Novel compounds with antibacterial action

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

 

Resistance of pathogens in relation to currently used antibiotics in many countries in recent years has increased significantly and may lead to dangerous consequences. The main problem with this is that the pathogens are resistant not only to any single antibiotic, but, as a rule, to a number of other antibiotics, i.e. a kind of multilateral, comprehensive resistance. This applies primarily to certain groups of gram-positive pathogens, such as staphylococci, pneumococci and enterococci (S.Ewig and others, Antibiotika-Resistenz bei Erregern ambulant erworbener Atemwegsinfektionen, Chemother. Journ. 11, 2002, p.12-26; F.Tenover, Development and spread of bacterial resistance to antimicrobial agents: an overview, Clin. Infect. Dis. 15 Sept. 2001, 33, pril, s-115).

Observed for a long time dangerous trend has been recently proved in practice: In the United States described the first strain of Staphylococcus aureus resistant not only to methicillin but also vysokonasyshchennye compared to vancomycin (Centers for Disease Control and Prevention, Staphylococcus aureus resistant to vancomycin are, United States, 2002, MMWR 51, 2002, s-567).

This situation, along with the relevant hygiene measures in hospitals requires intensify the search for new antibiotics with the maximum possible new structure and a new mechanism of action that would effectively solve "in aradise" the problem.

In the present application describes the connection of a new type with antibacterial activity. These compounds are also of interest because they are inhibitors of topoisomerase IV, as well as DNA gyrase.

The present invention relates accordingly to compounds of General formula (I)

in which

A represents an atom of oxygen or sulfur, NH-, alkylenes, alkenylamine, alkynylamino or heteroalkyl group,

X1X2X3X4and X5independently from each other represent a nitrogen atom or a group of the formula CH or CR4,

Su is cycloalkenyl, geteroseksualbnogo, Allenova or heteroarenes group,

R1represents a hydrogen atom, halogen atom, hydroxy-, amino-, Tilney, alkyl, heteroalkyl, alkyloxy, heteroalkyl-, cycloalkyl, geterotsyklicescoe, alkylcyclohexane, heteroalicyclic, cycloalkane, alkylalkoxy, heterocyclizations or heteroalicyclic,

each of the residues R2independently represents a halogen atom, hydroxy-, amino-, nitro - or Tilney group, alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, g is trialkylsilyl, heterologously, Aracely or heteroalkyl remnant or two of the residues R2together represent a part aryl, heteroaryl, cycloalkyl, geteroseksualbnogo, alkylcyclohexanes, heteroalicyclic, Arakelova or heteroalkyl rings,

R3represents alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest,

R4represents a halogen atom, hydroxy, alkyl, alkenylphenol, alkenylphenol or heteroalkyl group,

n denotes 0, 1 or 2 and

m denotes 0, 1 or 2,

or their pharmacologically acceptable salts, solvate, hydrate or a pharmacologically acceptable compositions.

The term "alkyl" refers to saturated hydrocarbon group with a straight or branched chain containing 1-20, preferably 1-12, particularly preferably 1-6, carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, n-bucilina, isobutylene, tert-Ballina, n-pencilina, n-exilda, 2,2-dimethylbutyl or n-aktiline group.

Under the concepts of "alkenyl" and "quinil" refers to at least partially unsaturated pleva Horodnya group with a straight or branched chain, containing 2-20, preferably 2-12, particularly preferably 2-6, carbon atoms, such as Attila, allyl, acetylenyl, propargyl, isoprenaline or Gex-2-anilina group. Preferably alkeneamine groups contain one or two (especially preferably one) double bond, and alkyline group - one or two (especially preferably one triple bond.

Under the terms "alkyl", "alkenyl" and "quinil" refers to next group in which one or more hydrogen atoms replaced by halogen atom (preferably F or Cl), such as 2,2,2-trichlorethylene or triptorelin group.

The term "heteroalkyl" mean alkyl, Alchemilla, respectively Alchemilla group in which one or more (preferably 1, 2 or 3) carbon atoms are replaced with atoms of oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur, preferably oxygen, sulfur or nitrogen). The term "heteroalkyl" there is, in addition, in view of the carboxylic acid or the group, which represents a carboxylic acid derivative, such as, for example, acyl, arylalkyl, alkoxycarbonyl, alloctype, aryloxyalkyl,carboxyaniline or alkoxycarbonylmethyl.

As examples heteroalkyl groups include groups of formula RaO-Ya-, Ra-SY a-, Ra-N(Rb)-Ya-, Ra-CO-Ya-, Ra-O-CO-Ya, Ra-CO-O-Ya, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, RaCS-Ya, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-O-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-O-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-Ya-, Ra-S-CO-Ya, Ra-CO-S-Ya, Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Ra-S-CO-O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya, Ra-S-CS-O-Ya, Ra-O-CS-S-Yawhere Rarepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, Rbrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, Rcrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-the 6alkylamino group, Rdrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group and Yarepresents a direct bond, C1-C6alkylenes,2-C6alkenylamine or2-C6alkynylamino group, each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine atoms or chlorine. Specifically as heteroalkyl groups include, among others, methoxy, triptoreline, ethoxy, h-propyloxy, isopropoxy-, tert-butylacrylate, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino-, dimethylamino-, diethylamino, isopropylethylene, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, simple enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, etoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Among other heteroalkyl groups include, for example, nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alternately group.

