Method of detecting compounds reducing functional activity of human immunodeficiency virus protease and method of inhibiting dimerisation of hiv protease subunits

FIELD: chemistry.

SUBSTANCE: method of detecting a compound which is a noncompetitive inhibitor of human immunodeficiency virus (HIV) protease (SEQ ID No:1) involves detection using alanine scanning methods and molecular docking of the compound at least with one atom of an amino acid residue selected from a group consisting of Asn98, Phe99, Asp29, Asp30, Arg8, Gly49, Gly51 and Gly52 SEQ ID NO:1, at a distance of not more than 5 Å.

EFFECT: increased effectiveness of the compounds.

4 cl, 2 dwg, 4 tbl, 1 ex

 

The technical field to which the invention relates.

The invention relates to the field of medical pharmacology, more specifically to the search for compounds that reduce the functional activity of the protease of human immunodeficiency virus (HIV protease) by inhibiting the Association of the subunits. The invention is focused on the development of new drugs.

The prior art of the present invention

Therapy based on the use of HIV protease inhibitors that prolong the lives of patients with acquired immunodeficiency syndrome (Sepkowitz KA AIDS - the first 20 years. N. Engl. J. Med. 2001, 344, 1764-1772). HIV protease is an enzyme that breaks down viral polyprotein on functionally active Mature protein required for reproduction and Assembly of HIV. Usually use competitive protease inhibitors, directly bind the active site of the enzyme. The efficacy of these inhibitors in the treatment decreases rapidly due to point mutations in the viral genome that suppress the binding of the protease inhibitor to a greater extent than its enzymatic activity. As a result, the body is affected emerging HIV strains that have acquired resistance to the inhibitor.

The alternative is the inhibition of the protease by blocking the formation of functionally active is army enzyme (Bannwarth L., Reboud-Ravanx M. An alternative strategy for inhibiting multidrug-resistant mutants of the dimeric HIV-1 protease by targeting the subunit interface. Biochem. Soc. Trans. 2007 Jun; 35(Pt 3):551-4), which is a dimer of homologous subunits. The main area of their contact is a beta-structure, the fibres of which are the C - and N-terminal fragments of subunits. It is shown that the peptides and peptidomimetics that mimic these fragments inhibit the Assembly of subunits acting as noncompetitive inhibitors of HIV protease (Zutshi R., Brickner, M., Chmielewski J. Inhibiting the assembly of protein-protein interfaces. Current Opinion in Chemical Biology, 1998, 2(1): 62-66(5)). Such inhibitors are preferable as medicines, because for the emergence of resistance necessary concomitant mutations in the notoriously conservative terminal polypeptide fragments of the protease (Archakov, A.I., Govorun V.M., Dubanov A.V., Ivanov Y.D., Veselovsky A.V., Lewi P., Janssen, P. Protein-protein interactions as a target for drugs in proteomics. Proteomics. 2003 Apr; 3(4):380-91).

Studied at the present time, the inhibitors of dimerization are modified peptides or peptidomimetics, as well as substances of synthetic and natural origin (Camarasa M.J., S. Velázquez, San Félix, A., Pérez-Pérez M.J., Gago F. Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: a single mode of inhibition for the three HIV enzymes? Antiviral Res. 2006 Sep; 71(2-3):260-7). Co structural point of view, these substances mimic stretches of the beta-structure.

Disclosed is e of the present invention

The invention relates to a method of search for new chemical compounds inhibitors of dimerization (ID) - can affect the Assembly of the subunits of the HIV protease by competitive interaction with the contact pad subunits protease as well as influencing the conformation of the subunits, reducing their affinity to each other.

To identify new ID has been used a method based on the computational method of selection by computer model of the structure of the protease. Using an approach known as "alanine screening and identified the amino acid residues that determine the force of interaction between the subunits of the protease. It was found that the replacement for the remainder of Alania in the structure of the protease amino acid residues listed in table 1 (hereinafter contact point), leads to a sharp decrease in the energy of interaction between subunits. For each contact point by the method of molecular docking was carried out the screening of a database of low molecular weight compounds and some designed peptidomimetics to identify candidates with high energy values connection with the subunit. Using a known ID was established threshold value for the evaluation function of the efficiency of interaction of the compounds with the contact point. The result were selected compounds, the nature of the generated values of the binding energy above a predetermined threshold, and those that were characterized by high affinity to the surface molecules of HIV protease. The latter was estimated by the method of molecular dynamics, in which were recorded the impact of the link connection with the surface elements of protein molecules on the conformational properties of the contact areas. Table 1 shows the numbers of amino acid residues in the subunit composition of proteases, which are decisive for the molecular mechanism of action ID. Thus, the applied computational method made it possible to select patterns selectively bind to the sites of interaction between subunits of the HIV protease, and influencing the spatial conformation of the subunit. Selected specified ID are shown in table 3.

