(1,10b-dihydro-2-(aminoalkylphenyl)-5h-pyrazolo[1,5-c][1,3] benzoxazin-5-yl) phenylmethanone derivatives as hiv viral replication inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to (5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone derivatives (I), useful as HIV viral replication inhibitors, as well as pharmaceutical compositions, use thereof as medicinal agents.

EFFECT: disclosed compounds are meant for preventing or treating HIV infection and treating AIDS.

7 cl, 2 tbl, 4 ex

 

The present invention relates to a derivative (5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone as inhibitors of viral replication of the HIV virus, methods for their preparation, and pharmaceutical compositions, their use as medicines, and containing diagnostic kits. The present invention also relates to combinations of these inhibitors of HIV with other antiretroviral agents. In addition, the present invention relates to the use of these compounds in the analysis as reference compounds or as reagents. Compounds of the present invention are designed to prevent or treat HIV infection and for the treatment of AIDS.

The number of people living with HIV/AIDS, consisted in December 2004 of approximately 40 million, of which more than 37 million are adults and approximately 2.2 million are children aged less than 15 years. The number of people newly infected with HIV in 2004 only increased to 4.9 million, while 3.1 million people sick with AIDS, died in 2004. In modern chemotherapy of those people infected with HIV/AIDS, used inhibitors of viral fusion, as well as the enzymes reverse transcriptase (RT) and protease. Due to the emergence of HIV strains that are resistant to modern generation inhibitors merge RT and protease is, there is an increasing need to develop new and improved antiviral drugs with different mechanisms of action.

EP 1359147 refers to benzoxazinones, in particular 1,4-dihydro-2H-3,1-benzoxazin-2-Onam or their stereoisomeric forms or mixtures, or pharmaceutically acceptable salts, which are intended for use as inhibitors of HIV reverse transcriptase containing pharmaceutical compositions and diagnostic kits, methods of use for treating viral infection or as a standard or reagent for analysis, methods for their preparation and intermediate compounds for their preparation.

Orlov V.D. et al. (1991) described substituted 1,10b-dihydro-5H-pyrazolo[1,5-c]-1,3-benzoxazines, in particular (1,10b-dihydro-2-phenyl-5H-pyrazolo[1,5-c]-1,3-benzoxazin-5-yl)phenylmethanone with potential physiological activity.

EP 0563733 refers to the application of the known 7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids and their esters as medicines, which have antiviral activity.

The task underlying the present invention is to provide inhibitors of viral replication of the HIV virus.

The present invention relates to compounds having formula (I)

and their N-oxides, stereoisomeric forms and Sol is m,

where

and is equal to zero, 1, 2, 3, 4 or 5;

L represents a C1-4alcander;

R1represents hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil,3-12cycloalkyl, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-10cycloalkyl, amino and mono - and disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl;

R2represents hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil,3-12cycloalkyl, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl, amino and mono - and disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl; or

R1and R2taken together with the nitrogen atom to which they are attached, form a 5-12 membered saturated or partially saturated a heterocycle with one or more heteroatoms, which are each individually selected from nitrogen atom, oxygen or sulfur, and where the heterocycle may be optionally substituted C1-10the alkyl, C2-10alkenyl,2-10al is anilam, With3-12cycloalkyl,1-6allyloxycarbonyl, Het, aryl or1-10by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl, amino and mono - and disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl;

R3is carboxyl, halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalogen1-10alkyl, cyano, amino, mono - or disubstituted by an amino group, aminocarbonyl, mono - or disubstituted aminocarbonyl,1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, pyrrolidinyl, piperidinyl, homopiperazine, morpholine, thiomorpholine or piperazinil, optionally substituted C1-10the alkyl, where the substituents of any of the amino groups, individually, is selected from C1-10of alkyl, C2-10alkenyl,3-12cycloalkyl, Het and aryl;

aryl represents phenyl, optionally substituted by one or more substituents selected from the group consisting of C1-10of alkyl, polyhalogen1-10of alkyl, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, nitro, cyano, halogen, C3-7cycloalkyl,1-10alkylcarboxylic, carboxyl,1-10allyloxycarbonyl is a, amino group mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl,1-10of alkyl, C2-10alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-10by alkyl;

Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic heterocycle with one or more heteroatoms, which are each individually selected from nitrogen atom, oxygen or sulfur, and which heterocycle may be optionally substituted with one or where possible, more than one Deputy, selected from the group consisting of C1-10of alkyl, polyhalogen1-10of alkyl, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, nitro, cyano, halogen, C3-7cycloalkyl,1-10alkylcarboxylic, carboxyl,1-10allyloxycarbonyl, an amino group mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl,1-10of alkyl, C2-10alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-1 the alkyl.

Used in this description, the term "halogen" as a group or part of a group is shared by fluorine, chlorine, bromine or iodine. The term "polyhalogen"used in this description as an attachment means radical, substituted by one or more halogen atoms. Examples of the use of the term "polyhalogen" as prefixes to the radical include, for example, polyhalogen1-10alkyl, polyhalogen1-6alkyl, polyhalogen1-4alkyl and the like, Particularly interest POLYHALOGENATED are deformity and trifluoromethyl.

The term "C1-4alkyl" as a group or part of a group means a saturated monovalent hydrocarbon radical with unbranched and branched chain containing 1-4 carbon atoms. Examples of such1-4alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

The term "C1-6alkyl" as a group or part of a group means a saturated monovalent hydrocarbon radical with unbranched and branched chain containing 1-6 carbon atoms. Examples of such1-6alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, pentyl, isoamyl, hexyl, 3-methylpentyl etc.

The term "C1-10alkyl" as a group or part of GRU the dust means saturated monovalent hydrocarbon radical with unbranched and branched chain, containing 1-10 carbon atoms. Examples of such1-10alkyl radicals include examples With1-6alkyl radicals and heptyl, octyl, nonyl, decyl, 3-atergatis etc.

The term "C2-6alkenyl" as a group or part of a group means a monovalent hydrocarbon radical with unbranched and branched chain, having at least one double bond and containing 2 to 6 carbon atoms. Examples of such2-6alkenyl radicals include ethynyl, propenyl, 1-butenyl, 2-butenyl, Isobutanol, 2-methyl-1-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-methyl-2-pentenyl etc.

The term "C2-10alkenyl" as a group or part of a group means a monovalent hydrocarbon radical with unbranched and branched chain, having at least one double bond and containing 2-10 carbon atoms. Examples of such2-6alkenyl radicals include examples With2-6alkenyl and 2-heptenyl, 3-heptenyl, 3-octenyl, 4-octenyl, 4-nonanol, 4-decenyl etc.

The term "C2-6quinil" as a group or part of a group means a monovalent hydrocarbon radical with unbranched and branched chain, having at least one triple bond and containing from 2 to 6 carbon atoms. Examples of such2-6etkinlik radicals include ethinyl, PROPYNYL, 1-butynyl, 2-butynyl, Isobutanol, 2-m is l-1-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-methyl-2-pentenyl etc.

The term "C2-10quinil" as a group or part of a group means a monovalent hydrocarbon radical with unbranched and branched chain, having at least one triple bond and containing 2-10 carbon atoms. Examples of such2-10etkinlik radicals include examples With2-6the quinil and 2-heptenyl, 3-heptenyl, 3-octenyl, 4-octenyl, 4-nonenal, 4-decenyl etc.

The term "C1-2alcander" as a group or part of a group means a divalent saturated hydrocarbon radical with unbranched and branched chain having 1 or 2 carbon atoms, such as, for example, methylene, ethane-1,2-diyl etc.

The term "C1-4alcander" as a group or part of a group means a divalent saturated hydrocarbon radical with unbranched and branched chain having 1-4 carbon atoms, such as examples With1-2elendilmir radicals and propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl etc.

The term "C3-7cycloalkyl" as a group or part of a group means a carbocyclic or zerocarboncity monovalent hydrocarbon radicals having from 3 to 7 carbon atoms in the main chain carbocycle or pyrocarbonate. Examples of such3-7cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, Spiro[2.4]heptanol, cycloheptyl etc.

The term "C3-12cycloalkyl" as a group or part of a group means a carbocyclic or zerocarboncity monovalent hydrocarbon radicals having from 3 to 12 carbon atoms in the main chain carbocycle or pyrocarbonate. Examples of such3-12cycloalkyl radicals include examples With3-7cycloalkyl and cyclooctyl, cycloneii, Spiro[4.4]nonyl, Spiro[4.5]decyl, Spiro[5.5]undecyl, cyclododecyl, Spiro[5,6]dodecyl, etc.

