1,5,6-substituted 2-oxo-3-cyano-1,6a-diazatetrahydrofluoranthenes

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , to their salts, where R1 and R2 each independently is hydrogen or C1-10alkyl which can be optionally substituted with substitutes selected from a group comprising a hydroxyl group, NR4R5, pyrrolidinyl, piperidinyl, morpholinyl; R3 is a radical of formula , where n equals 1; R3a is nitro; X is -NR7 - or -O-; R4 and R5 each independently is C1-6alkyl; R7 is hydrogen, C1-6alkyl, optionally substituted with pyrrolidinyl. The invention also pertains to use of the compounds, to a pharmaceutical composition, to a method of preparing the pharmaceutical composition, as well as to a method of obtaining the chemical compound in any of paragraphs 1-3.

EFFECT: obtaining new biologically active compounds with antiviral activity.

7 cl, 4 ex, 2 tbl

 

The present invention relates to substituted 2-oxo-3-cyano-1,6A-disasterresilient, their use as anti-infective funds and to pharmaceutical compositions containing these compounds.

Etiological agent of acquired immunodeficiency syndrome is the human immunodeficiency virus (HIV)identified two types, namely HIV-1 and HIV-2. Hereinafter in the description, the term HIV is used to refer to both of these types. Treatment of AIDS patients are currently carried out with the use of various drugs, such as inhibitors of reverse transcriptase (reverse transcriptase inhibitor - RTI) HIV inhibitors of HIV protease (protease inhibitor - PI) and inhibitors of introducing infection. There are several classes of RTI, namely nucleoside inhibitors of reverse transcriptase (nucleoside reverse transcriptase inhibitors - NRTIs)such as zidovudine, didanosine, salivation (zalcibatine), stavudine, abacavir and lamivudine, non-nucleoside reverse transcriptase inhibitors (non-nucleoside reverse transcriptase inhibitors - NNRTIS)such as nevirapine, delavirdine and efavirenz, and nucleotide reverse transcriptase inhibitors (nucleotide reverse transcriptase inhibitors-NtRTI), such as tenofovir.

HIV inhibitors are usually put in as part of combinations involving two or more compounds of the above classes of drugs Despite the wide use of the above antiviral drugs they have some drawbacks: that target enzymes in HIV-the virus is able to mutate in such a way that any of the known drug becomes less effective or even ineffective in respect of such mutant HIV viruses. In other words, HIV produces a constantly increasing resistance against any have today of medicines and the emergence of such resistance is the primary cause of insolvency therapeutic treatment.

In addition, it was shown that the resistant virus is transferred to the newly infected subjects, which leads to a significant limitation of variants of therapeutic agents for the treatment of such patients are not susceptible to the action of medicines. Moreover, the emergence of resistance forcing a doctor to prescribe higher doses and/or more frequent administration of a medicinal product to increase its content in the blood plasma and recovery efficiency. This leads to the development of so-called "medicinal aggravation" ("pill burden"), which is the main cause of non-compliance of the indicated course of treatment.

All members of the group RTI lead to increased occurrence of resistance, and are particularly sensitive to this phenomenon currently used NNRTIS due to mutations of the amino acid is t, surrounding the binding site NNRTIS. So today remains a need for new types of HIV inhibitors target site which is the reverse transcriptase of HIV and who are able to delay the emergence of resistance and is effective against a broad spectrum of mutants of HIV.

In the publications WO-02/055520 and WO-02/059123 describes derivatives benzoylcholine as antiviral compounds. In a number of publications Ryabova with co-authors (Ryabova et al.: Russian Chem. Bull. 2001, 50(8), 1449-1456; Chem. Heterocycl. Compd. (Engl. Translat.) 36; 3; 2000; 301-306; Khim. Geterotsikl. Soedin.; EN; 3; 2000; 362-367) describes the synthesis of some derivatives of benzoylcholine. In the publication WO-04/046143 describes some of substituted 1-phenyl-1,5-dihydropyrido[3,2-b]indol-2-ones as compounds with antiviral activity against HIV.