Table 1
List of amino acid residues of the subunits of the HIV protease involved in the contact with the ID specified in the form of spatial coordinates of rectangular cells in the coordinate system according to Annex 1.
The mechanism of actionAreaAmino acid residue
The binding sites of contactsync 1ASN98 RNE
2ASP29 ASP30
Binding to the surface of subunits1ARG8
2GLY49 GLY51 GLY52

To confirm the mechanism of action of selected compounds selectively tested according to the measuring circuit, based on high-precision registration of intermolecular interactions on the optical biosensor model Biacore-3000. In the measuring cell of the device were covalently immobilized molecules HIV protease in dimeric form. Then in the control cell subunit dimers HIV protease permanently associated with each other by additional covalent bonds, whereas in the measuring cuvette was carried out dissociation of dimers to monomers by rinsing with a stream buffer mixture.

Specified pilot scheme was used to monitor the interaction of the inhibitor with the individual subunits (monomers) protease, housed in the measuring channel, less interaction with the complex of two subunits (dimers) in the control channel. Discovered, found that the inhibitors affect the characteristics of the entries batch which I subunits and this does not affect the characteristics of the whole (the audience) protease dimer.

To test the influence of the ID found on the enzymatic activity of the protease standard method was used, which was based on the spectrophotometric measurement of the process of enzymatic hydrolysis of the test substrate. In the measuring cell was the volume of the buffer solution containing the protease, which made IDS in different concentrations and for 20 min was measured by absorption at a wavelength of 300 nm. On the basis of the obtained data was calculated values of the inhibition constants. The values obtained for 4 of the 15 selectively tested compounds varied with the range from 1.5 to 0.01 microns, which is comparable with the efficiency of currently known inhibitors of protease dimerization of HIV-1.

Thus, the present invention also relates to a method of inhibiting dimerization of the subunits of the HIV protease, involving contacting at least one compound is an inhibitor of HIV protease identified in accordance with the above described method, with the medium containing the HIV protease. The efficiency of inhibition of dimerization of the subunits of the HIV protease these compounds clearly confirmed below the experimental data.

Brief description of drawings

Figure 1 as an example of kinetic records changes in absorbance at 300 nm in BP the like in the presence of ID (product No. 10).

Figure 2 shows the dependence of the activity of pvic in the presence of various concentrations of ID (product No. 10). From the dependence of the activity of pvic in the presence of various concentrations of ID was calculated IC50.

An example implementation of the present invention

Example 1. Selection of compounds (a) and testing with virtual HIV protease (b)

(a)

1. Materials

1.1. The structure of HIV protease

As the coordinates of the original structure of the protease of HIV-1 was used coordinates obtained by x-ray diffraction method, deposited in the Protein Data Bank under code A. Date of Deposit of the 27/12/1998. Code of the enzyme in the EU: 3.4.23.16. Resolution PCM 2.0 angstroms.

Composition patterns:

1. Symmetric dimer of the following amino acid composition (99 amino acid residues in each chain)

PROGLNILETHRLEUTRPLYSARGPROLEUVALTHRILE
LYSILEGLY GLYGLNLEULYSGLUALALEULEUASPTHR
GLYALAASPASPTHRVALILEGLUGLUMETSERLEUPRO
GLYARGTRPLYSPROLYSMETILEGLYGLYILEGLYGLY
RNUILELYSVALARGGLNTYRASPGLNILEILE ILEGLU
ILECYSGLYHISLYSALAILEGLYTHRVALLEUVALGLY
PROTHRPROVALASNILEILEGLYARGASNLEULEUTHR
GLNILEGLYCYSTHRLEUASNRNU

2. Tripeptidyl competitive inhibitor

GLU ASP LEU

3. 216 water molecules.