Examples of 5 - or 6-membered heterocycles denoted Het include, but are not limited to, pyridine, pyrimidine, pyridazine, pyrazin, triazine, imidazole, thiazole, oxazole, oxadiazole, thiadiazole, isothiazol, isoxazol, pyrazole, furan, thiophene, pyrrole, quinoline, isoquinoline, benzoxazol, samesexual, benzothiazole, IsoBuster, benzimidazole, benzotriazole, tetrahydroquinolin, tetrahydroisoquinoline, piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, homopiperazin, homopiperazin, tetrahydrofuran and tetrahydrothieno. Each of the designated Het and mentioned as examples of the heterocycles may be optionally additionally substituted.

It is assumed that used in this description, the term C(=O) means the carbonyl portion of the term S(=O)2means sulfonyloxy part. As used in this description of the research Institute of the term "hydroxy" means-HE, the term "nitro" means-NO2the term "cyano" means-CN, the term "thio" means-S, the term "oxo" means =O.

Have in mind that whenever the terms "one or more substituents" or "substituted"used when referring to compounds of formula (I), indicate that one or more hydrogen atoms of the atom indicated in the expression using "one or more substituents" or "substituted"is replaced with a selection from the indicated group, provided that not exceeded the normal number of valences of a given atom, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to withstand the selection to the desired degree of purity of the reaction mixture and turn into a therapeutic agent.

For therapeutic purposes suitable salts of the compounds of the present invention are salts where the counterion is pharmaceutically or physiologically acceptable. However, salts with pharmaceutically unacceptable ion, may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds of the present invention. All salts, regardless of whether they are pharmaceutically acceptable or not included in the scope of the present invention.

Pharmaceutically acceptable or physiologically erinaceinae form acid additive salts, which is able to form compounds of the present invention, can suitably be obtained by using the appropriate acids, such as, for example, inorganic acids such as halogenation acid, e.g. hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, little new, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, ciclamino, salicylic, p-aminosalicylic, pamula and like acid.

Conversely, these forms of acid additive salts can be converted by treatment with a suitable base in the form of a free base.

Compounds of the present invention containing an acidic proton may also be converted into the form of a non-toxic metal salt or amino-additive salt by treatment with appropriate organic or inorganic bases. Suitable forms of the salts of the bases include, for example, ammonium salts, Quaternary ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, salt, benzathine, N-is ethyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine, etc.

Conversely, these forms of primary additive salts can be converted by treatment with a suitable acid in the form of the free acid.

The term "salt" includes hydrates and forms the joining of the solvent, which is able to form compounds of the present invention. Examples of such forms are, for example, hydrates, alcoholate and the like, the Term "salt" includes products of quaternization of the nitrogen atoms of these compounds. The basic nitrogen atom can be chernyshovathe any agent known to the person skilled in the art, including, for example, the lowest alkylhalogenide, diallylsulfide, alkylhalogenide long chain and arylalkylamine.

Have in mind that the form of N-oxides of these compounds include compounds where one or more atoms of nitrogen oxidized in the so-called N-oxide.

These compounds may also exist in their tautomeric forms. It is assumed that these forms, although they are not directly indicated in the above formula, is included in the scope of the present invention.

The term "stereochemical isomeric forms of the compounds of the present invention used in this description previously, means all possible compounds made up of the same atoms connected to the W is the sequence of links, but having different three-dimensional structures that are not vzaimootmenyaemymi and which can have compound of the present invention. If not specified or not specifically mentioned, the chemical definition of a connection involves a mixture of all possible stereochemical isomeric forms, which may be of the specified connection. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. It is assumed that all stereochemical isomeric forms of the compounds of the present invention, both in pure form and in the form of mixtures with one another, included in the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates described in this description, is defined as isomers, essentially not containing other enantiomeric or diastereomeric forms of the same basic molecular structure of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate compounds having a stereoisomeric excess of at least 80% (i.e. at least 80% of one isomer and a maximum of 20% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and no other), more specifically, to compounds or intermediate compounds, they shall provide stereoisomeric excess of 90% to 100%, more specifically, having a stereoisomeric excess of from 94% to 100%, and most specifically, having a stereoisomeric excess of from 97% to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood in the same way, but in this case related to the enantiomeric excess and diastereomeric excess, respectively, of the considered mixture.

Pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained according to methods known in this field. For example, the enantiomers can be divided from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, the enantiomers can be divided chromatographic methods using chiral stationary phases. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction proceeds in a stereospecific manner. Preferably, if you need a specific stereoisomer, the specified connection it is possible to synthesize stereospecific methods of getting. In such ways appropriate use enantiomerically pure source materials.

Diastereomeric the racemates of the compounds of the present invention m is should be divided into the individual diastereomers by standard methods. Suitable physical methods of separation, which can be used in an appropriate manner are, for example, selective crystallization and chromatography, such as column chromatography.

The compounds can contain one or more asymmetric centers and therefore may exist in different stereoisomeric forms. The absolute configuration of each asymmetric center, which can be present in the compounds, you can specify stereochemical designations R and S, and these designations R and S correspond to the rules described in Pure Appl. Chem. 1976, 45, 11-30.

It is also understood that the present invention includes all isotopes of atoms present in these compounds. Isotopes are atoms, which are atoms with the same atomic number but different mass number. As a General example, but without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Have in mind that whenever used in the present description, the terms "real connection", "connection of the present invention", "compounds of formula (I)" or similar terms include compounds of formula (I), their N-oxides, their stereoisomeric forms, their salts or any of their sub-group.

Interest compounds are compounds form the s (I) or any subgroup, where and are zero, 1 or 2, more specifically, where a is zero or 1.

Other interest compounds are the compounds of formula (I) or any subgroup, where R1represents hydrogen, C1-6alkyl, C2-6alkenyl,2-6quinil,3-7cycloalkyl, Het, aryl or1-6alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - and disubstituted amino, where the amino substituents each separately selected from C1-6the alkyl or C3-7cycloalkyl, especially compounds, where R1represents a C1-6alkyl, C3-7cycloalkyl, Het, aryl or1-6alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl and mono - and disubstituted amino, where the amino substituents each separately selected from C1-6the alkyl.

Other interest compounds are the compounds of formula (I) or any subgroup, where R2represents hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil,3-12cycloalkyl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - and disubstituted amino, where the substituents of the amino group, each is Telenesti, selected from C1-6of alkyl; especially compounds, where R2represents hydrogen, C1-6alkyl, C2-6alkenyl or1-6alkyl, substituted Deputy selected from the group consisting of arrow.

Other interest compounds are the compounds of formula (I) or any subgroup, where R1and R2taken together with the nitrogen atom to which they are attached, form a 5-12 membered saturated or partially saturated a heterocycle, where the heterocycle may be optionally substituted C1-6the alkyl, C2-6alkenyl,2-6the quinil,3-7cycloalkyl,1-6allyloxycarbonyl, Het, aryl or1-6by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each separately selected from C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, Het and aryl; in particular compounds, where R1and R2taken together with the nitrogen atom to which they are attached, form a 5-12 membered saturated or partially saturated a heterocycle, where the heterocycle may be optionally substituted C1-6the alkyl, C1-6allyloxycarbonyl or1-6the alkyl substituted by aryl; more specifically compounds, where R1and R2that is Satya together with the nitrogen atom, to which they are attached, form a heterocycle selected from the group consisting of piperazinil, homopiperazine, piperidine, homopiperazine, morpholine, thiomorpholine, pyrrolidine, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, where the heterocycle may be optionally substituted C1-6the alkyl, C2-6alkenyl,2-6the quinil,3-7cycloalkyl,1-6allyloxycarbonyl, Het, aryl or1-6by alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cycloalkyl, amino and mono - or disubstituted amino, where the amino substituents each separately selected from C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, Het and aryl; and even more specifically, the compounds where R1and R2taken together with the nitrogen atom to which they are attached, form a heterocycle selected from the group consisting of piperazinil, homopiperazine, piperidine, homopiperazine, morpholine, thiomorpholine, pyrrolidine, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, where the heterocycle may be optionally substituted C1-6the alkyl, C1-6allyloxycarbonyl or1-6the alkyl substituted by aryl.

Other interest compounds are the compounds of formula I or any subgroup, where R3is carboxyl, halogen, nitro, C1-6alkyl, C3-7cycloalkyl, polyhalogen1-4alkyl, cyano, amino, mono - or disubstituted by an amino group, aminocarbonyl, mono - or disubstituted aminocarbonyl,1-6alkyloxy,1-6alkylthio,1-6alkylsulfonyl, pyrrolidinyl, piperidinyl, homopiperazine, morpholine, thiomorpholine or piperazinil, optionally substituted C1-6the alkyl, where the substituents of any of the amino groups, individually, is selected from C1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, Het and aryl; in particular compounds, where R3represents halogen, nitro, C1-6alkyl, C3-7cycloalkyl, polyhalogen1-4alkyl, cyano, C1-6alkyloxy,1-6alkylthio,1-6alkylsulfonyl, piperidinyl, morpholinyl.