The present invention provides a new group of compounds that are structurally different from the compounds of the prior art and are active not only against wild-type HIV, but also against various mutants of HIV, including mutant viruses expressing resistance to the currently available inhibitors of HIV reverse transcriptase.

Thus, in accordance with one aspect of the present invention relates to substituted 2-oxo-3-cyano-1,6A-disasterresilient the am formula (I):

their salts and stereoisomeric forms;

where R1and R2each independently represents hydrogen or C1-10alkyl which may be optionally substituted by a Deputy selected from the group comprising hydroxyl group, cyano, NR4R5pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinyl, thiomorpholine, 1-Osotimehin, 1,1-dioxothiazolidine, aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolin, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxycarbonyl, C1-4alkylsulphonyl, (R4)(R5)N-carbonyl, C1-4allyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidine-1-ylcarbonyl, homopiperazin-1-ylcarbonyl, piperazine-1-ylcarbonyl, 4-(C1-4alkyl)piperazine-1-ylcarbonyl, morpholine-1-ylcarbonyl, thiomorpholine-1-ylcarbonyl, 1-Osotimehin-1-ylcarbonyl and 1,1-diocletianopolis-1-ylcarbonyl;

R3represents a radical of the formula

where n is 1, 2 or 3;

R3arepresents nitro, cyano, amino, halogen, hydroxyl group, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, C1-4allyloxycarbonyl, mono - or di(C 1-4alkyl)aminocarbonyl, C1-4alkylsulphonyl, methanimidamide, mono - or di(C1-4alkyl)methanimidamide, N-hydroxymaleimide or Het; or

R3represents a monocyclic or bicyclic aromatic heterocyclic ring system in which one, two, three or four atoms of the cycle are heteroatoms, each independently selected from nitrogen atoms, oxygen and sulfur, and the remaining atoms of the cycle are carbon atoms; and each of these heterocyclic ring systems optionally may be substituted by one, two, three, four, or five substituents, each of which is independently selected from halogen, cyano, nitro, C1-6of alkyl, hydroxys1-6of alkyl, C1-4alkoxyl1-6of alkyl, R5a)(R5b)N-C1-4of alkyl, polyhalogen1-6of alkyl, C3-7cycloalkyl, arils1-6of alkyl, formyl, C1-6alkylcarboxylic, radical-COOR6, (R5a)(R5b)N-carbonyl, (R5a)(R5b)N-sulfonyl, a hydroxyl group, a C1-6alkyloxy, arils1-6alkyloxy, polyhalogen-C1-6alkyloxy, formyloxy, C1-6alkylcarboxylic, aryloxy, radical (R5a)(R5b)N-, formylamino, C1-6alkylcarboxylic, C1-6allyloxycarbonyl, C1-6alkylsulfonamides, mercapto, C1-6Alki is thio, aaltio, arils1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylsulfonyl, aryl, -CH(=N-O-R5aand-C(=NH)-NH - R5a;

X represents-NR7-, -O - or-S-;

R4and R5each independently represents hydrogen, C1-6alkyl or C1-6alkyl, substituted Deputy selected from amino, mono - or di(C1-4alkyl)amino, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinyl, thiomorpholine, 1-oxathiolane and 1,1-dioxothiazolidine;

each R5a, R5bindependently represents hydrogen, C1-4alkyl or arils1-4alkyl;

R6represents hydrogen, C1-4alkyl or arils1-4alkyl;

R7represents hydrogen, C1-6alkyl, optionally substituted aryl, (R4)(R5)N-, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium, thiomorpholine, 1-OssetiaAlania or 1,1-dioxothiazolidine;

each aryl independently represents a phenyl, optionally substituted by 1, 2 or 3 substituents, each of which is independently selected from C1-6of alkyl, C1-4alkoxy, halogen, hydroxyl group, amino, trifloromethyl, cyano, nitro, hydroxys1-6of alkyl, tsianos1-6of alkyl, mono - and di(C 1-4alkyl)amino, amino1-4of alkyl, mono - or di(C1-4alkyl)amino1-4of alkyl;

