value.

Preferred combinatorial library to search for biologically active compounds leaders is a library consisting of substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula (1) and (2) or their pharmaceutically acceptable salts, N-oxides or hydrates.

Reagents used as the source, in most cases, are commercially available or easily obtained well-known literature methods.

Below the invention is described using specific examples of the preparation of specific compounds. 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 performed using special synths "CombiSyn-012-3000" [Mbaru, 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, http://www.chemdiv.com.].

The following examples illustrate, but not limit the invention.

General information.

All solvents and reagents were obtained from commercial East is nikov, such as ACROS (Acros) (Belgium), Sigma-Aldrich (Sigma-Aldrich) (United States), Lancaster (Lancaster) (England) 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 firm Varian (Varian) Gemini-300 (300 MHz) in CDCl3chemical shifts are given in the scale δ (ppm). The internal standard tetramethylsilane was.

The content of the basic substance was controlled by HPLC on the device Shimadzu (Shimadzu) 10-AV (column Luna C18, Phenomenex, 25 cm × 4.6 mm, UV detection at 215 and 254 nm) and LC-MS instrument Applied Biosystems (Shimadzu 10-AV LC, Gilson 215 of the automatic submission of the sample, the mass spectrometer API 150EX, detectors UV (215 and 254 nm) and ELS, column Luna C18, Phenomenex, 5 cm × 2 mm).

Analytical TLC was performed on silica gel on aluminium plates Silufol UV254(5 cm × 15 cm) (Kavalier, Czech Republic) or on glass plates with 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%.

Example 1. The original amide 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-carboxylic acid. The mixture 20.36 g (100 mmol) of method hydrochloride and 8.4 g (100 mmol) of amide tsianuksusnogo acid was dissolved by heating in 50 ml of absolute methanol. To the resulting warm solution was added 20.0 ml (200 mmol) of purified piperidine. The reaction mass was kept at 50°and With constant stirring for 45 minutes. The precipitation was filtered, washed with methanol (3×20 ml). The output of 17.2 g (74%). TPL-199°C.1H NMR (DMSO), δ: 2.48 (s, 3H), 4.65 (d, J=5.4 Hz, 2H), 5.30 (t, J=5.2 Hz, 1H), 7.70 (s, 1H), 8.19 (s, 1H), 8.50 (s, 1H), 9.04 (s, 1H), 9.39 (s, 1H). In further synthesis was used without further purification.

Example 2. A combinatorial library of 2-substituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ones 1.1 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer was loaded in 50 ml of m-butanol, 4.6 g (20 mmol) of amide 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-carboxylic acid, 40 mmol of the corresponding aldehyde and 1 ml of fresh piperidine. The reaction mass was heated under reflux until the formation of sediments. The reaction mass was cooled, precipitation was filtered, washed on the filter with methanol (3×20 ml) and was led from dimethylformamide or n-butanol. Received combinatorial library, including 5 compounds of General formula 1.1, including: 6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-one 1.1 {1) obtained with a yield of 84%, TPL>300°,1/sup> H NMR (DMSO), δ: 12.61 (br.s, 1H), 8.11 (s, 1H), 8.08 (d, 2H), 7.03 (d, 2H), 5.24 (t, 1H), 4.48 (d, 2H), 3.83 (s, 3H), 3.63 (s, 2H), 2.40 (s, 3H); 6-hydroxymethyl-9-methyl-2-(3-methoxyphenyl)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-one 1.1 {2} obtained with a yield of 86%, TPL>300 °,1H NMR (DMSO), δ: 12.88 (br.s, 1H), 8.12 (s, 1H), 7.69 (m, 2H), 7.43 (t, 1H), 7.14 (dd, 1H), 5.28 (t, 1H), 4.50 (d, 2H), 3.82 (s, 3H), 3.70 (s, 2H), 2.50 (s, 3H); 6-hydroxymethyl-9-methyl-2-(4-were)for 3,5-dihydro-4H-pyrido[4'3':5,6]pyrano(2,3-d]pyrimidine-4-one 1.1 {3} obtained with the yield 81%, TPL>300°,1H NMR (DMSO), δ: 12.80 (s, 1H), 8.13 (s, 1H), 8.02 (d, 2H), 7.33 (d, 2H), 5.25 (t, 1H), 4.50 (d, 2H), 3.61 (s, 2H), 2.37 (s, 3H), 2.49 (s, 3H); 6-hydroxymethyl-9-methyl-2-(2-forfinal)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano(2,3-d]pyrimidine-4-one 1.1 {4} obtained with a yield of 63%, TPL>300°,1H NMR (DMSO), δ: 12.85 (br.s, 1H), 8.14 (s, 1H), 7.58-7.77 (m, 2H), 7.37 (m, 2H), 5.28 (t, 1H), 4.51 (d, 2H), 3.70 (s, 2H), 2.49 (s, 3H); 6-hydroxymethyl-9-methyl-2-(4-forfinal)for 3,5-dihydro-4H-pyrido(4',3':5,6]pyrano[2,3-d]pyrimidine-4-one 1.1 {5} obtained with the yield 90%, TPL>300°,1H NMR (DMSO), δ: 12.40 (br.s, 1H), 8.16 (m, 2H), 8.11 (s, 1H), 7.36 (t, 2H), 5.24 (t, 1H), 4.45 (d, 2H), 3.70 (s, 2H), 2.48 (s, 3H).