1.2. Database of low molecular weight compounds

1. Database NCI Diversity Set, enabling the I information on 1990 chemical compounds selected from the NCI database (140,000 compounds available in the National cancer Institute, USA), with the exception of structurally similar compounds.

2. The NCI database that includes information on more than 250,000 chemical compounds.

2. Methods

2.1. Optimization of the structure

Of the original structure have been removed: molecule inhibitor, the water molecules. The coordinates of the hydrogen atoms restored using the program Reduce (Word, J.M.; Lovell, S.C.; LaBean, T.N.; Taylor, H.C.; Zalis, M.E.; Presley, B.K.; Richardson, J.S.; Richardson, D.C. J. Mol. Biol. 1999, 285, 1711-1733). The dimer structure was subjected to the procedure of simulation of molecular dynamics in vacuum. Was performed with the program CHARMM (Brooks, B.R.; Bruccoleri, R.; Olafson, B.; States, D.; Swaninathan, S.; Karplus, M. J. Comp. Chem. 1983, 4, 187-217), selected molecular-mechanical Merck force field (Halgren, T.A. J. Al. Chem. 1996, 17, 490-519). The time of equilibration of the system 50 NS with a step of 1 FS.

2.2. Alanine screening

The simulation procedure alanine scanning was performed by means of the program CHARMM using the molecular dynamics procedure. Own simulation time after trim is 10 PS (step 1 FS) with a record of intermediate States every 10 steps. For each intermediate state was conducted of consecutive virtual replacement of each amino acid residue subunit protease by alanine, during each of them spent the camping evaluation of changes in internal energy of the complex subunits (in kcal/mol) by the formula

,

where Eintthe energy of interaction between subunits, EAB- energy dimer EAEBthe energy of each of the chains.

2.3. Molecular docking

The selection of structures of low molecular weight compounds from databases for testing was performed by the method of molecular docking using the program Autodock (Morris, G.M.; Goodsell, D.S.; Halliday, R.S,; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. J. Comp. Chem. 1998, 19, 1639-1662). As seats in the docking procedure was used areas on the surface of one of the subunits of the dimer defined in the alanine scan. The second subunit has been removed, the conformation of the working subunit of the match obtained after the optimization procedure patterns. The locking procedure was carried out in two stages. The first stage consisted of locking all molecules database NCI Diversity Set no 10 attempts at each. Used the search procedure using a genetic algorithm, the search parameters by default. The second stage is the specification of the position selected in the first step of the molecules. Used the same algorithm and set of parameters, but the number of trials was increased to 50 and change the entry point in the pseudo-random number generator. For each result the last treatment option of the complex was carried out independent of OC is night function Autodock evaluation of the binding energy connections subunit of the HIV protease, using DS. To test the proposed connection with the binding energy of below 6 kcal/mol.

2.4. Additional search structures in the likeness

For successful locking of the molecules was carried out search for structurally similar compounds for the full database NCI. To found such compounds, the molecular docking procedure was repeated completely and were selected compounds with binding energy of below 6 kcal/mol.

3. The obtained results

3.1. Alanine screening

The results of the simulation alanine scanning are presented in table 2.

Table 2
The results of alanine scanning.
The number of the replaceable amino acidsThe standard deviation (S)The energy of interaction between subunits kcal/mol (Eint)D
49-310,28-90,09469-220,184
51-310,28-175,80623-134,472
52 -310,28-265,89658-44,3816
29-310,28-279,93672-30,3415
8-310,28-285,99873-24,2795
25-310,28-307,00792-3,2703

The number of the replaceable amino acidsThe standard deviation (S)The energy of interaction between subunits kcal/mol (Eint)D
30-310,28-308,0185-2,25972
99-310,28-309,44921-0,82901
60-310,28-311,432761,154543
98-310,28-311,669171,390953
35 -310,28-312,210231,932013
50-310,28-312,452462,174243
5-310,28-313,473153,194933
34-310,28-313,497343,219123

From the results of alanine screening selected those in which the difference between the standard deviation and energy subunits (D=S-Eint) is negative. Table 2 shows the first 15 rows, obtained after sorting the parameter d Of the selected amino acid residues were selected only those that are on the surface of the protein. Below are the numbers and names of amino acid residues, which results alanine screen define the contact ID from the subunit of the HIV protease.