Het represents a 5 - or 6-membered ring system in which one, two, three or four atoms in the ring are heteroatoms, each of which is individually and independently selected from nitrogen atoms, oxygen and sulfur, and the remaining atoms of the cycle are carbon atoms; and where any nitrogen atom in the ring may be optionally substituted C1-4by alkyl; and any carbon atom in the ring is optionally and independently may be substituted by the Deputy, is selected from C1-4of alkyl, C2-6alkenyl, C3-7cycloalkyl, a hydroxyl group, a C1-4alkoxy, halogen, amino, cyano, trifloromethyl, hydroxys1-4of alkyl, tsianos1-4of alkyl, mono - or di(C1-4alkyl)amino, amino1-4of alkyl, mono - or di(C1-4alkyl)amino1-4of alkyl, aryls1-4of alkyl, amino3-6alkenyl, mono - or di(C1-4alkyl)amino3-6alkenyl, furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C1-4allyloxycarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, C1-4alkylsulphonyl, oxo, and thio; where any of the above furanyl, Tien is La, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl may be optionally substituted C1-4the alkyl.

The term "C1-4alkyl"related to the group or part of a group, means a saturated hydrocarbon radicals with a straight or branched chain, containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 2-methylpropyl, etc. the Term "C1-6alkyl"related to the group or part of a group, means a saturated hydrocarbon radicals with a straight or branched chain, containing from 1 to 6 carbon atoms, such as, for example, the groups listed in the definition of C1-4of alkyl, and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl etc. of Particular interest among the C1-6Akilov are C1-4alkyl radicals. The term "C1-10alkyl"related to the group or part of a group, means a saturated hydrocarbon radicals with a straight or branched chain, containing from 1 to 10 carbon atoms, such as, for example, the groups listed in the definition of C1-6of alkyl, heptyl, octyl, nonyl, decyl, etc. of Particular interest among the C1-10Akilov are C1-6alkyl radicals.

The term "C2-6alkenyl"referring to a group or part of a group, means a hydrocarbon radicals with straight and razwell the authorized chain includes saturated carbon-carbon bonds, and, at least one double bond and containing from 2 to 6 carbon atoms, such as, for example, ethynyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl, etc. are Preferred C2-6alkenyl containing one double bond. Of particular interest among the C2-6alkenyl radicals are C2-4alkyl radicals. The term "C3-6alkenyl" means C2-6alkenyl, but is limited to unsaturated hydrocarbon radicals containing from 3 to 6 carbon atoms. When C3-6alkenyl connected to the heteroatom, the carbon atom connected to the heteroatom preferably is saturated.

The term "C3-7cycloalkyl" is a common name for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "polyhalogen1-6alkyl"related to the group or part of a group, such as "polyhalogen1-6alkoxy"means a mono - or polyhalogen-substituted C1-6alkyl, in particular C1-6alkyl, substituted one, two, three, four, five, six or more halo atoms is ENES, such as methyl or ethyl, substituted by one or more fluorine atoms, for example deformity, trifluoromethyl, triptorelin. Preferred is trifluoromethyl. The term also includes perftools1-6alkyl group, which represents C1-6alkyl group in which all hydrogen atoms substituted by fluorine atoms, such as pentaverate. In the case when the alkyl group, as defined by the term "polyhalogen1-6alkyl", attached a few of halogen atoms, the halogen atoms may be the same or different.

The term "methanimidamide" means the name of the radical H2N-C(=NH) according to the nomenclature of Chemical Abstracts Nomenclature (CAS), which may also be called "amidino". Similarly, N-hydroxymaleimide is the name in accordance with CAS radical H2N-C(=N-OH)- or tautomer HN=C(-NH-OH)-, which also may be called the "hydroxyamino".