Example 3. A combinatorial library of 2,3-disubstituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ones 1.2 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer downloaded by 10 mmol of the corresponding 2-substituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4'3':5,6]pyrano[2,3-d]pyrimidine-4-it and 10 ml of dimethylformamide. To the resulting solution was added 15 mmol of triethylamine and 10.1 mmol of the appropriate alkylating agent. The reaction mixture was stirred at 70°C for 1 hour. The amount of precipitation was filtered, washed with water (3×10 ml) and was led from dimethylformamide. Received combinatorial library, including 5 compounds of General formula 1.2, including: 6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-3-(4-terbisil)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-one 1.2 {1} obtained with the yield 89%, TPL>300°,1H NMR (DMSO), δ: 8.13 (d, 2H), 8.09 (s, 1H), 7.62 (m, 2H), 7,25 (m, 2H), 7.18 (d, 2H), 5.56 (s, 2H), 5.22 (t, 1H), 4.49 (d, 2H), 3.80 (s, 3H), 3.61 (s, 2H), 2.43 (s, 3H); 6-hydroxymethyl-9-methyl-2-(3-methoxyphenyl)-3-(4-terbisil)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-one 1.2 {2} obtained with a yield of 86%, TPL>300°,1H NMR (DMSO), δ: 8.14 (s, 1H), 7.71 (m, 2H), 7.60 (m, 2H), 7.42 (t, 1H), 7,24 (m, 2H), 7.15 (dd, 1H), 5.54 (s, 2H), 5.29 (t, 1H), 4.51 (d, 2H), 3.83 (s, 3H), 3.71 (s, 2H), 2.52 (s, 3H).

Example 4. A combinatorial library of 2-substituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-thiones 1.3 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer loaded with 20 ml of xylene, 10 mmol of the corresponding 2-substituted 6-hydroxymethyl-9-methyl-1-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-it and 5.55 g (25 mmol) of pentasulfide phosphorus. React the mixture was boiled under reflux for 2 hours and cooled, precipitation was filtered. The obtained precipitation was dissolved in 10 ml of boiling glacial acetic acid and filtered hot to remove insoluble impurities. The obtained filtrate was cooled, the amount of precipitation was filtered, washed with water (2×30 ml) and was led from dimethylformamide. Received combinatorial library, including 5 compounds of General formula 1.3, including: 6-hydroxymethyl-9-methyl-2-(3-chlorophenyl)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-tion 1.3 {1} obtained with the yield of 80%, TPL 265°,1H NMR (DMSO), δ:14.25 (br.s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.70 (d, 1H), 7.57 (t, 1H), 5.28 (t, 1H), 4.50 (d, 2H), 3.86 (s, 2H), 2.49 (s, 3H); 6-hydroxymethyl-9-methyl-2-phenyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-tion 1.3 (2} is obtained with a yield of 69%, TPL-84°With (p)1H NMR (DMSO), δ: 14.10 (s, 1H), 8.14 (s, 1H), 8.10 (dd, 2H), 7.50-7.65 (m, 3H), 5.28 (t, 1H), 4.51 (d, 2H), 3.82 (s, 2H), 2.49 (s, 3H); 6-hydroxymethyl-9-methyl-2-(2-chlorophenyl)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-tion 1.3 {3} obtained with a yield of 62%, TPL°,1H NMR (DMSO), δ: 14.41 (s, 1H), 8.18 (s, 1H), 7.48-7.68 (m, 4H), 5.30 (t, 1H), 4.49 (d, 2H), 3.90 (s, 2H), 2.49 (s, 3H); 6-hydroxymethyl-9-methyl-2-(4-were)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-tion 1.3 {4} obtained with a yield of 78%, TPL-69°With (p)1H NMR (DMSO), δ: 14.00 (s, 1H), 8.14 (s, 1H), 8.07 (d, 2H), 7.34 (d, 2H), 5.30 (t, 1H), 4.53 (d, 2H), 3.85 (s, 2H), 2.50 (s, 3H), 2.40 (s, 3H); 6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)for 3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]p is rimidine-4-tion 1.3 {5} obtained with the yield 82%, TPL°With (p)1H NMR (DMSO), δ: 13.53 (s, 1H), 8.16 (s, 1H), 7.76 (d, 1H), 7.58 (dt, 1H), 7.22 (d, 1H), 7.12 (t, 1H), 5.27 (t, 1H), 4.52 (d, 2H), 3.91 (s, 3H), 3.85 (s, 2H), 2.43 (s, 3H).