1) Asn98, Phe99. Cartesian coordinates of the rectangular area of the lock relative to the attached file (see Annex I):

- minimum values in the X, Y, Z - 15,290, 30,630, -4,210;

- the maximum values along the axes X, Y, Z - 37,790, 53,130, 18,290.

2) Asp29, Asp30 (interaction with region 3 on the opposite subunit).

3) Arg8 (interaction with region 2 on p is otivational the subunit).

4) Gly49, Gly51, Gly52.

3.2. Molecular docking

According to the results of the first phase locking was selected 300 compounds with the best binding energy.

According to the results of the second lock and independent of Autodock estimate the energy of interaction of ligands with the subunit of the HIV protease (threshold -6 kcal/mol) were selected 20 connection.

3.3. Additional search structures in the likeness

According to the results of the search by similarity, the complete cycle of opening and selection of energy (threshold -7 kcal/mol) were selected 14 compounds (see table 3).

4
Table 3
Compounds selected based on the results of the search by similarity, docking and energy performance.
NThe name of the substanceEvaluation of DS*, kcal/mol
17-chloro-5,6-dimethylbenzo[C]acridinevs.-7.9bn
29-chloro-5,6-dimethylbenzo[C]acridine-7,77
35,5'-bis(2-methyl-1H-indol-3-yl)-3,3'-bisoxazole-7,68
10-chloro-5,6-dimethylbenzo[C]acridineone-7,55
52-chloro-N-(2,5-dimetilfenil)-7-methyl-7H-purine-6-amine-7,51
62,3,6,8-tetrachlorinated-7,43
72-chloro-4-methylbenzo[h]quinoline-7,32
82-chloro-4-(2-phenylphenyl)quinoline-7,29
91,3,6,8-tetrachlorinated-7,2
102-(2-(2,4-dichlorophenyl)vinyl)quinoline-7,12
114-chloro-2-phenylphenol-7,04
12N-(4-chlorobenzylidene)-N-(N-fluoren-2-yl)Amin-7,02
133,6,8-trichloropyridin-7,02
142 chlorobenzo[h]quinoline-7,01
* DS is the free energy of binding between the ligand and HIV protease subunit

(6)

Measurement of the enzymatic activity of HIV protease in the presence of inhibitors.

1. Materials

1.1. The drug of the protease of HIV-1

The work was used recombinant HIV-1 protease company Bachem AG (Switzerland) (preparation of N-9040).

1.2. Chromogenic substrate for HIV protease

To analyze the enzymatic activity of HIV protease was used chromogenic substrate VII: H-Lys-Ala-Arg-Val-Tyr-p-nitro-Phe-Glu-Ala-Nle-NH2manufactured by Bachem AG (Switzerland) (preparation of N-1286).

1.3. Control the dimerization inhibitor (EID) of HIV protease

For a positive control was used known peptide ID (inhibitor Scar) (Palmitoyl-TVSYEL).

1.4. Samples of low molecular weight compounds

For experimental verification of potential inhibitors of dimerization on the enzymatic activity of HIV protease were taken 3 sample compounds selected during in vitro screening using ABOUT.

1.5. Other reagents and drugs

Other reagents and products used in the work were of analytical purity.

2. Methods.

2.1. Kinetic spectral measurements

To register the kinetics of the enzymatic reaction was used spectrophotometer Libra S32PC (Biochrom, England) in the "Kinetics". Metering the tion was made at 25°C. the decrease of absorption at 300 nm (peak absorption of the substrate (VII).

2.2. Analysis of the enzymatic activity of HIV protease

To measure the enzymatic activity of HIV protease was used chromogenic substrate VII, having the maximum absorption in the UV at 300 nm.

The preparation of HIV protease (100 ng) were incubated for 35 min at 25°C in 240 μl of buffer (1 M NaCl, 1 mm EDTA, 0,1% CHAPS, 8% DMSO, 0.1 M sodium acetate, pH 5.0) in the presence (experimental) or absence (control) of different concentrations of potential ID. The final concentration of the HIV protease was approximately 18 nm. Then the mixture was transferred into a quartz polymicrobic and start the reaction by adding 10 ál of substrate solution VII to final concentration of 25 μm.