More precisely, Het represents a 5-membered ring system, which is described above, rather Het represents a 5-membered ring system which includes one atom of oxygen, sulfur or nitrogen and, optionally, one, two or three additional nitrogen atom, in which the remaining atoms of the cycle are carbon atoms; the specified ring system is optionally substituted Het-substituents, per the above numerical in the definition of compounds of formula (I) or any of their sub-groups.

Examples of Het ring systems are furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolin, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.

R3represents a monocyclic or bicyclic aromatic heterocyclic ring system that is described above. In particular, R3may be a monocyclic or bicyclic aromatic heterocyclic ring system that is described above, where the ring system consists of one atom of oxygen, sulfur or nitrogen and, optionally, one, two or three additional nitrogen atom and the remaining atoms of the cycle are carbon atoms; this system is optionally substituted by the substituents described above in the definition of compounds of formula (I) or any of their sub-groups.

Examples R3ring systems are pyrrolyl, furyl,thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benstead azolyl, benzotriazolyl, purinol, chinoline, ethenolysis, cinnoline, hemolysins, phthalazine, honokalani, hintline, naphthyridine, pteridine, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine, isoxazolidine, oxazolopyridine, pyrazolopyrimidine, imidazopyridine, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, properidine, isothiazolinones, triazolopyrimidines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyridine, thienopyridines, properidine, isothiazolinones, triazolopyridazines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, oxadiazolidine, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazolidine, triazolopyrimidines, oxadiazolidine, thiadiazolidine, triazolopyridazines, imidazolidinyl, imidazothiazoles, imidazolidinyl, isoxazolidine, isothiazolinones, pyrazoloacridine, oxazolidinyl, diazolidinyl, imidazolidinyl, oxadiazole azinil, thiadiazolidine, triazolopyridazines, carbazolyl, acridines, phenazines, phenothiazines and phenoxazines; optionally substituted by the substituents described in the definition of compounds of formula (I) or any subgroup.

Specific examples of R3ring systems are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani, hintline, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine, isoxazolidine, oxazolopyridine, pyrazolopyrimidine imidazopyridine, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, properidine, isothiazolinones, triazolopyrimidines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, who savesoldier, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazolidine, triazolopyrimidines, carbazolyl, acridines, phenothiazinyl and phenoxazines; all optionally substituted by the substituents described above in the definition of compounds of formula (I) or any subgroup.

Of particular interest R3ring systems are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani and hintline; optionally substituted by the substituents described above in the definition of compounds of formula (I) or any subgroup.

It should be noted that the definitions used in this description and the claims include various isomers of various heterocycles. For example, oxadiazolyl can be a 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,3-oxadiazolyl; EN is logical, thiadiazolyl can be a 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl; and pyrrolyl can be a 1H-pyrrolyl or 2H-pyrrolyl.

It must be emphasized that the definitions used in this description and the claims, includes any of the provisions mentioned radicals on any fragment of the molecule when the molecule is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1 pencil, 2-pentyl and 3-pentyl.

When any variable (for example, halogen or C1-4alkyl) appears more than once in any structure fragment, each definition is independent.

It is implied that the term "compounds of formula (I)or any similar terms, such as "the compounds according to the present invention" and the like include any prodrugs, which can form compounds of formula (I). The term "prodrugs", when used herein, includes any pharmacologically acceptable derivatives such as esters, amides and phosphates, biotransformation, whichin vivoresults of the product, which represents the active drug specified in the definition of compounds of formula (I). An overview of the properties of prodrugs is provided in the publication Goodman and Gilman (The Pharmacological Basis of Therapetics, 8thed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", RR-15), which entered into this description by reference. Prodrugs are preferably characterized by excellent solubility, increased bioavailability and easily metabolised in vivo to the active inhibitors. Prodrugs of the compounds according to the present invention can be obtained by modifying functional groups present in the compound, so that the thus obtained modified derivatives broken down in the standard process of manipulation orin vivowith the receipt of the original connection.