Example 5. Combinatorial library 4-sulfanilamidnyh 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.1 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer was loaded in 10 ml of dimethylformamide and 10 mmol of the corresponding 2-substituted 6-hydroxymethyl-9-methyl-1-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-thione. To the resulting solution was added 15 mmol of triethylamine and 10.1 mmol of the appropriate alkylating agent. The reaction mass was kept at 70°With constant stirring for 1 hour and cooled. The amount of precipitation was filtered, washed with methanol (2×20 ml) and was led from dimethylformamide. Received combinatorial library, including 5 compounds of General formula 2.1, including: N1-(2-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.1 {1} obtained with the yield 79%, TPL°C (decomp.),1H NMR (DMSO), δ: 9.55 (s, 1H), 8.38 (d, 2H), 8.15 (s, 1H), 8.00 (d, 1H), 7.47 (m, 3H), 7.00 (dd, 2H), 6.84 (m, 1H), 5.31 (t, 1H), 4.55 (d, 2H), 4.37 (s, 2H), 3.95 (s, 2H), 3.65 (s, 3H), 2.48 (s, 3H)); N1-(3-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ACET the MFA 2.1 {2} obtained with the yield 68%, TPL-294°,1H NMR (DMSO), δ: 9.98 (s, 1H), 8.32 (d, 2H), 8.14 (s, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.18 (m, 2H), 5.32 (t, 1H), 4.55 (d, 2H), 4.27 (s, 2H), 3.95 (s, 2H), 3.67 (s, 3H), 2.50 (s, 3H); N1-(4-were)-2(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.1 {3} obtained with a yield of 71%, TPL-296°,1H NMR (DMSO), δ: 10.29 (br.s, 1H), 8.28 (d, 2H), 8.13 (s, 1H), 7.49 (d, 2H), 7.10 (d, 2H), 6.84 (d, 2H), 5.24 (m, 1H), 4.55 (d, 2H), 4.28 (s, 2H), 3.92 (s, 2H), 3.78 (s, 3H), 2.48 (s, 3H), 2.21 (s, 3H)); N1-(2-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.1 {4} obtained with a yield of 66%, TPL-278°,1H NMR (DMSO), δ: 9.51 (s, 1H), 8.33 (d, 2H), 8.13 (s, 1H), 8.02 (d, 1H), 6.98 (m, 3H), 6.87 (d, 2H), 5.30 (t, 1H), 4.54 (d, 2H), 4.35 (s, 2H), 3.92 (s, 2H), 3.78 (s, 3H), 3.66 (s, 3H), 2.50 (s, 3H));

N1-(4-forfinal)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.1 {5} obtained with the yield of 71%, TPL>300°,1H NMR (DMSO), δ: 10.51 (s, 1H), 8.27 (d, 2H), 8.14 (s, 1H), 7.64 (m, 2H), 7.14 (t, 2H), 6.83 (d, 2H), 5.30 (t, 1H), 4.55 (d, 2H), 4.28 (s, 2H), 3.92 (s, 2H), 3.77 (s, 3H), 2.48 (s, 3H).