The term "cycloalkyl" refers to saturated or partially saturated (e.g cycloalkenyl) tsiklicheski the group, containing one or more (preferably 1 or 2) cycles, which form the skeleton containing from 3 to 14, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7, carbon atoms. The concept of "cycloalkyl" refers to groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, SH, =S, NH2, =NH or NO2i.e. mean, for example, cyclic ketones such as cyclohexanone, 2-cyclohexenone or Cyclopentanone. As other examples cycloalkyl groups can be called cyclopropyl, cyclobutyl, cyclopentyl, Spiro[4,5]deganello, norbornylene, tsiklogeksilnogo, cyclopentyloxy, cyclohexadienyl, decolonising, bicyclo[4.3.0]nonalloy, tetralinyl, Cyclopentasiloxane, forceclosing or cyclohex-2-enelow group.

The term "heteroseksualci" means cycloalkyl group with its disclosed above values, in which one or more (preferably 1, 2 or 3 ring carbon atoms are replaced with atoms of oxygen, nitrogen, silicon, selenium, phosphorus or sulfur, preferably oxygen, sulfur or nitrogen). Preferably heterocytolysine group contains 1 or 2 cycles, composed of from 3 to 10 (especially 3, 4, 5, 6 or 7) atoms. The concept of "heteroseksualci" refers hereinafter to the group is, in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, SH, =S, NH2, =NH or NO2. As examples piperidinol, piperazinilnom, morpholinyl, urotropine, pyrrolidinyloxy, tetrahydrothiophene, tetrahydropyranyloxy, tetrahydrofuryl or 2-pyrazolidine group, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

The term "alkylsilanes" refers to the group that contains, in accordance with their disclosed above values as cycloalkyl, and alkyl, alkeline or alkyline group, i.e. mean, for example, alkylcyclohexane, cycloalkylation, alkylcyclohexanes, alkenylacyl and alkylcyclohexane group. Preferably the composition alkylcyclohexanes group is cycloalkyl group containing one or two cyclic systems, which form the skeleton containing from 3 to 10 (especially 3, 4, 5, 6 or 7) carbon atoms and one or two alkyl, alkeline or alkyline group with 1 or 2-6 carbon atoms.

The term "heteroalicyclic" refers to the above alkylcyclohexane groups in which one or more (preferably 1, 2 or 3) carbon atoms are replaced with atoms of oxygen, nitrogen, silicon, selenium, FOS is ora or sulfur, preferably oxygen, sulfur or nitrogen). Preferably heteroalicyclic group contains 1 or 2 cyclic system, composed of from 3 to 10 (especially 3, 4, 5, 6 or 7) atoms and one or two alkyl, alkeline, alkyline or heteroalkyl group with 1 or 2-6 carbon atoms. As examples of such groups may be called alkylchlorosilanes, alkylchlorosilanes, alkenylsilanes, alginolyticus, heteroalicyclic, heterooligomerization and heterooligomerization, this cyclic group is saturated or once, twice or three unsaturated.

The term "aryl" (abbreviated as "Ar") refers to an aromatic group which comprises one or more cycles and which forms a skeleton containing 6-14, preferably 6-10 (especially 6, carbon atoms. The term "aryl" refers to groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or HE-, SH-, NH2or NO2-group. As examples are phenyl, naftalina, biphenylene, 2-florfenicol, onlinelow, 3-nitroaniline or 4-hydroxyphenyl group.

The term "heteroaryl" refers to an aromatic group which comprises one or more cycles, and that the image is no skeleton, containing 5-14, preferably 5-10 (especially 5 or 6)carbon atoms and one or more (preferably 1, 2, 3, or 4 atoms of oxygen, nitrogen, phosphorus or sulfur (preferably O, S or N). The concept of "heteroaryl" refers to groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or HE-, SH-, NH2or NO2-group. As examples can be called 4-pyridyloxy, 2-imidazolidinyl, 3-phenylpyrrolidine, thiazolidine, oxazolidine, triazolyl, tetrazolyl, isoxazolyl, indazolinone, indolenine, benzimidazolyl, pyridazinyl, hyalinella, parinello, carbazolyl, criminology, pyramidalnou, 2,3'-biphenylol, 3-pyrazolidine and athinodorou group.

The term "aralkyl" refers to the group that contains, in accordance with their disclosed above values as aryl and alkyl, alkeline, alkyline and/or cycloalkyl groups, such as arylalkyl, arylalkyl, arylalkylamine, arylcyclohexylamine, arylcyclohexylamine,alkylalcohol and alkylaminocarbonyl group. As specific examples of aralkyl include, among others, toluene, xylene, mesitylene, styrene, benzylchloride, o-vtortola, 1H-inden, tetralin, dihydronaphthalene, indanan, vinylcyclopentane, Kum is l, cyclohexylphenol, fluoren and indan. Preferably, the corresponding kalkilya group contains one or two aromatic cyclic system (1 or 2 cycles) with 6-10 carbon atoms and one or two alkyl, alkeline and/or alkyline group with 1 or 2-6 carbon atoms and/or one cycloalkyl group with 5-6 carbon atoms.

The term "heteroalkyl" mean kalkilya group with its disclosed above values, in which one or more (preferably 1, 2, 3, or 4) carbon atoms are replaced with atoms of oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur, preferably oxygen, sulfur or nitrogen), i.e. the mean of the group, which in accordance with their disclosed above values are as aryl, respectively, heteroaryl, and alkyl, alkeline, alkyline, and/or heteroalkyl, and/or cycloalkyl, and/or heterocytolysine group. Preferably heteroalkyl group contains one or two aromatic cyclic system (1 or 2 cycles) with 5 or 6-10 carbon atoms and one or two alkyl, alkeline and/or alkyline group with 1 or 2-6 carbon atoms and/or one cycloalkyl group with 5-6 carbon atoms, of which 1, 2, 3 or 4 is replaced by oxygen atoms, sulfur or nitrogen.