Other interest compounds are the compounds of formula (I) or any subgroup, where aryl represents phenyl, optionally substituted by one or more substituents selected from the group consisting of C1-6of alkyl, polyhalogen1-6of alkyl, C1-6alkyloxy,1-6alkylthio,1-6alkylsulfonyl, nitro, cyano, halogen, C3-7cycloalkyl,1-6alkylcarboxylic, carboxyl,1-6allyloxycarbonyl, amino group, mono - or disa is protected amino group, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl,1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-6by alkyl; in particular compounds, where aryl represents phenyl, optionally substituted one, two or three substituents selected from the group consisting of C1-6of alkyl, C1-6alkyloxy, nitro, cyano, halogen, amino, mono - or disubstituted amino, where the substituents of any of the amino groups, individually, is selected from C1-6the alkyl.

Other interest compounds are the compounds of formula (I) or any subgroup, where Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, which are each individually selected from nitrogen atom, oxygen or sulfur, and which heterocycle may be optionally substituted with one or where possible, more than one Deputy, selected from the group consisting of C1-6of alkyl, polyhalogen1-6of alkyl, C1-6alkyloxy,1-6alkylthio,1-6alkylsulfonyl, nitro, cyano, halogen, C3-7 cycloalkyl,1-6alkylcarboxylic, carboxyl,1-6allyloxycarbonyl, an amino group mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl,1-6of alkyl, C2-6alkenyl,3-12cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-6by alkyl; in particular compounds, where Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, which are each individually selected from nitrogen atom, oxygen or sulfur, and which heterocycle may be optionally substituted C1-6by alkyl; more specifically compounds, where Het represents a heterocycle selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, teinila, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, imidazolyl, tetrahydropyranyl, tetrahydrofuryl, imidazoline, DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, homopiperazine, DIOXOLANYL, morpholinyl, thiomorpholine, where the heterocycle may be optionally substituted by one or, to the GDS may more than one Deputy, selected from the group consisting of C1-6of alkyl, polyhalogen1-6of alkyl, C1-6alkyloxy,1-6alkylthio,1-6alkylsulfonyl, nitro, cyano, halogen, C3-7cycloalkyl,1-6alkylcarboxylic, carboxyl,1-6allyloxycarbonyl, an amino group mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl,1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-6by alkyl; even more specifically, compounds, where Het represents a heterocycle selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, pyrrolyl, furanyl, teinila, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, imidazolyl, tetrahydropyranyl, tetrahydrofuryl, imidazoline, DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, homopiperazine, DIOXOLANYL, morpholinyl, thiomorpholine, where the heterocycle may be optionally substituted C1-6the alkyl.

The following interest compounds are the compounds of formula (I) or any subgroup, where Het represents the t of a heterocycle, selected from the group consisting of pyridinyl, furanyl, teinila, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, where the heterocycle may be optionally substituted with one or where possible, more than one Deputy, selected from the group consisting of C1-6of alkyl, polyhalogen1-6of alkyl, C1-6alkyloxy,1-6alkylthio,1-6alkylsulfonyl, nitro, cyano, halogen, C3-7cycloalkyl,1-6alkylcarboxylic, carboxyl,1-6allyloxycarbonyl, an amino group mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, where the substituents of any of the amino groups, each individually selected from phenyl,1-6of alkyl, C2-6alkenyl,3-7cycloalkyl, pyrrolidinyl, piperidinyl, homopiperazine or piperazinil, optionally substituted C1-6by alkyl; in particular compounds, where Het represents a heterocycle selected from the group consisting of pyridinyl, furanyl, teinila, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, where the heterocycle may be optionally substituted C1-6the alkyl.

Suitable subgroups of compounds are the compounds of formula (I)corresponding to one or more of the following conditions:

(a) (a is zero or 1;

b) R1represents a C1-10alkyl, C3-12cyclea the keel, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl;

(C) R2represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted aryl;

d) R1and R2taken together with the nitrogen atom to which they are attached, form a 5-12 membered saturated or partially saturated a heterocycle, where the heterocycle may be optionally substituted C1-10the alkyl, C1-6allyloxycarbonyl or1-10the alkyl substituted by aryl;

e) L is a1-2alcander;

f) R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalogen1-10alkyl, cyano, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl;

(g) aryl represents phenyl, optionally substituted by one or more substituents selected from the group consisting of C1-10alkyloxy, halogen, mono - or disubstituted amino, where the substituents of any of the amino groups, individually, is selected from C1-10of alkyl;

h) Het represents a 5 - or 6-membered aromatic, saturated or partially saturated with the first, monocyclic or bicyclic a heterocycle with one or more heteroatoms, which are each individually selected from nitrogen atom, oxygen or sulfur, and which heterocycle may be optionally substituted C1-10the alkyl.

Specific compounds are compounds of formula (I) or a subset, such as interest compounds, above, part of the-C(=O)-NR1R2is paraprotein phenyl ring, which is linked to position 2 of the structure 1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene (also referred to as structure 1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazine), as shown in the following figure the compound of formula (Ia)

Other specific compounds are compounds of formula (I) or any subgroup, such as interest compounds, mentioned above, where a is zero or 1 and R represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalogen1-10alkyl, cyano, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl.

Other specific compounds are compounds of formula (I) or (Ia) or any subgroup, such as interest compounds, mentioned above, where R1represents a C1-10alkyl, C3-12qi is loukil, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl; R2represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted aryl; or R1and R2taken together with the nitrogen atom to which they are attached, form a 5-12 membered saturated or partially saturated a heterocycle, where the heterocycle may be optionally substituted C1-10the alkyl, C1-6allyloxycarbonyl or1-10the alkyl substituted by aryl.

The preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interest and specific compounds listed above, where

and zero or 1;

R1represents a C1-10alkyl, C3-12cycloalkyl, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl;

R2represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted aryl; or

R1and R2in atie together with the nitrogen atom, to which they are attached, form a 5-12 membered saturated or partially saturated a heterocycle, where the heterocycle may be optionally substituted C1-10the alkyl, C1-6allyloxycarbonyl or1-10the alkyl substituted by aryl;

R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalogen1-10alkyl, cyano, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl.

Other preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interest and specific compounds listed above, where

and zero or 1;

R1represents a C1-10alkyl, C3-12cycloalkyl, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and mono - or disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl;

R2represents hydrogen, C1-10alkyl, C2-10alkenyl or1-10alkyl, substituted aryl; or

R1and R2taken together with the nitrogen atom to which they are attached, form a 5-12 membered saturated or partially saturated a heterocycle, where the heterocycle may be optionally Zam is converted With 1-10the alkyl, C1-6allyloxycarbonyl or1-10the alkyl substituted by aryl;

R3represents halogen, nitro, C1-10alkyl, C3-12cycloalkyl, polyhalogen1-10alkyl, cyano, C1-10alkyloxy,1-10alkylthio,1-10alkylsulfonyl, piperidinyl, morpholinyl;

aryl represents phenyl, optionally substituted by one or more substituents selected from the group consisting of C1-10alkyloxy, halogen, mono - or disubstituted amino, where the substituents of any of the amino groups, individually, is selected from C1-10of alkyl;

h) Het represents a 5 - or 6-membered aromatic, saturated or partially saturated, monocyclic or bicyclic a heterocycle with one or more heteroatoms, which are each individually selected from nitrogen atom, oxygen or sulfur, and which heterocycle may be optionally substituted C1-10the alkyl.

More preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interest and specific compounds listed above, where

and zero or 1;

R1represents a C1-6alkyl, C3-7cycloalkyl, Het, aryl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-7cyclea the Qila and mono - or disubstituted amino, where the substituents of the amino group, individually selected from C1-10of alkyl;

R2represents hydrogen, C1-6alkyl, C2-6alkenyl or1-6alkyl, substituted Deputy selected from the group consisting of arrow; or

R1and R2taken together with the nitrogen atom to which they are attached, form a heterocycle selected from the group consisting of piperazinil, homopiperazine, piperidine, homopiperazine, morpholine, thiomorpholine, pyrrolidine, indoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, where the heterocycle may be optionally substituted C1-6the alkyl, C1-6allyloxycarbonyl or1-6the alkyl substituted by aryl;

R3represents halogen, nitro, C1-6alkyl, C3-7cycloalkyl, polyhalogen1-4alkyl, cyano, C1-4alkyloxy,1-6alkylthio,1-6alkylsulfonyl, piperidinyl, morpholinyl;

aryl represents phenyl, optionally substituted one, two or three substituents selected from the group consisting of C1-6of alkyl, C1-6alkyloxy, nitro, cyano, halogen, amino, mono - or disubstituted amino, where the substituents of any of the amino groups, individually, is selected from C1-6of alkyl;

Het represents a heterocycle selected from the group comprised the soup from pyridinyl, furanyl, teinila, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, where the heterocycle may be optionally substituted C1-6the alkyl.