Example 6. Combinatorial library 4-sulfanilamidnyh 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.2 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer loaded with 20 ml of benzene, 10 mmol of the corresponding 4-sulfanilamidnov 6-hydroxymethyl-9-ethyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine and 11 mmol m-chloroperoxybenzoic acid. The reaction mass was heated to 60°C and kept at this temperature and under stirring for 60 minutes the mixture was cooled, was added an aqueous solution of sodium bicarbonate, the amount of precipitation was filtered, washed on the filter with water (3 x 50 ml), ethanol (2 25 ml) and was led from a mixture of ethanol - dimethylformamide. Received combinatorial library, including 5 compounds of General formula 2.2, including:

N1-(2-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.1 {1} obtained with the yield 82%, TPL°C (decomp.),1H NMR (DMSO), δ: 9.55 (s, 1H), 8.38 (d, 2H), 8.15 (s, 1H), 8.00 (d, 1H), 7.47 (m, 3H), 7.00 (dd, 2H), 6.84 (m, 1H), 5.31 (t, 1H), 4.55 (d, 2H), 4.37 (s, 2H), 3.95 (s, 2H), 3.65 (s, 3H), 2.48 (s, 3H); N1-(3-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.2{2} obtained with a yield of 91%, TPL° (sec.),1H NMR (DMSO), δ: 9.98 (s, 1H), 8.32 (d, 2H), 8.14 (s, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.18 (m, 2H), 5.32 (t, 1H), 4.55 (d, 2H), 4.27 (s, 2H), 3.95 (s, 2H), 3.67 (s, 3H), 2.50 (s, 3H); N1-(4-were)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.2 {3} obtained with a yield of 92%, TPL°C (decomp.),1H NMR (DMSO), δ: 10.29 (br.s, 1H), 8.28 (d, 2H), 8.13 (s, 1H), 7.49 (d, 2H), 7.10 (d, 2H), 6.84 (d, 2H), 5.24 (m, 1H), 4.55 (d, 2H), 4.28 (s, 2H), 3.92 (s, 2H), 3.78 (s, 3H), 2.48 (s, 3H), 2.21 (s, 3H); N1-(2-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-p the Rideau[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.2 {4} obtained with the yield of 85% TPL-277°,1H NMR (DMSO), δ: 9.51 (s, 1H), 8.33 (d, 2H), 8.13 (s, 1H), 8.02 (d, 1H), 6.98 (m, 3H), 6.87 (d, 2H), 5.30 (t, 1H), 4.54 (d, 2H), 4.35 (s, 2H), 3.92 (s, 2H), 3.78 (s, 3H), 3.66 (s, 3H), 2.50 (s, 3H);

N1-(4-forfinal)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.2 {5} obtained with the yield 90%, TPL°,1H NMR (DMSO), δ: 10.51 (s, 1H), 8.27 (d, 2H), 8.14 (s, 1H), 7.64 (m, 2H), 7.14 (t, 2H), 6.83 (d, 2H), 5.30 (t, 1H), 4.55 (d, 2H), 4.28 (s, 2H), 3.92 (s, 2H), 3.77 (s, 3H), 2.48 (s, 3H).

Example 7. Combinatorial library 4-sulfanilamidnyh 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.3 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer was loaded in 50 ml of glacial acetic acid and 10 mmol of the corresponding 4-sulfanilamidnov 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine. In each of the reactors at once made 50 mmol of perhydrol in 20 ml of glacial acetic acid and heated with stirring to 70°C. the Contents of the reactor were poured into 300 ml of cold water, the excess hydrogen peroxide was dissolved in a weak solution of potassium permanganate.

The resulting solution was extracted with chloroform (2×50 ml), the combined extracts were dried, evaporated under vacuum and was led from a mixture of ethanol - dimethylformamide. Received combinatorial library, including 5 connect the rd General formula 2.3, including:

N1-(2-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.3 {1} obtained with the yield 84%, TPL°C (decomp.),1H NMR (DMSO), δ: 9.57 (s, 1H), 8.38 (d, 2H), 8.17 (s, 1H), 8.04 (d, 1H), 7.46 (m, 3H), 6.95 (d, 2H), 6.83 (m, 1H), 5.32 (t, 1H), 4.57 (d, 2H), 4.37 (s, 2H), 4.10 (d, 1H, J=5 Hz), 3.96 (d, 1H, J=5 Hz), 3.65 (s, 3H), 2.48 (s, 3H); N1-(3-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.3 {2} obtained with a yield of 92%, TPL°C (decomp.),1H NMR (DMSO), δ: 10.00 (s, 1H), 8.34 (d, 2H), 8.14 (s, 1H), 7.46 (m, 2H), 7.36 (m, 3H), 7.18 (m, 2H), 5.33 (t, 1H), 4.55 (d, 2H), 4.27 (s, 2H), 4.22 (d, 1H, J=7 Hz), 3.95 (d, 1H, J=7 Hz), 3.65 (s,, 3H), 2.50 (s, 3H); N1-(4-were)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.3 {3} obtained with a yield of 90%, TPL°C (decomp.),1H NMR (DMSO), δ: 10.26 (br.s, 1H), 8.27 (d, 2H), 8.13 (s, 1H), 7.49 (d, 2H), 7.10 (d, 2H), 6.85 (d, 2H), 5.24 (m, 1H), 4.58 (d, 2H), 4.28 (s, 2H), 4.18 (d, 1H, J=6 Hz), 3.95 (d, 1H, J=6 Hz), 3.78 (s,, 3H), 2.47 (s, 3H), 2.21 (s, 3H); N1-(2-methoxyphenyl)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)ndimethylacetamide 2.3 {4} obtained with a yield of 91%, TPL-277°C (decomp.),1H NMR (DMSO), δ: 9.53 (s, 1H), 8.36 (d, 2H), 8.13 (s, 1H), 8.02 (d, 1H), 6.99 (m, 3H), 6.83 (d, 2H), 5.32 (t, 1H), 4.57 (d, 2H), 4.35 (s, 2H), 4.15 (d, 1H, J=6 Hz), 3.90 (d, 1H, J=6 Hz), 3.80 (s,, 3H), 3.66 (s, 3H), 2.50 (s, 3H); N1-(4-forfinal)-2-(6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ylsulphonyl)AC the Tamid 2.3 {5} obtained with the yield of 93%, TPL>300°,1H NMR (DMSO), δ: 10.50 (s, 1H), 8.25 (d, 2H), 8.18 (s, 1H), 7.62 (m, 2H), 7.15 (t, 2H), 6.87 (d, 2H), 5.31 (t, 1H), 4.54 (d, 2H), 4.25 (s, 2H), 4.20 (d, 1H, J=7 Hz), 3.93 (d, 1H, J=7 Hz), 3.77 (s,, 3H), 2.48 (s, 3H).

Example 8. Combinatorial library 4-aminotoluene 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.4 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer loaded with 20 ml of an alcohol solution of NaOH, 10 mmol of the corresponding 2-substituted-6-hydroxymethyl-9-methyl-1-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-thione and 25 mmol of the corresponding amine. The reaction mixture was boiled under reflux for 12 hours and cooled, the precipitate was filtered, washed with water (2×30 ml) and was led from dimethylformamide. Received combinatorial library, including 5 compounds of General formula 2.4, including the following: 4-[N-(2-methoxyphenyl)amino]-6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.4 {1} obtained with the yield 65%, TPL>300°,1H NMR (DMSO), δ: being 9.61 (s, 1H), 8.38 (d, 2H), 8.13 (s, 1H), 8.00 (d, 1H), 7.39 (m, 3H), 7.02 (dd, 2H), 6.82 (m, 1H), 5.31 (t, 1H), 4.54 (d, 2H), 4.37 (s, 2H), 3.65 (s. 3H). 2.48 (s, 3H); 4-(N-(3-methoxyphenyl)amino]-6-hydroxymethyl-9-methyl-2-phenyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.4{2} obtained with the yield of 70%, TPL>300°,1H NMR (DMSO), δ: 10,10 (s, 1H), 8.32 (d, 2H), 8.14 (s, 1H), 7.41 (m, 2H), 7.32 (m, 3H), 7.18 (m, 2H), 5.33 (t, 1H), 4.56 (d, 2H) 4.27 (s, 2H), 3.67 (s, 3H), 2.49 (s, 3H);