Preferred prodrugs are pharmaceutically acceptable esters, capable of either hydrolyzedin vivoderived from compounds of formula (I)containing a hydroxyl or carboxyl group. Can either hydrolyzedin vivoester is an ester which is hydrolyzed in the human or animal with the receipt of the original acid or source of alcohol. Suitable pharmaceutically acceptable esters for carboxy-compounds include complex C1-6alkoxymethyl esters, for example methoxymethyl ether, C1-6alkanoyloxy esters, for example pivaloyloxymethyl, Caligraphy esters, C3-8cycloalkylcarbonyl1-6alkyla the haunted esters, for example, 1-cyclohexyloxycarbonyloxy ether; 1,3-dioxolan-2-animationy esters, for example 5-methyl-1,3-dioxolan-2-animationy ether; and (C1-6alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethylene ether, which can be obtained at any carboxy group in the compounds according to the present invention.

Liable to undergo hydrolysisin vivoester compounds of formula (I)containing a hydroxy group includes inorganic esters such as phosphate esters and simple α-aryloxyalkyl esters and related compounds, which after hydrolysis of esterin vivoproduce the original hydroxyl group. Examples of simple α-aryloxyalkyl esters include acetoxymethyl - and 2.2-dimethylphenylacetate-esters. The list of groups that form with a hydroxyl group is able to decomposein vivoester, includes alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (for alkalicarbonate esters), dialkylamino and N-(dialkylaminoalkyl)-n-allylcarbamate (for carbamates), dialkylaminoalkyl and carboxyethyl. Examples of the substituents on the benzoyl include morpholine and piperazine derivatives, from United atom of the nitrogen cycle through a methylene group to the benzoyl is the resultant loop in position 3 or 4. Complex alkanolamine esters, for example, represent any complex C1-30alkanolamine esters, in particular C8-30alkanolamine esters, more precisely, C10-24alkanolamine esters, more accurately - C16-20alkanolamine esters, where the alkyl part can contain one or more double bonds. Examples alkanoyloxy esters are decanoate, palmitate and stearate.

It is implied that the term "compound of formula (I)or any similar terms, such as "the compounds according to the invention" and the like include any metabolites, which are formedin vivowith the introduction of drugs. Some examples of metabolites according to the invention include, but without limitation: (a) when the compound of formula (I) contains a methyl group, it hydroxymethylene derived; (b) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative; (C) when the compound of formula (I) contains a tertiary amino group, its derivative containing a secondary amino group; (d) when the compound of formula (I) contains a secondary amino group, its derivative containing a primary amino group; (e) when the compound of formula (I) contains a phenyl fragment, its phenolic derivative; (f) when the compound of formula (I) contains an amide group, its derivative containing a carboxylic acid group.

Means is I, the term "compounds of formula (I)or any similar terms, such as "the compounds according to the invention" and the like, also include the N-oxide forms of the compounds of formula (I), i.e. compounds of formula (I)in which one or more atoms of nitrogen oxidized to N-oxide form.

For therapeutic applications acceptable salts of compounds of formula (I), in which the counterion is pharmaceutically or physiologically acceptable. However, can find application and salts containing pharmaceutically unacceptable counterion, for example, to get or purification of pharmaceutically acceptable compounds of formula (I). All of these salts, regardless of whether they are pharmaceutically acceptable or not included in the scope of the present invention.

Pharmaceutically acceptable or physiologically acceptable salt additive form, which is able to form compounds according to the present invention can be obtained by standard methods using suitable acids, such as, for example, inorganic acid, such as halogen acids, in particular hydrochloric or Hydrobromic acid, sulphuric acid, semiseria, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, aspartic acid, modellerna, heptane, hexane, nicotine, propane is Wai hydroxyestra, dairy, peruvemba, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, ciclamino, salicylic, p-aminosalicylic, Mamonova, etc. acids.