Other more preferred compounds are the compounds of formula (I) or (Ia) or any subgroup, such as interest, specific and preferred compounds mentioned above, where R2represents hydrogen and R3represents cyano.

Other more preferred compounds are the compounds of formula (I) or any subgroup, such as interest, specific and preferred compounds mentioned above, where a is 1 and R3represents halogen, cyano, C1-4alkyl, C1-4alkylthio, morpholinyl,1-4alkyloxy, nitro, C1-4alkylsulfonyl, trifluoromethyl.

The most preferred compounds include

4-[2-(4-diethylaminomethyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;

4-{2-[4-(benzylamino)phenyl]-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl}benzonitrile;

4-[2-(4-{[(pyridine-4-ylmethyl)amino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;

4-[2-(4-{[(4-methoxybenzyl)methylamino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;

(4-tert-butyle who yl)-[2-(4-{[(4-methoxybenzyl)methylamino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;

(4-tert-butylphenyl)-[2-(4-{[(pyridine-4-ylmethyl)amino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;

(4-tert-butylphenyl)-[2-(4-diethylaminomethyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;

4-{2-[4-(2-diethylaminoethyl)phenyl]-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl}benzonitrile;

4-(2-{4-[(cyclopentylmethyl)methyl]phenyl}-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;

4-(2-{4-[4-(4-methoxybenzylamine)butyl]phenyl}-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl)benzonitrile;

(4-methanesulfonyl)-[2-(4-{[(pyridine-4-ylmethyl)amino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;

(4-methanesulfonyl)-[2-(4-{[(4-methoxybenzyl)methylamino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;

[2-(4-diethylaminomethyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]-(4-methanesulfonyl)metano

and their N-oxides, stereoisomeric forms and salts.

Due to the fact that the compounds of formula (I) are inhibitors of HIV replication, the compounds of formula (I) are intended for the treatment of warm-blooded animals, especially humans, infected with HIV. Conditions associated with HIV, which can be prevented or treated by the compounds of the present invention, include With the ID, AIDS-associated complex (ARC), progressive generalized lymphadenopathy (PGL), and chronic CNS diseases caused by retroviruses, such as, for example, mediated HIV dementia and multiple sclerosis.

Compounds of the present invention can therefore be used as medicines. Compounds of the present invention can be applied in the manufacture of a medicinal product intended for the treatment of conditions associated with HIV infection.

Compounds of the present invention can also be applied against the above state, or in a method of treatment of such conditions. This method of treatment comprises the systemic introduction of an effective therapeutic amount of the compounds of formula (I) HIV-infected warm-blooded animal, especially for HIV-infected people.

In one embodiment, the invention relates to the use of compounds of the present invention in the manufacture of drugs to prevent HIV transmission or infection by HIV or associated with HIV disease of warm-blooded animals, especially humans, and especially transmission or infection through unprotected sex or close contact between partners. Thus, the invention relates also to a method of preventing HIV transmission or HIV infection or related the data with HIV disease, involving the introduction of a warm-blooded animal, especially man, is effective to prevent a number of the compounds of formula (I), especially for preventing the transmission of or infection through unprotected sex or close contact between partners.

The favorable properties of these compounds in relation to their ability to inhibit viral replication of HIV can be demonstrated by analysis of virus replication, which directly measures the continuous replication of the HIV virus wild type in MT4 cells through specific interaction of HIV tat with LTR sequences associated with GFR (MT4-LTR-EGFP cells). Using the above analysis steps against viral replication was found that these compounds inhibit the replication panel resistant to reverse transcriptase of the virus resistant to protease viruses or resistant to a combination of reverse transcriptase and protease viruses (so-called resistant to many drugs of viruses).

These compounds were tested in the experiment by adding time. Experiments by adding time show at what point of time the test compound inhibits viral replication in the cellular environment. In particular, compound nastojasih the invention was added at different time intervals to HIV-1 MT4 cells expressing the reporter gene of HIV-1 LTR-luciferase (MT4-LTR-Luc), or MT4 cells expressing the reporter gene of HIV-1-LTR-EGFP (MT4-LTR-EGFP). The first time point of addition of the test compounds were 30 minutes after synchronization of the virus.

These compounds were also experienced in the analysis of the introduction of the reporter (ERA), which measures the inhibition of fusion cells between cell line, stably expressing HIV (line cells-effector) and the cell line expressing CD4 and CXCR4 (line target cells)with LTR-EGFP, using data read FACS.

Analysis of toxicity, in which reduced expression of protein-GFP reporter (MT4-CMV-EGFP cells) serves as a marker for cellular toxicity of the test compounds, can be used to measure the toxicity of these compounds.

In General, the compounds of the present invention can be obtained by a sequence of synthesis shown in scheme 1.

Scheme 1

In scheme 1, intermediate compounds of formula 1.1 can be condensed with salicylic aldehyde of formula 1.2, in the presence of a suitable base, such as a mineral base such as potassium hydroxide or sodium hydroxide, in a suitable solvent system, such as, for example, a mixture of alcohol and water, for example, a mixture of ethanol and in the s. Alternatively, it is possible to use an organic base, such as pyrrolidine, in a suitable solvent, such as tetrahydrofuran or dichloromethane. Have in mind that the symbol ”PG” in the intermediate connection 1.2 denoted by a protective group for hydroxyl group, such as, for example, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl or methoxyethoxymethyl (MEM). Below, in figure 3, it is shown how the reaction obtain the intermediate compounds of formula 1.2, where the protecting group is a MEME. The resulting intermediate compound above the condensation reaction scheme 1 is Halcon formula 1.3 (also described in J. Med. Chem, 2000, 43, 4868-4876). Sheltered chalcone formula 1.3, you can remove the protection in acidic medium, for example, using hydrochloric acid in a suitable solvent, such as, for example, tetrahydrofuran, dichloromethane or alcohol, obtaining thus the intermediate compounds of formula 1.4. The intermediate connection 1.4 can then be subjected to interaction with hydrazine in a suitable, mixed with water, a solvent such as, for example, dioxane, toluene or alcohol, similar to alcohol, with getting dihydropyrazolo formula 1.5 (J. Ind. Chem. Soc., 1989, 66, 893-896). The compound of formula 1.7 can then be obtained by combining dihydropyrazolo formula 1.5 with a suitable glyoxal forms the 1.6 crystals in a suitable solvent, such as toluene or dioxane, and in the presence of catalytic amount of acid, such as paratoluenesulfonyl acid. The intermediate connection 1.7 it is possible to oxidize the reagent dess-Martin or another oxidizer, known in the field of chemistry, such as conditions Swarna, in a suitable solvent such as dichloromethane or hexane, to obtain the aldehyde 1.8. The required amines 1.9 can then be obtained by reductive amination of the aldehyde 1.8 using triacetoxyborohydride sodium or cyanoborohydride sodium in a suitable solvent, such as dichloromethane, dichloroethane or tetrahydrofuran (THF).

Scheme 2

In scheme 2, the compound of formula a, which is used as the starting material in scheme 1, can be obtained from commercially available acetilsalicilico using a reducing agent such as triacetoxyborohydride sodium in a suitable solvent, such as dichloroethane.

In addition, in scheme 2, the compound of formula 1.1.b can be obtained by acylation of the Friedel-Crafts acetate a using a reagent, a Lewis acid such as aluminum chloride or tribromide boron, in a suitable solvent, such as dichloromethane, simple ether or hexane, followed by hydrolysis of ester 2.3 obtaining demand is about connection 1.1.b.

Scheme 3

The intermediate compounds of formula a with the MEME as a protective group may be carried out by the interaction of salicylic aldehyde 3.1, which is commercially available, with harmacokinetics in the presence of a base such as sodium hydride or potassium hydride, in the presence of a suitable solvent like N,N-dimethylformamide or tetrahydrofuran.

Scheme 4

Getting glyoxal of the formula 1.6 can be made based on the intermediate compounds of formula 4.1, the method described in J. Het. Chem. 1987, 24, 441-451, or equivalent means. More specifically, acetyl compound of formula 4.1 can oxidize with getting glyoxal of the formula 1.6 in a solvent such as dioxane, using selenium oxide as the oxidizing agent.

When the receipts described above, the reaction products can be isolated from the reaction medium and, if necessary, then clean according to methods generally known in this field, such as, for example, extraction, crystallization, distillation, trituration and chromatography.