The mixture was rapidly stirred and the activity of HIV protease were recorded at 25°C. the decrease of absorption at 300 nm for 35 minutes the Activity of HIV protease (µmol of substrate/(min·mg of enzyme) was calculated by the formula

where Δ300the change in optical density,

V - total volume of the mixture (l)

E is the molar extinction coefficient of the substrate (M-1cm-1),

m is the mass of the protease (mg),

t - measurement time (min)

l - thickness measuring cuvette (cm).

Inhibitory effect of potential ID and the KID was expressed by the value of the IC50(the concentration of inhibitor that inhibits 50% of enzyme activity).

3. Results.

Figure 1 as an example will throw the ical account changes in absorbance at 300 nm over time in the presence of ID. You can see that the ID inhibits the enzymatic reaction. From the dependency of the activity of HIV protease in the presence of various concentrations of ID (as an example see figure 2) were calculated IC50. The results are shown in table 4.

Table 4
The values of the IC503 potential ID and the KID.
no medication41014KID
IC50(µm)3,41,28,51,1

Thus, all three potential ID selected in vitro using the test system on ABOUT, showed considerable inhibitory activity comparable with the control peptide ID (inhibitor of Scar).

1. Method of identifying compounds that are non-competitive inhibitor of the protease of human immunodeficiency virus (HIV) (SEQ ID NO: 1)to identify methods of alanine skanirovaniya and molecular docking connection, at least one atom which is in contact with at least one atom of amino acid OST the TKA, selected from the group consisting of Asn98, Phe99, Asp29, Asp30, Arg8, Gly49, Gly51 and Gly52 SEQ ID NO: 1, at a distance of not more than 5 Å.

2. The method according to claim 1, in which alanine screening is conducted by means of the program CHARMM using the molecular dynamics procedure.

3. The method according to claim 1, whereby its own simulation time after trim is 10 PS (step 1 FS) with a record of intermediate States every 10 steps, and for each intermediate state is consistent virtual replacement of each amino acid residue subunit protease by alanine, during each of which assesses changes in the internal energy of the complex subunits (in kcal/mol) according to the formula:
,
where Eintthe energy of interaction between subunits, EAB- energy dimer EAndEInthe energy of each of the chains.

4. The method according to claim 1, whereby in the docking procedure as seats are areas on the surface of one of the subunits of the dimer defined in the alanine scanning, namely, Asn98, Phe99, Asp29, Asp30, Arg8, Gly49, Gly51 and Gly52 SEQ ID NO: 1.



 

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9 cl, 170 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

Casr antagonist // 2315036

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound represented by the following formula (1) , its pharmaceutically acceptable salts or optically active isomers wherein each symbol is given in the invention description. Proposed compound possesses antagonistic effect with respect to calcium-sensitive receptor (CASR). Also, invention relates to a therapeutically medicinal agent used in treatment of osteoporosis based on this compound, to a method for treatment of osteoporosis, calcium receptor antagonist and to agent promoting secretion of parathyroid hormone (PTH).

EFFECT: valuable medicinal properties of antagonist.

33 cl, 66 tbl, 5 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

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

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: improved treatment method, valuable medicinal properties of compounds and composition.

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-ene nitrile. Method involves interaction of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde with acetonitrile in the presence of a base to obtain mixture of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-ene nitrile and 3-[2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl]-3-hydroxypropionitrile and the following addition of a dehydrating agent to the reaction mixture for carrying out dehydration. Under usual conditions new 3-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3-hydroxyprionitrile is formed in the above said reaction as an intermediate compound. However, if the above said interaction reaction is carried out in organic solvent with dielectric permeability 10 or lower in the range of temperature from 20°C to 25°C then 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-prop-2-ene nitrile is formed directly. 3-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-prop-2-ene nitrile is used as the parent compound for synthesis of quinolyl propenal derivative that is used for synthesis of cholesterol-reducing agent. Invention provides simplifying method in preparing 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-prop-2-ene nitrile.

EFFECT: improved preparing method.

18 cl, 7 ex

The invention relates to a method for the preparation of 3-((2-cyclopropyl-4-(4-forfinal)-3-chinolin)prop-2-inala formula (3), which is an intermediate compound in the synthesis of reducing cholesterol agents

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

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