These acid additive salt forms can be converted into the free base by treatment with a suitable base.

The compounds of formula (I)containing an acidic proton may also become a form of non-toxic primary additive metal salts or amine salts by treatment with appropriate organic or inorganic bases. Suitable primary additive salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, geranamine salts and salts with amino acids such as arginine, lysine, etc.

These basic additive salt form can turn into a free acid form by treatment with a suitable acid.

The term "salt" also includes a hydrate and solvate forms, which can form compounds according to the present invention. Examples of such forms are, for example, hydrates, alcoholate, etc.

With the unity according to the present invention may also exist in tautomeric forms. Assume that such forms, although it is not indicated in the formulas in this description and the claims included in the scope of the present invention. For example, 1,2,4-oxadiazol in the definition of Het may be substituted by hydroxyl or mercapto group in the 5 position, exists in equilibrium with the tautomeric form, as shown below.

The term "stereochemical isomeric forms, when used in the description, defines all possible compounds made up of the same atoms connected in the same sequence, but having different three-dimensional structures, which can have compound according to the invention and are not interchangeable. Except where otherwise stated, the chemical definition of a connection involves a mixture of all possible stereochemical isomeric forms, which can have these connections. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. Assumes that all stereochemical isomeric forms of the compounds according to the present invention, both in pure form and in the form of mixtures with each other form included in the scope of the present invention, including any racemic mixture or racemate.

The term h is simple stereoisomeric forms of the compounds and intermediates which is found in the description means isomers, essentially free from other enantiomeric or diastereoisomeric forms of the same basic molecular structure of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate products containing at least 80% of the excess (i.e. with a minimum content of 90% one possible isomer and a maximum content of 10% of the other possible isomer) and up to 100% excess (i.e. 100% of one isomer and no other), more specifically to compounds or intermediate products with a stereoisomeric excess in the range from 90% to 100%, even more preferably from stereoisomeric excess in the range from 94% to 100% and most preferably from stereoisomeric excess in the range from 97% to 100%. The term "enantiomerically pure" and "diastereomers net have the same value, but the enantiomeric excess and diastereomeric excess of the considered mixture, respectively.

Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained using methods known in the art. For example, the enantiomers can be razdeleny selective crystallization of the diastereomeric salts with optically active acids or basis of what be. Examples of such acids are tartaric acid, dibenzoyltartaric acid, dItalia acid and campostoma acid. Alternatively, the enantiomers may be separated chromatographic methods using chiral stationary phases. These pure stereochemical isomeric form can be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction proceeds in a stereospecific. Preferably, if you want to obtain stereospecific isomer, the indicated compound is synthesized stereospecific ways. These methods are mainly applied to enantiomerically pure source materials.

Diastereomeric the racemates of the formula (I) can be obtained separately by standard methods. Suitable methods of physical separation, which are useful include, for example, selective crystallization and chromatography, such as column chromatography.

Understood that this invention includes all isotopes of atoms present in the compounds according to the invention. For example, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include C-13 and C-14.

It is also understood that the terms "compounds of formula (I)", "connection", "connection according to this is the overarching invention" or any equivalent terms and, similarly, the terms of the subgroups of compounds of formula (I)", "subgroups presents connections", "subgroups of the compounds according to the present invention" or any equivalent terms include compounds of General formula (I) or subgroups of compounds of General formula (I)and their N-oxides, salts, stereoisomers, prodrugs, esters and metabolites, in particular their salts and stereoisomers.