The compounds of formula (I)obtained by the methods described above can be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be from the elite from each other by known in this field separation methods. Racemic compounds of the formula (I) can be converted into the appropriate form diastereomeric salts by interaction with a suitable chiral acid. These form the diastereomeric salts are then separated, for example, selective or fractional crystallization, and the enantiomers separated from them by alkali. An alternative method of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction proceeds in a stereospecific manner. Preferably, if you want a specific stereoisomer, the specified connection it is possible to synthesize stereospecific methods of getting. In these ways are appropriate to use enantiomerically pure starting compound.

Compounds of the present invention can therefore be used as pharmaceuticals per se, in mixtures with one another or in the form of pharmaceutical preparations for animals, preferably to mammals, and particularly humans.

In addition, the present invention relates to pharmaceutical preparations which as active components contain eff is active dose of at least one of the compounds of formula (I) in addition to customary pharmaceutically innocuous excipients and auxiliary agents. The pharmaceutical preparations normally contain 0.1 to 90 wt.% such connection. The pharmaceutical preparations can be produced by a method known per se to the person skilled in the art. For this purpose, at least one compound of the present invention, together with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if necessary, in combination with other pharmaceutically active compounds, in turn suitable for administration form or dosage form which can then be used as pharmaceutical agents in human or veterinary medicine.

Pharmaceuticals which contain a compound according to the invention, can be administered orally, parenterally, for example intravenously, rectally, by inhalation or topically, preferably the introduction depends on the individual case, for example, a particular flow being treated with disease. It is preferable to oral administration.

The specialist in this area known excipients, which are suitable for the desired pharmaceutical preparation. Addition of suitable solvents are also gelling agents, suppositories, excipients to obtain tablets and other media for connections, antioxi the antes, dispersing agents, emulsifiers, protivovspenivayushchie tools, corrigentov, preservatives, soljubilizatory, the agents to achieve a depot, buffer substances or dyes.

Compounds of the present invention may also find application in the inhibition of ex vivo samples containing HIV, or samples, which were exposed to HIV. Therefore, these compounds can be used for inhibition of HIV present in the sample of body fluid, which contains or is assumed to contain or have been exposed to HIV.

In addition, as a medicinal product can be used in combination antiretroviral compounds and compounds of the present invention. Thus, the present also relates to a product containing (a) compound of the present invention and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections. So, to combat HIV infections or treatment of HIV infections or infection and disease associated with HIV infections, such as acquired immunodeficiency syndrome (AIDS) or AIDS-associated complex (ARC), the compounds of this invention can jointly enter into a combination, for example, inhibitors of the binding such as for example, dextran sulfate, suramin, polyanion, soluble CD4, binder gp120, such as BMS378806, connections against CD4 Ab, such as PRO-542 or TNX-355; inhibitors of the merger, such as, for example, T20, T, inhibitors of the binding of coreceptor, such as, for example, AK-602, SCH-C, SCH-D, AMD 3100 (Bellamy), AMD-070, TAK 779, TAK 220, UK-427-857, PRO-140; RT inhibitors, such as, for example, foscarnet and prodrugs; nucleoside RTI, such as, for example, AZT, 3TC, DDC, DDI, D4T, abacavir, FTC, FTC, DAPD, the dOTC; nucleotides RTI, such as, for example, RMEA, RMR, tenofovir; NNRTIS, such as nevirapine, delavirdine, efavirenz, teveren, lowered, etravirine, dapivirine, rilpivirine, TMS, TMS, MKC-442, UC 781, capravirine, DPC 961, DPC963, DPC082, DPC083, calanolide A, SJ-3366, TSAO, 4”-diaminononane TSAO; inhibitors of RNase H, such as, for example, SP1093V, PD126338; TAT inhibitors, such as, for example, RO-5-3335, K12, K37; integrase inhibitors, such as, for example, L 708906, L 731988; protease inhibitors, such as, for example, darunavir, APV, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir, latinovic, ATV, BMS 186316, DPC 681, DPC 684, tipranavir, AG1776, DMP 450, L 756425, PD178390, PNU 140135; inhibitors glycosylation, such as, for example, castanospermine, deoxynojirimycin.

Particularly of interest are the products, including (i) a compound of formula (I) and (ii) darunavir and amplifier, so the AK ritonavir, as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

Particularly of interest are the products, including (i) a compound of formula (I) and (ii) etravirine, as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

Particularly of interest are the products, including (i) a compound of formula (I) and (ii) dapivirine, as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

Particularly of interest are the products, including (i) a compound of formula (I) and (ii) rilpivirine, as a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections.

Compounds of the present invention can also type in combination with immunomodulators (e.g., bropirimine, an antibody against alpha-interferon in human, IL-2, mentionedearlier, interferon-alpha and naltrexone) or antibiotics (for example, pentanedinitrile) to reduce the intensity of symptoms, infection control HIV or eliminate HIV infection and its symptoms.

To obtain forms for the pen is the real introduction of the compounds of the present invention is mixed with suitable additives, such as excipients, stabilizers or inert diluents, and the mixture is transformed using conventional methods suitable for such administration forms such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert carriers are Arabian gum, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the drug can be manufactured in the form of dry or moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcohol solutions are water, ethanol, solutions of sugars or mixtures thereof. The glycols and polypropylenglycol are also suitable as additional auxiliary substances for other forms for injection.

For subcutaneous or intravenous administration, the active compounds, if necessary, enter into solution, suspension or emulsion with the substances suitable for this, such as solubilization, emulsifiers or further auxiliaries. Connections can also be liofilizovane, and received lyophilizate can be applied, for example, to obtain drugs for inye the tion or infusion. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerin, in addition also the solutions of sugars such as glucose or mannitol, or, alternatively, a mixture of these solvents.

Suitable pharmaceutical preparations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds or their physiologically-tolerated salts in a pharmaceutically acceptable solvent such as ethanol or water, or mixtures of such solvents. If necessary, the product may additionally contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as the propellant. This product usually contains the active compound in concentrations of from about 0.1 to 50%, especially from about 0.3 to 3 wt.%.

To improve the solubility and/or stability of the compounds in pharmaceutical preparations can appropriately be used α-, β - or γ-cyclodextrins or their derivatives. In addition, the solubility and/or stability of the compounds in pharmaceutical compositions can improve co-solvents, such as alcohols. When receiving water compositions additive salts of the considered compounds is not omnino are more suitable due to their high solubility in water.

Appropriate cyclodextrins are α-, β - or γ-cyclodextrins (CDS) or ethers and mixed ethers, where one or more of the hydroxy groups of links anhydroglucose cyclodextrin substituted by alkyl, especially, stands, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyethyl, particularly carboxymethyl or carboxyethyl; alkylsulphonyl, especially acetyl; allyloxycarbonyl or carboxylicacid, especially carboxyphenoxypropane or carboxitherapy; alkylcarboxylic, especially 2-acetyloxybenzoic. Particularly noteworthy as complexing agents and/or solubilization are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy)propyl-β-CD, and especially, 2-hydroxypropyl-β-CD (2-HP-β-CD).

The term "simple mixed ether" means derivative of cyclodextrin, where at least two of the hydroxy-group of the cyclodextrin converted into ethers with different groups, such as, for example, hydroxypropyl and hydroxyethyl.

Of interest, the method of manufacture of these compounds in combination with cyclodextrin or its derivatives described in EP-A-721331. Although it describes the pre is Arata contain active antifungal ingredients, they are equally of interest for the manufacture of preparations of the compounds of the present invention. Described in the mentioned patent drugs are particularly suitable for oral administration and include antifungal agent as an active ingredient, a sufficient amount of cyclodextrin or its derivative as a solubilizer, the aqueous acidic medium as a bulk liquid carrier and an alcoholic co-solvent, which significantly simplifies the manufacture of the composition. These drugs can also be made more palatable by the addition of pharmaceutically acceptable sweeteners and/or corrigentov.

Other conventional methods of increasing the solubility of the compounds of the present invention in the pharmaceutical compositions described in WO 94/05263, PCT application number PCT/EP 98/01773, EP-A-499299, WO 97/44014 and WO 01/22938, all of which are included in this description by reference.

More specifically, these compounds can be manufactured in the form of pharmaceutical compositions containing a therapeutically effective amount of particles consisting of a solid dispersion comprising (a) compound of the present invention and (b) one or more pharmaceutically acceptable water-soluble polymers.

The term "solid dispersion" refers to a system in the solid state (in protivopolojnosti liquid or gaseous state), comprising at least two components, where one component is dispersed more or less evenly throughout the other component or components. When the specified variance of the components is such that the system is chemically and physically uniform or homogenous throughout the dispersion or consists of one phase, as defined in thermodynamics, such a solid dispersion is called a "solid solution". Solid solutions are preferred physical systems because the components are readily bioavailable to the organisms in which they are administered.