As examples arylheteroacetic, Ari is heterocytolysine, allgemeingultige, arrangementvalentine, arrangedelementcollection, arylaminomethylidene, arrangementvalentine, heteroallyl, heteroarylboronic, heteroallyl, heterooligomerization, heteroalicyclic, heteroarylboronic, heterooligomerization, heterooligomerization, heteroresistance, heterooligomerization, heterooligomerization, heterooligomerization and heterooligomerization groups and cyclic groups are saturated or once, twice or three unsaturated. As specific examples tetrahydroisoquinolinium, benzoyloxy, 2 - or 3-ethylindole, 4-methylpyridine, 2-, 3 - or 4-metoksifenilny, 4-ethoxyphenyl, 2-, 3 - or 4-carboxypenicillins group.

The concept of "cycloalkyl", "heteroseksualci", "alkylsilanes", "heteroalicyclic", "aryl", "heteroaryl", "aralkyl and heteroaryl" also belong to groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, - SH, -S, NH2, =NH or NO2.

The term "optionally substituted" refers to groups in kataraktis or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, SH, =S, NH2, =NH or NO2. These concepts are further to the group, which is substituted by unsubstituted C1-C6alkyl, C2-C6alkenylamine,2-C6alkenylamine, C1-C6heteroalkyl,3-C10cycloalkenyl,2-C9heteroseksualnymi,6-C10aryl, C1-C9heteroaryl, C7-C12Uralkalij or2-C11heteroalkyl groups.

Due to the peculiarities of their replacement compounds of formula (I) can contain one or more centers of chirality. Accordingly the scope of the present invention included as all pure enantiomers and all pure diastereoisomers and mixtures thereof in any ratio. In addition, the scope of the present invention includes all CIS - and TRANS-isomers of compounds of General formula (I), as well as mixtures thereof. In the scope of the present invention also includes all tautomeric forms of the compounds of formula (I).

It preferred are such compounds of formula (I), where a is an atom of oxygen or sulfur or a group of the formula CH2CH2CH2CH2N(C1-C4alkyl), N(C1-C4alkyl)CH2CH2O co2CH2S, SCH2CH2CH(OH), CH(OH), CH(OH)CH 2, NHCO, CONH, S(=O)CH2or CH2C(=O).

Preferred are further such compounds of formula (I)where three, four or five groups X1X2X3X4and X5represent a CH group.

Further, these preferred compounds of formula (I), where R1represents a C1-C4alkyloxy or1-C4heteroantiserum, in which one or more hydrogen atoms may be replaced by fluorine atoms.

Particularly preferably, R1represents a methoxy group.

It preferred are such compounds of formula (I), where R2represents a hydroxy-group, With1-C4alkyl, C1-C4heteroalkyl or6-C12heteroalkyl group.

Further, these preferred compounds of formula (I), where R3represents heteroalicyclic or heteroaryl group.

Especially preferred are such compounds of formula (I), where R3represents a group of formula-B-Y, which denotes alkylenes group (primarily1-C4alkylenes group), alkenylamine, alkynylamino or heteroalkyl group (primarily1-C4heteroalkyl group), a Y is aryl, heteroaryl Uralkaliy, heteroalkyl, cycloalkyl, geterotsyklicescoe, alkylcyclohexane or heteroalicyclic group (primarily geterotsyklicescoe or analgeticalkie group).

Also preferably Y is a group one of the following structural formulas:

or

where X6X7and X8independently from each other represent nitrogen atoms, or a group of formula CR9X9and X10independently of one another denote oxygen atoms or sulfur or a group of the formula NR10, o denotes 0, 1 or 2, R5, R6, R7, R8and R9independently of one another represent hydrogen atoms, halogen atoms, hydroxy-group, alkyl, alkeline, alkyline or heteroalkyl group, and R10and R11independently of one another represent hydrogen atoms, alkyl, alkeline, alkyline or heteroalkyl group.

Particularly preferably, Y represents a group of one of the following structural formulas:

or

Preferably the linker is-(CH2)has a chain length of 2 or 3 atom.

It preferred are also the compounds of formula (I), where R4represents a fluorine atom or chloral 1-C4alkyloxy or3-C6dialkylaminomethyl group one or more hydrogen atoms can be replaced by fluorine atoms.

Preferred are further such compounds of formula (I), where su is cycloalkenyl or geteroseksualbnogo group containing one or two cycles with 4, 5, 6, 7, 8, 9 or 10 atoms.

Particularly preferably, the su is a group one of the following structural formulas:

or

where U denotes a nitrogen atom or a group of the formula CH or a DREAM, and V denotes the nitrogen atom or the CH group, and p represents 0 or 1. The substituents may be connected with this group as Equatorial and axial.

The present invention relates also to the use of compounds of formula I, their pharmacologically acceptable salts, respectively solvate and hydrate, as well as compositions and pharmaceutical compositions in therapeutics.

The pharmaceutical compositions according to the invention contain as active ingredient at least one compound of formula (I) and optionally carriers and/or adjuvants.