4-[N-(4-were)amino]-6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.4 {3} obtained with a yield of 75%, TPL>300°,1H NMR (DMSO), δ: 10.10 (s, 1H), 8.28 (d, 2H), 8.13 (s, 1H), 7.49 (d, 2H), 7.10 (d, 2H), 6.84 (d, 2H), 5.24 (m, 1H), 4.55 (d, 2H), 4.28 (s, 2H), 3.78 (s, 3H), 2.48 (s, 3H), 2.21 (s, 3H); 4-[N-(4-methoxyphenyl)amino]-6-hydroxymethyl-9-methyl-2-(2-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.4 {4} obtained with a yield of 63%, TPL°,1H NMR (DMSO), δ: 9.60 (s, 1H), 8.31 (d, 2H), 8.13 (s, 1H), 7.98 (d, 1H), 7.00 (m, 3H), 6.87 (d, 2H), 5.30 (t, 1H), 4.54 (d, 2H), 4.33 (s, 2H), 3.78 (s, 3H), 3.66 (s, 3H), 2.50 (s, 3H); 4-[N-(4-forfinal)amino]-6-hydroxymethyl-9-methyl-2-(4-methoxyphenyl)-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine 2.4 {5} obtained with the yield of 80%, TPL>300°,1H NMR (DMSO), δ: 10.51 (s, 1H), 8.24 (d, 2H), 8.10 (s, 1H), 7.61 (m, 2H), 7.11 (t, 2H), 6.84 (d, 2H), 5.31 (t, 1H), 4.56 (d, 2H), 4.24 (s, 2H), 3.73 (s, 3H), 2.47 (s, 3H).

Example 9. Effect on apoptosis compounds, derivatives of 6-hydroxymethyl-9-methyl-5H-pyrido(4',3':5,6]pyrano[2,3-d]pyrimidine Compounds belonging to a derivative of 6-hydroxymethyl-9-methyl-5H-pyrido [4',3':5,6]pyrano[2,3-d)pyrimidines were tested for their ability to induce apoptosis in tumor cells, causing their death. Induction of apoptosis was carried out by treatment of cells with compound within 24-48 hours with subsequent determination of the number of surviving cells using a fluorescent dye resazurin, fluorescence stress which is moved when the restoration of living cells. Fluorescence was measured using mikrotalasna Registrar (VICTOR2V, PerkinElmer) in 96-well plates. Table 1 shows the results of such testing for the most active compounds.

Table 1
No ConnectionStructureFluorescence resazurin% cell death
Control98500
1.2 {1}825384
1.2 {2}876489
1.2 {3}756877
1.2 {4}8563 in order87
1.2 {5}658967
1.3 {1}789580
1.3 {2}569558
Continuation of table 1
1.3 {3}896591
2.1 {1}7236 overall73
2.1 {3}698471

Cells T-47D (cell line derived from mammary gland tumors) were planted in wells of 96-well plates overnight. The next day, each well was added to the test substance at a concentration of 10 μm and the plate was left for 24 to 48 hours of incubation. After incubation the wells were added resazurin and incubated for 2 hours required for the formation of fluoresceine product recovery. Fluorescence in the presence of the tested substances was compared with a control, and the percentage of inhibition of fluorescence reflects the degree of cell death.

1. Substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula (1) or (2):

in which:

X represents a sulfur atom or oxygen;

Y represents a sulfur atom, a group SO that the group of SO2, a NH group or a group NR6;

R1is aryl, substituted aryl, hetaryl;

R2, R5represents a hydrogen atom, alkyl, allyl, substituted benzyl, CH2-C(O)R3CH2-C(O)NR3R4;

R3, R4, R6are inert Zam is stitely, or their pharmaceutically acceptable salt, N-oxide or hydrate.

2. Compounds according to claim 1, which represents a 2-substituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ones of General formula 1.1:

in which R1is aryl, substituted aryl, hetaryl.

3. Compounds according to claim 1 which represents a 2,3-disubstituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-ones of General formula 1.2:

in which R1is aryl, substituted aryl, hetaryl;

R2represents a hydrogen atom, alkyl, allyl, substituted benzyl, CH2-C(O)R3CH2-C(O)NR3R4;

R3, R4represent inert substituent.

4. Compounds according to claim 1 which represents a 2-substituted 6-hydroxymethyl-9-methyl-3,5-dihydro-4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine-4-thiones General formula 1.3:

in which R1has the above value.

5. Compounds according to claim 1 which represents a 4-sulfanilamides 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.1:

in which R1and R5have the above value.