The term "solid dispersion" also includes dispersion, which are less homogeneous over the entire dispersion than solid solutions. Such dispersions are not chemically and physically homogeneous throughout the dispersion or include more than one phase.

A water-soluble polymer in the particles is suitable polymer that has an apparent viscosity of 1-100 MPa, when dissolved in 2% aqueous solution at 20°C.

Preferred water-soluble polymers are hydroxypropylmethylcellulose or a receiver array. A receiver array having a degree of substitution of methoxy from about 0.8 to about 2.5 molar substitution of hydroxypropyl from approximately 0.05 to approximately 3.0, are usually water-soluble. The degree of substitution of methoxy refers to the average number presets the existing groups simple methyl ester on the link anhydroglucose molecules of cellulose. The molar substitution of hydroxypropyl refers to the average number of moles of propylene oxide, which react with each link in anhydroglucose molecules of cellulose.

Particles, which are defined above, can be obtained first by preparing solid dispersion components, and then optionally grinding or by grinding the obtained dispersion. There are various ways to obtain a solid dispersion comprising a melt extrusion, spray drying and evaporation of the solution.

Further suitable may be the manufacture of these compounds in the form of nanoparticles which have a surface modifier adsorbed on their surface in a quantity sufficient to maintain an effective average particle size of less than 1000 nm. It is believed that a suitable surface modifiers include modifiers, which physically adhere to the surface of antiretroviral agent, but not chemically associated with antiretroviral agent.

Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, oligomers, low molecular weight, natural products, and surfactants. Preferred surface modifiers include nonionic is anionic surfactant.

Another interesting way of manufacturing these compounds include a method of manufacturing a pharmaceutical composition in which the compounds of this invention include hydrophilic polymers and the resulting mixture is applied in the form of a film coating on a set of small granules, and thus, a composition with good bioavailability, which can suitably be manufactured and which is suitable for pharmaceutical dosage forms for oral administration.

These granules include (a) a Central, rounded or spherical core, (b) film-coating of a hydrophilic polymer and an antiretroviral agent and (C) hermetically covering polymer layer.

Substances suitable for use as a core granules are varied, provided that these substances are pharmaceutically acceptable and have suitable dimensions and stability. Examples of such substances are polymers, inorganic substances, organic substances and sugars and their derivatives.

Another aspect of the present invention relates to a collection or container containing the compound of the present invention in an amount effective for use as a standard or reagent in a test or analysis of DL which measure the ability of a potential pharmaceutical to inhibit the penetration of HIV the growth of HIV, or both. This aspect of the invention may find its application in pharmaceutical research programs.

The dose of these compounds or their physiologically-tolerated salts, which is injected depends on the individual case and, as usual, must be adapted to the individual case to achieve optimal actions. So, it depends of course on the frequency of administration and the effectiveness and duration of action of the compounds used in each case for therapy or prevention, but also on the nature and severity of the infection and symptoms and gender, age, weight and individual responsiveness subjected to the treatment of a human or animal, and on whether the management of acute or preventive. Usually a daily dose of a compound of the present invention in the case of the introduction of patient weighing approximately 75 kg is from 1 mg to 5 g, preferably from 10 mg to 2 g, more preferably from 20 mg to 1 g Dose can be administered in the form of a single dose or divided into several, for example two, three, four or even more single doses.

Experimental part

Example 1: synthesis of 4-[4-(4-cyanobenzoyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-2-yl]-N,N-diethylaniline a (compound 1)

Synthesis of 4-hydroxymethylbenzene a

To a solution of 4-acetyl is soldered (9 g, 61 mmol) in 1,2-dichloroethylene (1,2-DCE) (100 ml) was added NaHB(OAc)3or triacetoxyborohydride sodium (19.3 g, 90 mmol)and the reaction mixture is refluxed for 7 hours. The mixture is then poured on NH4Cl (saturated, aqueous) and extracted with CH2Cl2(3×50 ml). The combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrate. The product was then purified column chromatography (ethyl acetate/heptane=70/30), receiving 8,08 g of the product a (yield 89%).

The synthesis of compounds 2.3.a

To a solution of compound a (20 ml, 112 mmol) in CH2Cl2(1000 ml) add aluminofluoride (14.9 g, 112 mmol) and the mixture cooled to 0°C. and Then added dropwise a solution of acetylchloride (8 ml, 112 mmol) in CH2Cl2while maintaining the temperature below 0°C. Then add another equivalent of aluminum chloride and the mixture is stirred at 0°C for 1.5 hours. The mixture is then poured into a mixture of ice and water and add ~20 ml of concentrated HCl. The organic layer is separated, washed with saturated salt solution, dried (Na2SO4) and concentrate. The resulting oil is purified column chromatography (ethyl acetate/heptane=1/1)to give 12.1 g 2.3.b (yield 49%).

The synthesis of compounds 1.1.b

Connection 2.3.a (12.1 g, 55 mmol) dissolved in a mixture of THF/water (400 ml, 1/1) and add sodium hydroxide (2.3 g, 57 mmol). actionnow the mixture is stirred at room temperature for 6 hours. Then the THF layer was separated and the aqueous layer was extracted with Et2O, or diethyl ether (2×50 ml). The combined organic layers washed with saturated salt solution, dried (Na2SO4and concentrate, receiving 1.1.b in the form of a white solid (9.4 g, yield 96%).

Synthesis of 2-(2-methoxyethoxyethoxy)benzaldehyde 1.2

The intermediate connection 2.1 (20 mmol) dissolved in THF (150 ml). The resulting mixture is cooled to 0°C. Add sodium hydride (30 mmol), the mixture is stirred at room temperature for 1 hour and add harmacokinetics (20 ml). The mixture is stirred at room temperature for 16 hours. Add water (200 ml) and the mixture extracted with dichloromethane. The organic layer is separated, dried over MgSO4), filtered and the solvent is evaporated to dryness. The residue is filtered on silica gel using dichloromethane as eluent. The solvent is removed, receiving the connection a with the release of 95%.

Synthesis of 4-{3-[2-(2-methoxyethoxyethoxy)phenyl]acryloyl}benzyl alcohol a

To a solution of compounds a (8 g, 53 mmol) and a (11.2 g, 53 mmol) in ethanol (350 ml) is added KOH (5,94 g, 106 mmol) in N2O (5 ml). The reaction mixture was stirred at K.T. for 20 hours and then poured on NH4Cl (aqueous saturated) and extracted with ethyl acetate (EtOAc) (3×100 ml). The combined organic layers Ave is myauth saturated salt solution, dried (Na2SO4) and concentrate. The product was then purified column chromatography (ethyl acetate/heptane=1/1)to give 15.5 g of the product a (yield 85%, purity according to LC-MS 90%).

Synthesis of 4-[3-(2-hydroxyphenyl)acryloyl]benzyl alcohol, a

Connection a (15.5 g, 45 mmol) dissolved in THF (350 ml) and add 1M HCl (95 ml). The reaction mixture is refluxed for 20 hours, followed by evaporating the solvent. Then add CH2Cl2(50 ml) and the organic layer extracted twice 1M NaOH (100 ml). Merged layers NaOH

acidified using 1M HCl and the product precipitated from solution. The product is separated by filtration and dried in a vacuum oven, gaining 9.3 g of the product a (yield 81%).

Synthesis of 4-[5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazole-3-yl]benzyl alcohol a

Connection a (9.3 g, 37 mmol) is dissolved in ethanol (EtOH) (350 ml) and one portion add hydrazine (7,3 g, 146 mmol). The reaction mixture is stirred for 2 hours at room temperature. The product precipitated from solution, was separated by filtration and dried in a vacuum oven, obtaining 6.2 g of product a (yield 63%).

Synthesis of 4-(2-oxoacyl)benzonitrile a

To a solution of 4-cyanoazobenzene a (6 g, 41 mmol) in dioxane (250 ml) was added selenium dioxide (9,1 g, 82 mmol). The reaction mixture is refluxed for 20 hours is in, cooled to room temperature, filtered and concentrated. The residue is dissolved in CH2Cl2and the solution is again filtered. The solvent is evaporated and the residue purified column chromatography (ethyl acetate/heptane=1/1)to give 5.2 g of glyoxal a (yield 80%).