As examples of pharmacologically acceptable salts of the compounds of formula (I) include salts with physiologically compatible mineral acids, such as hydrochloric acid is one sulfuric acid and phosphoric acid, or organic acid salts, such as methanesulfonate acid, p-toluensulfonate acid, lactic acid, acetic acid, triperoxonane acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Among other pharmacologically acceptable salts of the compounds of formula (I) include salts of alkaline or alkaline earth metals such as sodium, potassium, lithium, calcium and magnesium, ammonium salts or salts of organic bases such as methylamine, dimethylamine, triethylamine, piperidine, Ethylenediamine, lysine, kolingerova, meglumin, morpholine and arginine. The compounds of formula (I) can be subjected to solvation, primarily hydration. Hydration can occur, for example, in the process of producing compounds or due to hygroscopicity initially anhydrous compounds of formula (I). In the presence of the compounds of formula (I) asymmetric C-atoms, these compounds can be represented either in the form of achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.

Part of prodrugs, which are also the object of the present invention includes a compound of formula (I) and at least one pharmacologically acceptable protective group, Tsaplya the traveler in physiological conditions, for example alkoxy, Arakelov-, acyl or alloctype, such as ethoxy-, benzyloxy-, acetyl or acetyloxy.

The use of these active substances to obtain the appropriate medicines is also an object of the present invention. As a rule, the compounds of formula (I), including their well-known and acceptable modifications introduced in the body individually or in combination with any other therapeutic agent. Similar to that used in therapeutics tools can be assigned for oral administration, such as tablets, coated tablets, pills, semi-solid substances, soft or hard capsules, solutions, emulsions or suspensions for parenteral use, for example, in the form of solution for injection, for rectal use, for example, in the form of suppositories, inhalation, for example, in the form of powdered or spray and transdermal or nasal application. For such tablets, pills, semi-solid substances, coated tablets, dragées and hard gelatin capsules intended for therapeutic purposes, the product can be mixed with pharmaceutically inert, inorganic or organic carriers, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc,stearic acid or its salts, skimmed milk powder, etc. To obtain soft capsules you can use devices such as, for example, vegetable oils, refined petroleum, animal or synthetic oils, wax, fat, polyhydric alcohols, etc. To obtain liquid solutions and syrups, you can use devices such as, for example, water, alcohols, aqueous salt solutions, aqueous dextrose, polyols, glycerol, vegetable oils, refined petroleum, animal or synthetic oils. For suppositories can be used in devices such as, for example, vegetable oils, refined petroleum, animal or synthetic oils, wax, fat and polyhydric alcohols. For aerosol compositions can be used compressed gases suitable for such purposes, such as oxygen, nitrogen and carbon dioxide. Means pharmaceutical purposes can also contain preservatives, stabilizers, emulsifiers, flavorings, flavoring agents, salts for modifying the osmotic pressure, buffers, additives used for coating, and antioxidants.

Part combinations with other therapeutic means can also include other antibacterial and antifungal active substances.

For the prevention and/or treatment of the above disease the dosage proposed in the invention the biologically active compound may vary within wide limits, taking into account individual patient. Typically, the desired effect can provide a daily dose of from 10 to 4000 mg, preferably from 50 to 3000 mg, In certain cases, this dose may be administered below or above these values. The daily dose may be calculated on a one-introduction or spread across multiple methods. A typical single dose contains the active substance in quantities of 50, 100, 250, 500 mg, 1 or 2,

Examples

Example 1: (R,S)-6-{1-hydroxy-2-[4-(7-methoxynaphthalene-1-intoximeter)piperidine-1-yl]ethyl}-4H-benzo[1,4]oxazin-3-one

Synthesis of tert-butyl ester 4-(7-methoxynaphthalene-1-intoximeter)piperidine-1-carboxylic acid

To a solution of triphenylphosphine (1,14 g, 4.3 mmole) in THF (5 ml) was added dropwise dithiosalicylic (755 mg, 4.3 mmole). After this first) was added tert-butyl ether 4-hydroxyethylpiperazine-1-carboxylic acid (850 mg, of 3.95 mmole), and then 7-methoxy-1-naphthol (synthesized similarly Aust. Journ. Chem. 46, 1993, s) (668 mg, of 3.95 mmole). The yellow solution was stirred over night at room temperature, concentrated and purified column chromatography on silica gel (hexane/EtOAc (ethyl acetate) in the ratio 4:1). The result was a 1.11 g (76%) of colorless oil.

MS (ESI+): 372,3 [M+H+].

Synthesis of 4-(7-methoxynaphthalene-1-intoximeter)piperidine

A solution of tert-bouteloua ester of 4-(7-IU ocinaplon-1-intoximeter)piperidine-1-carboxylic acid (1,11 g) in dichloromethane (10 ml) was mixed at room temperature in an argon atmosphere with triperoxonane acid (2 ml) and was stirred for 2 hours Then the reaction mixture was concentrated in a rotary evaporator, dissolved in dichloromethane and washed with a concentrated solution of ammonia. The organic phase was dried over MgSO4and concentrated.

Synthesis of 6-{2-[4-(7-methoxynaphthalene-1-intoximeter)piperidine-1-yl]acetyl}-4H-benzo[1,4]oxazin-3-one

A mixture of 4-(7-methoxynaphthalene-1-intoximeter)piperidine (271 mg, 1 mmol) and 6-(2-chloroacetyl)-4H-benzo[1,4]oxazin-3-one (225 mg, 1 mmol) in THF (5 ml) was mixed with triethylamine (1 ml), and within 2 h was heated to 50°C. Then the reaction mixture was poured into water and was extracted with EtOAc. The organic phase was washed with a solution of NH4Cl, dried over MgSO4and concentrated. The crystalline residue is stirred with Meon and EtOAc and separated on a suction filter. The result was 250 mg (52%) of pure product.

MS (ESI+): 461 [M+H+].