Examples of embodiments of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(1) n in R3ais 1 or 2; or

(1-a) n in R3ais 1.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(2) R1represents hydrogen or C1-10alkyl, optionally substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium; thiomorpholine, 1-OssetiaAlania, 1,1-dioxo-thiomorpholine, aryl, TuranAlem, teinila, pirrallo, oxazolium, thiazolium, imidazolium, isoxazolyl, isothiazolines, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridium, pyrimidinium, pyrazinium, pyridazinyl, triazinyl, hydroxycu what Bonilla, C1-4alkylcarboxylic, (R4)(R5)N-carbonyl, C1-4allyloxycarbonyl;

(2-a) R1represents hydrogen or C1-6alkyl, optionally substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium; thiomorpholine, 1-OssetiaAlania, 1,1-dioxo-thiomorpholine, aryl, TuranAlem, teinila, pirrallo, oxazolium, thiazolium, imidazolium, triazolium, pyridium, pyrimidinium, pyrazinium, hydroxycarbonyl, C1-4alkylcarboxylic, (R4)(R5)N-carbonyl, C1-4allyloxycarbonyl;

(2-b) R1represents hydrogen or C1-6alkyl, optionally substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium; thiomorpholine, 1-OssetiaAlania, 1,1-dioxothiazolidine, hydroxycarbonyl, (R4)(R5)N-carbonyl;

(2-c) R1represents hydrogen or C1-6alkyl, substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium; thiomorpholine;

(2-d) R1is Soboh is hydrogen or C 1-6alkyl, substituted hydroxyl group, -NR4R5, pyrrolidinium, piperidinium;

(2-e) R1represents hydrogen.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(3) R2represents hydrogen or C1-10alkyl, optionally substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium; thiomorpholine, 1 - OssetiaAlania, 1,1-dioxo-thiomorpholine, aryl, TuranAlem, teinila, pirrallo, oxazolium, thiazolium, imidazolium, isoxazolyl, isothiazolines, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridium, pyrimidinium, pyrazinium, pyridazinyl, triazinyl, hydroxycarbonyl, C1-4alkylcarboxylic, (R4)(R5)N-carbonyl, C1-4allyloxycarbonyl;

(3-a) R2represents hydrogen or C1-6alkyl, optionally substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium; thiomorpholine, 1-OssetiaAlania, 1,1-dioxothiazolidine, aryl, TuranAlem, teinila, PI is rollem, oxazolium, thiazolium, imidazolium, triazolium, pyridium, pyrimidinium, pyrazinium, hydroxycarbonyl, C1-4alkylcarboxylic, (R4)(R5)N-carbonyl, C1-4allyloxycarbonyl;

(3-b) R2represents hydrogen or C1-6alkyl, optionally substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium; thiomorpholine, 1-OssetiaAlania, 1,1-dioxothiazolidine, hydroxycarbonyl, (R4)(R5)N-carbonyl;

(3-c) R2represents hydrogen or C1-6alkyl, substituted hydroxyl group, cyano, -NR4R5, pyrrolidinium, piperidinium, homopiperazine, piperazinil, 4-(C1-4alkyl)piperazinil, morpholinium or thiomorpholine;

(3-d) R2represents hydrogen or C1-6alkyl, substituted hydroxyl group, -NR4R5, pyrrolidinium, piperidinium or morpholinium;

(3-e) R2represents hydrogen, C1-6alkyl, substituted hydroxyl group, di-C1-4alkylamino or pyrrolidino;

(3-f) R2represents hydrogen.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of the Fort the uly (I), where

(4) X represents-O-, -NR7-;

(4-a) X represents-NR7-;

(4-b) X represents-O-.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(5) R3represents phenyl, optionally substituted with one or two R3aradicals selected from nitro, cyano, amino, halogen, hydroxyl group, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, C1-4allyloxycarbonyl, C1-4alkylsulphonyl, mono - or di(C1-4alkyl)methanimidamide,Nhydroxymethylimidazole or Het; or

R3represents a monocyclic or bicyclic aromatic heterocyclic ring system, where the ring system contains one atom of oxygen, sulfur or nitrogen, and optionally one, two or three additional nitrogen atom and the remaining atoms of the cycle are carbon atoms; the specified ring system is optionally substituted one, two, three, four, or five substituents, each of which is independently selected from nitro, cyano, amino, halogen, hydroxyl group, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, C1-4alkyloxy is bonila, C1-4alkylsulphonyl, -CH(=N-O-R5aor-C(=NH)-NH - R5a;