Synthesis of 4-[4-(4-cyanobenzoyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-2-yl]benzyl alcohol a

Connection a (5.5 g, 20 mmol) was placed in toluene (200 ml) and subjected to the action of ultrasound for 30 minutes. Then the solution is heated to 80°C and stirred at this temperature for 30 minutes. Then add paratoluenesulfonyl acid (0,19 g, 1 mmol). Further added dropwise a solution of glyoxal a (3.6 g, 23 mmol) in THF (20 ml) and the reaction mixture was stirred at 80°C for 1.5 hours. After this time the solvent is evaporated and the product purified column chromatography (CH2Cl2/Meon=99/1)to give 5.3 g of the product a (yield 63%). "Meon" refers to methanol.

Synthesis of 4-[4-(4-cyanobenzoyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-2-yl]benzaldehyde a

Connection a (2 g, 4.9 mmol) dissolved in CH2Cl2(60 ml) and the reaction mixture periodinane dess-Martin (14 ml, 15 wt.% in CH2Cl2, 6,83 mmol). The reaction mixture is stirred for 4 hours at room temperature. Then add the NaHCO 3(water saturated) and Na2S2O3(1 EQ.) and the mixture is vigorously stirred for 15 minutes. The organic layer is separated, washed with saturated salt solution, dried (Na2SO4) and concentrate. The product was then purified column chromatography (ethyl acetate/heptane=30/70)to give 1.22 g of product a (yield 61%).

Example 2:General methods of synthesis of compounds 1.9

To a solution of aldehyde 1.8 and the appropriate amine (1.1 EQ.) in CH2Cl2added NaHB(OAc)3(1,1-equivalent). The reaction mixture was stirred at room temperature overnight and then poured on NaHCO3(water saturated). The organic layer is separated and the aqueous layer was extracted 2 times, CH2Cl2. The combined organic layers washed with saturated salt solution, dried (Na2SO4) and concentrate. Products purified column chromatography using a mixture of CH2Cl2/Meon. The outputs comprise 20-70%.

The compounds listed in the table below, get methods similar to those described in examples 1 or 2.

Table 1

Example 3: virological properties of the compounds of this image is etenia

Compounds were tested in cell analysis using cells MT4-LTR-EGFP on antiviral activity. The analysis showed that these compounds exhibit strong anti-HIV activity against laboratory HIV strain (strain LAI HIV-1) and HIV-1 virus that are resistant to many drugs (HIV-1-MDR). Cell analysis was performed by the following method.

HIV-positive or false-infected cells MT4-LTR-EGFP were incubated for three days in the presence of various concentrations of inhibitor. After infection with GFP-reporter is activated by the viral tat protein. At the end of the incubation period was measured the GFP signal. In the virus control samples (in the absence of any inhibitor) received the maximum fluorescent signal. Monitoring inhibitory activity of compounds was performed on virus infected cells and was expressed as EU50EU90. These values represent the number of connections required to protect 50% and 90%, respectively, of cells from viral infection.

Table 2
Values RES50(defined as the negative logarithm of the result, expressed as the EU50for the tested compounds are shown below. For some compounds of this izaberete the Oia conducted more than one series of tests. In this case, to determine the activity of the class used the average Rees50.
No. of connectionsActivity class for testing for HIV-1-LAI (values RES50)Activity class for testing for HIV-1-MDR (values RES50)
17,72of 8.06
27,587,83
3to 6.887,08
46,416,25
56,226,5
67,137,28
76,55of 6.49
87,81the 7.85
97,287
10of 6.496,79
11of 7.64to 7.59
127,167,35
138,328,62
146,416,34
155,425,52
165,65,51
175,56lower than the 5.37
185,475,47
195,395,43
207,426,51
215,235,2
225,525,47
235,385,32
24is 4.93a 4.83
256,535,04
265,284,86
27are 5.365,15
287,497,63
29of 8.478,56
307,97,95
314,855,38
327,086,72
336,356,07
346,256,12
355,76of 5.81
367,457,18
376,12of 6.31

Example 4:the pharmaceutical composition

Capsules

The active ingredient, in case the compounds of formula (I), dissolved in an organic solvent, such as ethanol, methanol or methylene chloride, preferably a mixture of ethanol and methylene chloride. Polymers such as a copolymer of polyvinylpyrrolidone with vinyl acetate (PVP-VA) or hypromellose (receiver array), typically MPa, dissolved in organic solvents, such as ethanol, methanol, methylene chloride. Suitable polymer dissolved in ethanol. The polymer solutions and compounds are mixed and the mixture is then dried by spraying. The ratio of compound/polymer selected from 1/1 to 1/6. Intermediate ranges are from 1/1,5 to 1/3. A suitable ratio is 1/6. Dried spray powders, solid dispersion, then fill capsule for introduction. The drug load in one capsule in an amount of from 50 to 100 mg, depending on the size of the used capsules.

Film-coated tablets

Obtain core tablets

A mixture of 100 g of the active ingredient, in the case of the compounds of formula (I), 570 g lactose and 200 g starch mix well and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone approximately 200 ml of water. The wet mixture of powders sieved, dried, and sift again. Then the mixture was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All components are well-mixed and pre is put into a pill, getting 10,000 tablets, each contains 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then to the solution was added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The resulting solution is added to the first, then there is added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated suspension of the coloring matter and the whole mass is homogenized. Core tablets cover the thus obtained mixture in device for a covering.

1. The compound having the formula

its stereoisomeric form or salt,
where a is 1;
L represents a C1-4alcander;
R1represents a C1-10alkyl, C3-12cycloalkyl or1-10alkyl, substituted Deputy selected from the group consisting of Het, aryl, C3-12cycloalkyl and disubstituted amino, where the amino substituents each separately selected from C1-10of alkyl;
R2represents hydrogen, C1-10alkyl;
R3represents a C1-10alkyl, cyano or1-10alkylsulfonyl;
aryl represents phenyl, optionally substituted by one or several is likemy substituents, selected from the group consisting of C1-10alkyloxy and disubstituted amino group;
Het represents a heterocycle selected from pyridinyl and pyrrolidinyl.

2. The compound according to claim 1, which represents the
4-[2-(4-diethylaminomethyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;
4-{2-[4-(benzylamino)phenyl]-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl}benzonitrile;
4-[2-(4-{[(pyridine-4-ylmethyl)amino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;
4-[2-(4-{[(4-methoxybenzyl)methylamino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;
(4-tert-butylphenyl)-[2-(4-{[(4-methoxybenzyl)methylamino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;
(4-tert-butylphenyl)-[2-(4-{[(pyridine-4-ylmethyl)amino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;
(4-tert-butylphenyl)-[2-(4-diethylaminomethyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;
4-{2-[4-(2-diethylaminoethyl)phenyl]-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl}benzonitrile;
4-(2-{4-[(cyclopentylmethyl)methyl]phenyl}-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-carbonyl]benzonitrile;
4-(2-{4-[4-(4-methoxybenzylamine)butyl]phenyl}-1,9b-dihydro-5-oxa-3,3A-disallowment[a]n is Talin-4-carbonyl)benzonitrile;
(4-methanesulfonyl)-[2-(4-{[(pyridine-4-ylmethyl)amino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;
(4-methanesulfonyl)-[2-(4-{[(4-methoxybenzyl)methylamino]methyl}phenyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]metano;
[2-(4-diethylaminomethyl)-1,9b-dihydro-5-oxa-3,3A-disallowment[a]naphthalene-4-yl]-(4-methanesulfonyl)methanon
or its stereoisomeric form or salt.

3. The compound according to claim 1 or 2, intended for use as drugs having the ability to inhibit HIV replication.

4. The use of compounds according to claim 1 or 2 in the manufacture of a medicinal product intended for the treatment of conditions associated with HIV infection.

5. The use of compounds according to claim 1 or 2 in the manufacture of a medicinal product intended for preventing the transmission of HIV or prevent HIV infection or preventing disease associated with HIV infection.

6. The method of treatment, including systemic injection of a therapeutically effective amount of a compound according to claim 1 or 2 HIV-infected warm-blooded animal, especially for HIV-infected people.

7. Pharmaceutical drug that has the ability to inhibit the replication of HIV comprising as an active component an effective dose of a compound according to claim 1 Il is 2, and optionally containing conventional non-toxic pharmaceutical excipients and excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I and to their physiologically compatible salts. In general formula I , X denotes identical or different groups =C(-R)- or =N-, wherein at least one =C(-R-)- is substituted by =N-; Y is -O-; R denotes identical or different hydrogen, halogen, (C1-C6)-alkyl; R1 denoes (C4-C16-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl, (C9-C10)-bicyclic ring, wherein the aryl can be singly or multiply substituted with (C1-C6)-alkyl; R2 denotes hydrogen; or R1 and R2 together with the nitrogen atom which it is bonded form a monocyclic, saturated 6-member ring in which separate members of the ring system can be substituted with -CHR4-; R4 denotes (C1-C6)-alkyl. The invention also relates to a pharmaceutical composition having inhibiting action on endothelial lipase (EL) and containing one or more compounds of formula I, to use of the disclosed compounds to prepare a medicinal agent and to methods of producing compounds of formula I.