Synthesis of (R,S)-6-{1-hydroxy-2-[4-(7-methoxynaphthalene-1-intoximeter)piperidine-1-yl]ethyl}-4H-benzo[1,4]oxazin-3-one

A solution of 6-{2-[4-(7-methoxynaphthalene-1-intoximeter)piperidine-1-yl]acetyl}-4H-benzo[1,4]oxazin-3-one (150 mg) in EtOH (2 ml) was mixed with NaBH4(1 EQ.) and within 2 hours was stirred at room temperature. Then the reaction mixture was concentrated, dissolved in water and the white crystals were separated by suction filter, after which they were dried under high vacuum. In the received 140 mg of pure product.

MS (ESI+: 463,5 [M+H +].

Example 2: (R,S)-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(7-methoxynaphthalene-1-intoximeter)piperidine-1-yl]alanon

Synthesis of 6-oxiranyl-2,3-dihydrobenzo[1,4]dioxin

In a round flask with a volume of 50 ml was dissolved in acetonitrile (15 ml) of 2,3-dihydrobenzo[1,4]dioxin-6-carbaldehyde (1 g, 6,09 mmole), to this solution was added iodide trimethylsilane (1.28 g, 6,28 mmole) and KOH (2.4 g) and a few drops of water, then left for 1.5 h stirring at 60°C. Then the reaction mixture was concentrated in a rotary evaporator. The residue was dissolved with water and was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was chromatographically using hexane and EA in the ratio of 1:1. The result was obtained 1 g (100%) of pure product.

1H-NMR (CDCl3): 6,80-6,77 (m, 3H), 4,27 (s, 4H), of 3.78 (dd, J=2,61, was 4.02, 1H), 3,11 (dd, J=was 4.02, 5,4, 1H), and 2.79 (dd, J=2,61, 4,5, 1H).

Synthesis of (R,S)-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(7-methoxynaphthalene-1-intoximeter)piperidine-1-yl]ethanone

To a solution of 4-(7-methoxynaphthalene-1-intoximeter)piperidine (100 mg, of 0.36 mmole) and 6-oxiranyl-2,3-dihydrobenzo[1,4]dioxin (66 mg, of 0.36 mmole) in DMF (1 ml) was added lithium perchlorate (39,2 mg of 0.36 mmole) and potassium carbonate (101,9 mg, 0.73 mmole). Then the reaction mixture was stirred over night at 80°C., concentrated under high vacuum, astoral in the water and was extracted with EtOAc. The organic phase was dried over Na2SO4and concentrated. The product was purified by chromatography on SiO2(EtOAc). The result was 62.5 mg (38%) of foamy substance beige color.

MS (ESI+): 450,5 [M+H+].

Example 3: (R,S)-6-{1-hydroxy-2-[4-(7-methoxypyrazine-1-intoximeter)piperidine-1-yl]ethyl}-4H-benzo[1,4]oxazin-3-one

Synthesis of 1-chloro-7-methoxyflavanone

A mixture of 7-methoxy-2H-phthalazine-1-she (2.2 g, 12.5 mmole, receiving method, described in Journ. Am. Chem. Soc. 1924, S. 1889) and POCl3(10 ml) was heated for 6 h under reflux. Then the excess POCl3drove by rotary evaporator and the residue was dissolved in EtOAc. The organic phase is washed with water and bicarbonate solution, dried over MgSO4and concentrated. The obtained product was purified column chromatography (hexane/EtOAc to 1:1 ratio).

1H-NMR (CDCl3): was 9.33 (s, 1H), 7,92 (d, J=8.7 Hz, 1H), 7,58 (dd, J=8,7, 2.2 Hz, 1H), 7,52 (d, J=2.2 Hz, 1H), 4,0 (s, 3H).

MS (ESI+): 195/197 [M+H+].

Synthesis of tert-butyl ester 4-(7-methoxypyrazine-1-intoximeter)piperidine-1-carboxylic acid

A solution of tert-bouteloua ether 4-hydroxyethylpiperazine-1-carboxylic acid (475 mg, 2.2 mmole) in DMF (10 ml) was mixed with the dispersion of NaH (55%, 96 mg) and left for 5 minutes for mixing. Then was added dropwise a solution of 1-chloro-7-methoxyflavanone 430 mg, 2.2 mmole) in DMF and the reaction mixture was stirred for 4 h at room temperature, then diluted with EtOAc and water. The organic phase is washed with water, dried over MgSO4and concentrated. The product was purified by chromatography on SiO2(EtOAc). The result was 709 mg (86%) of pure product.

MS (ESI+): 374,5 [M+H+].

Synthesis of 7-methoxy-1-(piperidine-4-ylethoxy)phthalazine

Used protective SIDE (tert-butoxycarbonyl) group was removed as in example 1 using TFOC (triperoxonane acid) in THM.

MS (ESI+): 284,5 [M+H+].

Synthesis of 6-{2-[4-(7-methoxypyrazine-1-intoximeter)piperidine-1-yl]acetyl}-4H-benzo[1,4]oxazin-3-one

A mixture of 7-methoxy-1-(piperidine-4-ylethoxy)phthalazine (273 mg, 1 mmol) and 6-(2-chloroacetyl)-4H-benzo[1,4]oxazin-3-one (225 mg, 1 mmol) in THF (5 ml) was mixed with triethylamine (1 ml), and within 2 h was heated to 50°C. the thus formed yellow precipitate, which was separated on a suction filter and stirred with a mixture of Meon/EtOH/THF. In this way received 80 mg of pure product.