6. Compounds according to claim 1 PR is dostavlyaya a 4-sulfonylamine 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.2:

in which R1and R5have the above value.

7. Compounds according to claim 1 which represents a 4-sulfonylamine 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.3:

in which R1and R5has the above value.

8. Compounds according to claim 1 which represents a 4-aminotoluene 6-hydroxymethyl-9-methyl-5H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of General formula 2.4:

in which R1is aryl, substituted aryl, hetaryl;

R9represents a hydrogen atom or an inert Deputy, R5have the above values.

9. A combinatorial library to search for biologically active compounds leaders, including at least one substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidine of the General formula (1) or (2) according to any one of claim 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.



 

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EFFECT: valuable medicinal properties of substance.

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The invention relates to the field of macrolides

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

FIELD: organic chemistry, medicine, gastroenterology, oncology.

SUBSTANCE: invention relates to a new agent used in treatment of gastroenteric tumors. Invention describes an agent for treatment of gastroenteric tumors representing compounds of the general formula: A-X1-NO2 or their salts wherein A means -RCO(X)t wherein t represents a whole number from 0 to 1; X means oxygen atom (O); R is taken among the following groups: (IA), (IIA), (IIIA), (IVA), (VA) and (VIA) such as given in the invention claim; X1 in the formula A-X1-NO2 means a bivalent binding bridge taken among the following: -YO- wherein Y means a liner or when possible a branched (C1-C20)-alkylene comprising preferably from 2 to 5 carbon atoms, or possibly a substituted cycloalkylene comprising from 5 to 7 carbon atoms of the formula: wherein n3 means a whole number from 0 to 3; wherein nf means a whole number from 1 to 6 but preferably from 2 to 4; wherein R1f means hydrogen atom (H), -CH3; nf means a whole number from 1 to 6 but preferably from 2 to 4. Invention provides a new medicinal agent used in treatment of gastroenteric tumors.

EFFECT: valuable medicinal properties of agent.

2 cl, 11 tbl, 18 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine, veterinary science.

SUBSTANCE: the present innovation deals with treating malignant tumors. For this purpose, its is necessary to provide a blood supply of an agent that destroys extra-cellular blood DNA. This agent should be introduced in dosages providing alteration of electrophoretic profile of extra-cellular blood DNA. Agent, also, should be introduced at the dosages and modes that provide the level of DNA-hydrolytic activity of blood plasma measured in blood plasma being above 150 Kunz units/l plasma during totally above 12 h daily. Therapy may last without intervals for 2 d, not less. As an agent destroying extra-cellular blood DNA one may apply DNAse, in peculiar case, bovine pancreatic DNAse or recombinant human DNAse. The innovation suggests, also, to apply and agent that binds extra-cellular blood DNA, for example, anti-DNA antibodies. The method provides low-toxic and efficient treatment of tumors, particularly at prolonged, even one's life-long therapy with preparations mentioned.

EFFECT: higher efficiency of therapy.

10 cl, 7 ex, 6 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating gastric Helicobacter pylori-associated MALT-lymphomas. For this purpose, one should perorally introduce "Vitaflor" preparation as a ferment at daily dosage being not less than 40 g for 4 wk to an empty stomach or in intervals between meals, and in case of no complete regress of lymphoma at monotherapy with "Vitaflor" it is necessary to conduct additional courses of chemotherapy. The method provides cytostatic impact directly upon the tumor and suppresses proliferation of tumoral cells in case of complete absence of chemotherapy-accompanying side effects.

EFFECT: higher efficiency of therapy.

3 cl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves administering local tumor cell radiomodification with following radiation therapy and radical surgical operation being applied. The local radiomodification is carried out by applying endovascular tumor tissue perfusion with 5% Metronidasole via superior rectal artery in superoampular rectal cancer cases and via superior rectal artery and one of internal iliac arteries in medial and inferoampular rectal cancer cases with said blood vessel occlusion done using non-lytic radiopaque emboli. Single remote radiation therapy is carried out at a dose of 10 Gy 1 h later after radiomodification being over. Surgical operation is done not later than in 24 h after the irradiation.

EFFECT: increased radiation therapy destruction effectiveness.

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacology.