EFFECT: high effectiveness of derivatives.

11 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzoxazines

in which substitute R1 denotes a hydrocarbyl residue having 1-3000 carbon atoms, and substitutes R2, R3, R4 and R5 independently denote hydrogen atoms, hydroxyl groups or hydrocarbyl residues, having 1-3000 carbon atoms, respectively, and in which substitutes R3 and R4 or R4 and R5 with a partial structure -O-CH2-NR7-CH2-, bonded to the benzene ring, can also form a second tetrahydrooxazine ring, where R7 denotes hydrocarbyl residues having 1-3000 carbon atoms, provided that at least one of substitutes R1, R2, R3, R4, R5 or R7 are polyisobutenyl, having 3000 carbon atoms and the rest of the substitutes from the group R1, R2, R3, R4, R5 or R7, if they denote hydrocarbyl residues, have 1-20 carbon atoms, respectively, as anti-oxidants for stabilising mineral oil and fuel products against the effect of light, oxygen and heat. The invention also describes jet fuel and jet fuel additive concentrate containing tetrahydrobenzoxazine of formula (I).

EFFECT: preparation of stabilisers having improved stabilisation of nonliving organic material, particularly jet fuel against the effect of light, oxygen and heat.

9 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a compound of formula , where R1 is an alkyl or aryl group, or a pharmaceutically acceptable salt or solvate thereof, including hydrate, involving reaction of a compound of formula with a Grignard reagent of formula , where X is a halogen selected from Cl, Br and I, and R1 is an alkyl or aryl group; and optional conversion of the obtained free base compound of formula (I) to a pharmaceutically acceptable salt. The invention also relates to a compound of formula II; a compound of formula , where X is a halogen selected from O, Br and I and to use of formula II and IIIA compounds in synthesis of delmopinol and a derivative of the formula I compound.

EFFECT: novel method for synthesis of a compound of formula I using novel intermediate compounds of formulae II and IIIA.

18 cl, 11 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: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethanon of formula , possessing ability to inhibit HIV replication, where values of R1, R2, R3 substitutes are given in invention formula. Also describes is pharmaceutical preparation and application of compound for obtaining medication applied for treatment of conditions associated with HIV infection.

EFFECT: claimed compounds are applicable for prevention or treatment of HIV-produced infection and for AIDS treatment.

15 cl, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds described by a structural formula wherein: R1 is chosen from a group including R9-phenyl, and R2 is chosen from a group including H and (C1-C6)-alkyl; R3 is chosen from a group including (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl- and R9-(C6-C10)-aryl; R4, R5, R6 and R7 are independently chosen from a group including H and (C1-C6)-alkyl; R8 is chosen from a group including и ; R9 means 1, 2 or 3 substitutes independently chosen from a group, including H, halogen and -CF3; R10 is chosen from a group including H and (C1-C6)-alkyl; R11 is (C3-C10)-cycloalkyl-S (O2)-; R15 and R16 are independently (C1-C6)-alkyl; R17 is R20O-; R20 is chosen from a group including H, and (C1-C6)-alkyl-(C6-C10)-aryl; Q is N; Z is CH; n is equal to 0; s is equal to 2; and t is equal to 2. Also, the invention concerns a pharmaceutical composition exhibiting properties of a chemokine receptor inhibitor, based on these compounds.

EFFECT: produced are the new compounds and based pharmaceutical composition can find application in medicine for treating human immunodeficiency virus (HIV) infection.

8 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-substituted pyrimidines of general formula (I), their pharmaceutically acceptable additive salts probably in form of their stereochemically isomeric form. In general formula (I), A represents -CH2-CH2-, -CH=CH-; each of R1 independently represents hydrogen; R2 represents cyano; X1 represents -NR1-; R3 represents H, C1-6-alkyl, halogen; R4 represents H, C1-6-alkyl, halogen; R5 represents nitro, amino, mono- and di(C1-4-alkyl)amino, phenyl, probably substituted by halogen, halogen, -CO-H-, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8; R6 represents C1-4-alkyl, amino, mono- or di(C1-4-alkyl)amino or polyhalogen-C1-6-alkyl; R7represents hydrogen, C1-6-alkyl; R8 represents hydrogen, C1-6-alkyl. Invention also relates to pharmaceutical composition based on novel compounds.

EFFECT: elaborated are compounds which possess antiviral activity with respect to HIV infection.

7 cl, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses pharmaceutical composition for controlled release regarding toxic active compounds, in particular, bioactive proteins from class of interferons. Composition contains bio-degradable block-copolymer made of poly(ethyleneglycol)terephthalate (PEGT) in amount from 50 to 95%, and poly(butyleneterephthalate) (PBT). Agent may be represented as injection microparticles, injection liquid, capable of independent gel or solid implant formation. Besides, invention provides a pharmaceutical set, including specified composition, methods of composition making and pharmaceutical versions of its application.

EFFECT: invention provides for initial release within 4 hours of not more than approximately 10% of included amount of one or more alpha-interferons and at least 80% of one or more alpha-interferons are released in monomer non-aggregated form.

31 cl, 8 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: present invention refers to a spray drying production process of a solid pharmaceutical powder containing microcrystalline cellulose in a solid dispersion of the anti-HIV compound etravirine (TMC125) in a water-soluble polymer. In a parent mixture, the relation of the water-soluble polymer to TMC 125 makes 10:1 to 1:1, and of microcrystalline cellulose to TMC 125 - 1:1 to 1:3. Said parent mixture of microcrystalline cellulose, a solution of the water-soluble polymer and etravirine is sprayed in the form of drops into a drying chamber by atomisers to form a solid dispersion of TMC 125 powder.

EFFECT: better solubility and bioavailability of the antiviral compound etravirine.

10 cl, 9 dwg, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which have anti HIV-1 activity, of general formula (I) , where X stands for NH, as well as their pharmaceutically acceptable additive salt. Invention also relates to pharmaceutical composition, method of obtaining pharmaceutical composition and method of obtaining compound.

EFFECT: novel compounds possessing anti-HIV-1 activity.

5 cl, 7 dwg, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess properties inhibiting HIV replication, of general formula (I) , in form of E-isomer, in which -a1=a2-a3=a4- represents bivalent radical of formula -CH=CH-CH=CH- (a-1); -b1=b2-b3=b4. Represents bivalent radical of formula -CH=CH-CH=CH- (b-1); n equals 0; m equals 2; each of R1 radicals independently on each other stands for hydrogen atom; C1-6alkyl; R2a stands for cyanogroup; X1 stands for -NR1-; R3 represents C2-6alkenyl, substituted with cyanogroup; R4 stands for C1-6alkyl; R5 represents radical of formula -Y-Alk-L, -Alk'-Y-L or -Alk'-Y-Alk-L; each of radicals Alk or Alk' independently represents bivalent C1-6alkyl or C2-6 alkenyl group; L stands for aryl or Het; Y stands for NR1; -CH=N-O-; Het stands for 5- or 6-member fully saturated ring system, in which one, two or three ring elements represent heteroatoms, each of which is independently selected from group, including nitrogen, oxygen and sulphur, and in which other ring elements represent carbon atoms; and, if possible, any nitrogen ring element can be optionally substituted with C1-6alkyl; and ring system can be optionally bound with benzene ring; and in which any carbon atom of ring, including any carbon atom of optionally bound benzene ring, each independently can be substituted with substituent selected from such groups as halogen atom, C1-6alkyl, hydroxyC1-4alkyl, carboxyC1-4alkyl, C1-4 alkylcarbonyloxyC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, aryloxy, morpholinyl, aryl, Het1; Het1 stands for thienyl, isoxazolyl, thiadiazolyl, each of which can be optionally substituted with one or two C1-4alkyl radicals; Q stands for hydrogen atom; each aryl represents phenyl or phenyl, substituted with one, two substituents, each of which is independently selected from such groups as halogen atom, C1-6alkyl, C2-6alkinyl, cyano, polyhalogen C1-6alkyl or Het1, as well as to its pharmaceutically acceptable additive salts Invention also relates to pharmaceutical composition.

EFFECT: creation of novel compounds, which possess properties inhibiting HIV replication

5 cl, 7 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and medicine and concerns method of improvement of pharmakinetic characteristics of peroral medication, directly metabolised by UGT1A1, of formula (I), which includes peroral introduction to mammal, which needs drug treatment, of combination of medication, or its pharmaceutically acceptable salt, and atasanavir, or its pharmaceutically acceptable salt.

EFFECT: improvement of pharmakinetic characteristics of medication.

13 cl, 2 dwg, 14 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

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