MS (ESI+): 463,5 [M+H+].

Synthesis of (R,S)-6-{1-hydroxy-2-[4-(7-methoxypyrazine-1-intoximeter)piperidine-1-yl]ethyl}-4H-benzo[1,4]oxazin-3-one

A solution of 6-{2-[4-(7-methoxypyrazine-1-intoximeter)piperidine-1-yl]acetyl}-4H-benzo[1,4]oxazin-3-one (40 mg) in EtOH (2 ml) and THF (2 ml) was mixed with NaBH4(1 EQ.) and for 2 h p is remedial at room temperature. Then the reaction mixture was adsorbing on SiO2and purified by chromatography (DHM/Meon in the ratio of 9:1+1% NH4OH). The result received 25 mg of pure product.

MS (ESI+): 465,5 [M+H+].

Example 4: (R,S)-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(7-methoxypyrazine-1-intoximeter)piperidine-1-yl]ethanol

To a solution of 7-methoxy-1-(piperidine-4-ylethoxy)phthalazine (100 mg, of 0.36 mmole) and 6-oxiranyl-2,3-dihydrobenzo[1,4]dioxin (66 mg, of 0.36 mmole) in DMF (1 ml) was added lithium perchlorate (39,2 mg of 0.36 mmole) and potassium carbonate (101,9 mg, 0.73 mmole). Then the reaction mixture was stirred over night at 80°C, then concentrated under high vacuum, dissolved in water and was extracted with EtOAc. The organic phase was dried over Na2SO4and concentrated. The product was purified by chromatography on SiO2(EtOAc). The result was of 58.7 mg (35%) of a white foamy substance.

MS (ESI+): 452,5 [M+H+].

Example 5: 6-{1-hydroxy-2-[4-(7-methoxyethanol-1-intoximeter)piperidine-1-yl]ethyl}-4H-benzo[1,4]oxazin-3-one

Synthesis of 1-chloro-7-methoxyethylamine

A mixture of 7-methoxy-2H-isoquinoline-1-she (6.5 g, 37 mmol, obtaining technology, similar to that described in Journ. Heterocycl. Chem. 22, 1985, s) and POCl3(50 ml) for 6 h was heated under reflux. Then the excess POCl3agonalis by rotary evaporator and the residue was dissolved in EtOAc. The organic phase was washed with a mixture of water and ice and a solution of bicarbonate, dried over MgSO4and concentrated. The obtained product was purified column chromatography (hexane/EtOAc in a ratio of 3:1).

MC (ESI+): 194,5 [M+H+].

Synthesis of tert-butyl ester 4-(7-methoxyethanol-1-intoximeter)piperidine-1-carboxylic acid

A solution of tert-butyl methyl ether 4-hydroxyethylpiperazine-1-carboxylic acid (1075 mg, 5 mmol) in THF (20 ml) was mixed with the dispersion of NaH (55%, 240 mg) and left for 5 minutes for mixing. Then was added dropwise a solution of 1-chloro-7-methoxyethylamine (965 mg, 5 mmol) in THF and the reaction mixture for 5 h and stirred at 50°C and overnight at room temperature, then was diluted simple ether and water. The organic phase is washed with water, dried over MgSO4and concentrated. The product was purified by chromatography on SiO2(hexane/EtOAc in a ratio of 3:1). The result was of 1.16 g (62%) of pure product.

MC (ESI+): 373,5 [M+H+].

Synthesis of 7-methoxy-1-(piperidine-4-ylethoxy)of isoquinoline

Used protective tert-butoxycarbonyl group was removed as in example 1 using TFOC (triperoxonane acid) in THM.

1H-NMR (CDCl3): 7,8 (d, J=5,97 Hz, 1H), 7,58 (d, J=8,91, 1H), 7,43 (d, J=2,52, 1H), 7,24, (dd, J=8,91, 2,52, 1H), was 7.08 (d, J=5,91, 1H), 4,32 (d, J=6,51, 2H), 3,88 (s, 3H), 3,26-3,24 (m, 2H), 2,88-2,70 (m, 2H), 2.1 to 2,05 (, 1H), a 2.0 to 1.9 (m, 2H), 1.60-to of 1.46 (m, 2H).

Synthesis of 6-{2-[4-(7-methoxyethanol-1-intoximeter)piperidine-1-yl]acetyl}-4H-benzo[1,4]oxazin-3-one

A mixture of 7-methoxy-1-(piperidine-4-ylethoxy)isoquinoline (272 mg, 1 mmol) and 6-(2-chloroacetyl)-4H-benzo[1,4]oxazin-3-one (225 mg, 1 mmol) in THF (5 ml) was mixed with K2CO3(1 EQ.) and during the night were heated to 50°C. Then the reaction mixture was concentrated and the residue was purified by chromatography on SiO2(EtOAc). In this way received 250 mg (54%) of pure product.

MC (ESI+): 462,5 [M+H+].

Synthesis of 6-{1-hydroxy-2-[4-(7-methoxyethanol-1-intoximeter)piperidine-1-yl]ethyl}-4H-benzo[1,4]oxazin-3-one

A solution of 6-{2-[4-(7-methoxyethanol-1-intoximeter)piperidine-1-yl]acetyl}-4H-benzo[1,4]oxazin-3-one (200 mg, 0.5 mmole) in EtOH (20 ml) was mixed with NaBH4(40 mg) and within 2 hours was stirred at room temperature. Then the reaction mixture was adsorbing on SiO2and purified by chromatography (DHM/Meon in the ratio of 9:1 + 1% NH4OH). The product was led from simple ether. The result was 55 mg (28%) of pure product.