SUBSTANCE: invention relates to the development of a method for inhibition in interaction of metalloproteinase 2 with integrin αvβ3 in host cells. Method involves contact of integrin with the amount of compound inhibiting this interaction and represented by the formula (I): wherein each of G1 and G2 represents independently -NH-C(O)-O-R1, -NH-C(O)-O-(CH2)v-(C6H4)-X3, -NH-C(O)-NH-(CH2)v-(C6H4)-X3, -O-C(O)-NH-(CH2)v-(C6H4)-X3, -O-C(O)-O-(CH2)v-(C6H4)-X3 or -NH-C(O)-CH2-(C6H4)-X3; each of Y1 and Y2 represents independently -OH, (C1-C4)-alkyl, (C1-C4)-hydroxyalkyl, (C1-C4)-alkoxy-group, phenyl, benzyl or -NH2; R1 represents (C1-C4)-alkyl; each of X1 and X2 represents independently halogen atom or (C1-C4)-alkoxy-group; X3 represents halogen atom, nitro-group, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or (C1-C4)-perfluoroalkyl; Z represents -C≡C-, -C6H4-, cis-CH=CH-, trans-CH=CH-, cis-CH2-CH=CH-CH2-, trans-CH2-CH=CH-CH2-, 1,4-naphthyl, cis-1,3-cyclohexyl, trans-1,3-cyclohexyl, cis-1,4-cyclohexyl or trans-1,4-cyclohexyl; A represents hydrogen atom (H) or a covalent bond; each of m and n represents independently a whole number o or 1; t represents a whole number o or 1; each of p, r and v represents a whole number 1 or 2 and under condition that when A means hydrogen atom (H) then t is 0; when A means a covalent bond then t = 1, and when m = 0 then Y1 represents (C1-C4)-hydroxyalkyl, and when n = o then Y2 represents (C1-C4)-hydroxyalkyl. Also, invention describes a method for apoptosis induction involving administration of abovementioned substance in the therapeutically effective dose.

EFFECT: improved method for tumor inhibition, expanded assortment of antitumor agents.

37 cl, 9 dwg, 7 ex

FIELD: organic chemistry, amino acids, medicine, pharmacy.

SUBSTANCE: invention relates to using derivatives of cysteine for preparing a medicinal agent. The proposed agent is designated for treatment of diseases arising as a result of formation of heterotrimeric protein G, and to new derivatives of cysteine, and pharmaceutical composition based on thereof. Derivatives of cysteine, in particular, involve the following compounds: bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[2,2a]-pyrazine]-disulfide and bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-91-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2a]-pyrazine-7-yl]-disulfide. Invention provides high effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds.

6 cl, 7 dwg, 2 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out radiation treatment combined with textile material application on the tumor. Tumor-transformed vaginal uterus neck portion volume is determined with ultrasonic examination techniques. Koletex napkin impregnated with therapeutic cytostatic preparation dose is used as the textile material. The napkin pattern is produced on the basis of ultrasonic examination data. The napkin is quilted with ligature along the perimeter and fixed at the level of vagina fornix by drawing tightly in purse-string mode. Napkin is changed every 24 h within 10-20 days long treatment course.

EFFECT: improved life quality.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: medicine, psychiatry, neurology.

SUBSTANCE: the present innovation deals with treating affected amnestic functions in women after uterine and adnexal extirpation. For this purpose, after a 7-d-long introduction of estradiol as suppositories at curative dosage of 8-20 mcg/kg body weight patients should be additionally injected with galanthamine intramuscularly once daily for 7-10 d at the dosage 5 mg, moreover, decreasing the number of estradiol injections up to once/3 d. The innovation suggested provides high antiamnestic effect at decreased dosage of preparations due to their agonistic action.

EFFECT: higher efficiency of therapy.

FIELD: medicine, gerontology.

SUBSTANCE: the present innovation deals with rehabilitation therapy of cerebrovascular diseases. One should introduce microcirculators and nootropic preparations to conduct training neuropsychological procedures. Moreover, microcirculatory and nootropic preparations should be introduced as intravenous infusions for 10 d, ten during 1 mo it is necessary to introduce tableted forms of the same preparations at simultaneous neuropsychological training directed to improving household skills valuable for a patient that deal with memorizing different names, important dates, names of medicinal preparations and location of domestic articles. On achieving a success the tasks should be complicated. Training should last for 30 min carried out thrice weekly: therapy course includes 12 trainings. The innovation widens the number of preparations for treating elderly and senile patients at discirculatory encephalopathy stage III and coarse cognitive deficiency.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

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