MS (ESI+): 464 [M+H+].

Example 6: Synthesis of 1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(7-methoxyethanol-1-intoximeter)piperidine-1-yl]ethanol.

To a solution of 7-methoxy-1-(piperidine-4-ylethoxy)isoquinoline (100 mg, of 0.36 mmole) and 6-oxiranyl-2,3-dihydrobenzo[1,4]dioxin (6 mg, of 0.36 mmole) in DMF (1 ml) was added lithium perchlorate (39,2 mg of 0.36 mmole) and potassium carbonate (101,9 mg, 0.73 mmole). Then the reaction mixture was stirred over night at 80°C, then concentrated under high vacuum, dissolved in water and was extracted with EtOAc. The organic phase was dried over Na2SO4and concentrated. The product was purified by chromatography on SiO2(EtOAc). The result was of 58.7 mg (35%) of a white foamy substance.

MC (ESI+): of 451.5 [M+H+].

Example 7: 2-(3-{[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amino]methyl}piperidine-1-yl)-1-(3-methoxyaniline-5-yl)ethanol

Synthesis of tert-butyl methyl ether 3-azidopyridine-1-carboxylic acid

To a solution of tert-bouteloua ether (3R)-hydroxyethylpiperazine-1-carboxylic acid (2 g, 9,29 mmole retrieval technology, similar to that described in Tetrahedron Lett. 43, 2002, S. 8917 and Gazz. Chim. Ital. 102, 1972, p.189) in DHM (30 ml) at 0°C was added dropwise at first triethylamine (2.6 ml, of 18.6 mmole), and then methanesulfonanilide (0.8 ml, 10.3 mmole). Within 30 min the reaction mixture was stirred at this temperature. Next to it was added a saturated solution of NaHCO3(20 ml) and DHM (30 ml). The two phases were separated and the organic phase was washed with brine (20 ml), dried over MgSO4and concentrated. The crude product was rapidly filtered through silica (EtOAc/hexane in a ratio of 1:). Then the crude product was dissolved in DMF (40 ml) and mixed with sodium azide (1.2 g, an 18.4 mmole). This mixture for 5 h and stirred at 80°C, concentrated in a rotary evaporator and mixed with simple ether and water. The organic phase was dried over MgSO4and concentrated. The crude product was purified by chromatography on SiO2(hexane/EtOAc in a ratio of 4:1). The result was found to be 2.16 g (9 mmol) of product in the form of oil.

MS (EI) m/z: 241.4 M. [M+H+].

Synthesis of (R)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperidine-3-ylmethylamino

A solution of tert-butyl methyl ether 3-azidopyridine-1-carboxylic acid (2.16 g, 9 mmol) in THF (60 ml) and water (1 ml) was mixed with immobilized to the polymer by triphenylphosphine (6.3 g, 3.6 mmole/g). The mixture for 4 days was stirred at room temperature and was filtered. The filtrate was concentrated and dissolved in methanol (35 ml). Then was added 1,4-benzodioxan-6-carboxaldehyde (1.48 g, 9 mmol) and molecular sieve with a pore size of 3 Angstrom (9.6 g). Then the reaction mixture for 5 h and stirred at room temperature, then added borohydride sodium (1.2 g, and 31.7 mmole). The mixture continued to stir for 16 h at room temperature, then concentrated and dissolved in water (100 ml). The aqueous phase was extracted with DHM (2×200 ml). The combined organic the basics were dried over MgSO 4and concentrated. The residue was purified by chromatography on SiO2(DHM/Meon in the ratio 19:1). The result was obtained 2.2 g of product in the form of oil. This oil was dissolved in TFOC (10 ml) and was stirred for 1 h Then the mixture was concentrated, dissolved in aqueous ammonia solution and was extracted with DHM (2×30 ml). The combined organic phases were dried over MgSO4and concentrated. The result was found to be 1.44 g (of 5.53 mmole) of the product as oil.

MS (EI) m/z: 263,0 [M+H+].

Synthesis of 2-bromo-1-(3-methoxyaniline-5-yl)ethanone (83 Synthesis, 2002)

A solution of 3-brainline (10.4 g, 50 mmol) in concentrated H2SO4(50 ml) was mixed at room temperature with N-BS (N-bromosuccinimide) (10.7 g, 60 mmol) and was stirred over night. Then the reaction mixture was poured on ice, podslushivaet aqueous solution of ammonia and was extracted with simple ether. The organic phase was dried over MgSO4and concentrated. The product was purified by chromatography on SiO2(DHM/hexane in the ratio of 6:4, DHM, EtOAc) and recrystallized from methanol. The result was 8 g (56%) of 3,5-dibromononane in the form of white crystals.

1H-NMR (CDCl3): 8,91 (d, J=2.2 Hz, 1H), 8,80 (d, J=2.2 Hz, 1H), 8,07 (d, J=7.8 Hz, 1H), 7,88 (d, J=7.8 Hz, 1H),7,60 (t, J=7.8 Hz, 1H).

MC (ESI+) m/z: 285/287/289 [M+H+].

This dibromide (2 mmole) was dissolved interaction with sodium methylate (4 mmole) wcgmc (triamide hexamethylphosphoric acid (8 ml) (Tetrahedron 58, 2002, s) and within 2 minutes was heated in a microwave oven to 90°C. This operation was repeated 6 times. The combined mixture was poured into ice water, extracted by a simple ether, dried over MgSO4and concentrated. The product was purified by chromatography on SiO2(hexane/EtOAc in a ratio of 4:1). The result was 2,78 g (67%) of 5-bromo-3-methoxyquinoline.

This 5-bromo-3-methoxyaniline according to the method described in the literature (WO 02/08224), was converted into 1-(3-methoxyaniline-5-yl)Etalon.

1-(3-methoxyaniline-5-yl)alanon (500 mg, 2.5 mmole) in Asón (10 ml) was mixed with Br2(1 EQ.) and HBr (33%in the Asón). Then the mixture for 2 h and was stirred at room temperature. According to mass spectrometric analysis was formed a mixture of mono - and dibromononane product. The reaction mixture was diluted with water and was extracted with DHM. The organic phase was washed with water and bicarbonate solution, dried over MgSO4and concentrated. The product was separated by chromatography on SiO2(hexane/EtOAc 2:1). The result was 225 mg of 2-bromo-1-(3-methoxyaniline-5-yl)ethanone.

1H-NMR (CDCl3): is 8.75 (d, J=2.2 Hz, 1H), 8,65 (d, J=2.2 Hz, 1H), with 8.33 (d, J=7.8 Hz, 1H), 8,13 (d, J=7.8 Hz, 1H), to 7.64 (t, J=7.8 Hz, 1H)and 4.65 (s, 2H), 4,01 (s, 3H).

MC (ESI+) m/z: 280/282 [M+H+].

Synthesis of (1-RS)-2-(3(S)-{[(2,3-dihydrobenzo-[1,4]-dioxin-6-ylmethyl)amino]methyl}piperidine-1-yl)-1-(3-methoxyaniline-5-yl)ethanol

A solution of 2-bromo-1-(3-methoxyaniline-5-yl)ethanone (0,113 g, 0.4 mmole) and (R)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)piperidine-3-ylmethylamino (0,106 g, 0.4 mmole) in THF (3 ml) was stirred overnight at room temperature. Then the reaction mixture was concentrated and the residue was dissolved in methanol (2 ml). After cooling to 0°C was added NaBH4(0,031 g, 0.8 mmole). The mixture for 1 h, stirred at 0°C. was Further added water (3 ml) and the mixture was concentrated. The residue was purified by chromatography (DHM/Meon in the ratio of 9:1 + 1% NH4OH). The result was (1-RS)-2-(3(S)-{[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amino]methyl}piperidine-1-yl)-1-(3-methoxyaniline-5-yl)ethanol (0,097 g of 0.21 mmole).

MC (ESI+) m/z: 464,5 [M+H+].

Below is the connection that received the same way as described above:

1. The compounds of formula (I)
,
in which a represents an oxygen atom, alkylenes, alkenylamine or heteroalkyl group in which the group CH2replaced by a NH group, and these groups optionally can be substituted by the groups HE =O or CH2HE
X1X2X3X4and Xsup> 5independently from each other represent a nitrogen atom or a group of the formula CH or CR4,
Su is cycloalkenyl or geteroseksualbnogo group containing at least one nitrogen atom,
R1represents a hydrogen atom, alkyl or alkyloxy,
R2represents a halogen atom, a hydroxy-group, alkyl or heteroalkyl the rest, and these groups optionally can be substituted by the groups HE, NH2and/or a group =O,
R3represents a group of formula-B-Y, in which
In denotes alkylenes, alkenylamine or heteroalkyl group, and these groups optionally can be substituted by the groups HE, NH2, COOH or a group =O,
Y represents optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or optionally substituted bicyclic a heterocycle in which one ring is a phenyl or pyridyl and the other ring is a 5-, 6 - or 7-membered heteroaryl or geterotsyklicescoe group containing up to 3 heteroatoms selected from nitrogen atoms, oxygen and sulfur,
R4represents a halogen atom,
n denotes 0, 1 or 2, and
m denotes 0 or 1,
or their pharmacologically acceptable salts, Almaty, hydrates or pharmaceutically acceptable composition.

2. Compounds according to claim 1, where a represents an oxygen atom or a group of the formula CH2CH2CH2CH2O, OCH2CH2CH(OH), CH(OH), CH(OH)CH2, NHCO, CONH, C(=O)CH2or CH2C(=O).

3. Compounds according to claim 1, where three, four or five groups X1X2X3X4and X5represent a CH group.

4. Compounds according to claim 1, where R1represents a C1-C4alkyloxy.

5. Compounds according to claim 1, where R1represents a methoxy group.

6. Compounds according to claim 1, where Y represents a group of one of the following structural formula:
or.
where X6X7and X8independently from each other represent nitrogen atoms, or a group of formula CR9X9and X10independently of one another denote oxygen atoms or sulphur, represents 0, 1 or 2, R5, R6, R7, R8and R9independently of one another represent hydrogen atoms or halogen atoms, and R11is a hydrogen atom.

7. Compounds according to claim 6, where Y is a group one of the following structural formula:
or.

8. Compounds according to claim 1, where the linker-A-(CH2)nhas t the universi length 2 or 3 atom.

9. Compounds according to claim 1, where R4represents a fluorine atom or chlorine.

10. Compounds according to claim 1, where su is a group one of the following structural formula:
or,
where U denotes a nitrogen atom or a group of the formula CH or a DREAM, and V denotes the nitrogen atom or the CH group, and p represents 0 or 1.

11. Pharmaceutical composition having antibacterial activity containing a compound according to claims 1 to 10 as an active ingredient and optionally carriers and/or adjuvants.

12. The use of the compounds or pharmaceutical composition according to one of claims 1 to 11 for the treatment of bacterial infections.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

Cytokine inhibitors // 2394029

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

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