(5-a) R3represents phenyl, substituted with one or two R3aradicals selected from nitro, cyano, halogen, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono - or di(C1-4alkyl)methanimidamide,Nhydroxymethylimidazole or Het; or R3represents pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, cinnoline, hemolysins, phthalazine, honokalani, hintline, naphthyridine, pteridine, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine, isoxazolidine, oxazolo-pyridyl, pyrazolopyrimidine, imidazopyridine, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, f is apyrimidinic, isothiazolinones, triazolopyrimidines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazo-pyrimidinyl, pyrrolopyridine, thienopyridines, properidine, isothiazolinones, triazolopyridazines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, oxadiazolidine, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazolidine, triazolopyrimidines, oxadiazole-pyridazinyl, thiadiazolidine, triazolopyridazines, imidazolidinyl, imidazothiazoles, imidazolidinyl, isoxazolidine, isothiazolinones, pyrazoloacridine, oxazolidinyl, diazolidinyl, imidazolidinyl, oxadiazolidine, thiadiazolidine, triazolopyridazines, carbazolyl, acridines, phenazines, phenothiazines or phenoxazines; each of which is optionally substituted by one, two, three or four substituents, each of which is independently selected from nitro, cyano, halogen, C1-4alkyloxy, hydroxycarbonyl or aminocarbonyl;

(5-b) R3represents phenyl substituted by one or two radicals selected from nitro, cyano, halogen, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono - or di(C1-4alkyl)met nimodipine, Nhydroxymethylimidazole, furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, where each of these furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl may be optionally substituted by one or two substituents selected from the group comprising C1-4alkyl, C2-6alkenyl, C3-7cycloalkyl, a hydroxyl group, a C1-4alkoxy, amino, cyano, trifluoromethyl, hydroxy-C1-4alkyl, tsianos1-4alkyl, mono - or di(C1-4alkyl)amino, amino1-4alkyl, mono - or di(C1-4alkyl)amino1-4alkyl, aryls1-4alkyl, amino-C3-6alkenyl, mono - or di(C1-4alkyl)amino3-6alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolin, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C1-4allyloxycarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, C1-4alkylsulphonyl, oxo or thio; where any of the above furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyrazolyl, oxadiazolyl, thiadiazolyl and treat the Lila may be optionally substituted C 1-4the alkyl, or

R3represents pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani, hintline, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine, isoxazolidine, oxazolo-pyridyl, pyrazolopyrimidine, imidazopyridine, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, properidine, isothiazolinones, triazolopyrimidines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, oxadiazolidine, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazolidine, triazolopyrimidines, carbazolyl, acridines, fanatasy the silt or phenoxazines; optionally substituted by one, two or three substituents, each of which is independently selected from halogen, cyano, nitro, C1-6of alkyl, hydroxys1-6of alkyl, C1-4alkoxyl1-6of alkyl, R5a)(R5b)N-C1-4of alkyl, CF3C3-7cycloalkyl, formyl, C1-6alkylcarboxylic, radical-COOR6, (R5a)(R5b)N-carbonyl, a hydroxyl group, a C1-6alkyloxy, radical (R5a)(R5b)N-, mercapto, C1-6alkylthio, C1-6alkylsulfonyl, aryl, -CH(=N-O-R5aor-C(=NH)-NH-R5a;

(5-c) R3represents phenyl substituted by one or two radicals selected from nitro, cyano, halogen, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono - or di(C1-4alkyl)methanimidamide,Nhydroxymethylimidazole, oxadiazolyl, teinila, thiazolyl, furanyl and isoxazolyl, where each of these oxadiazolyl, teinila, thiazolyl, furanyl, isoxazolyl may be optionally substituted C1-4by alkyl; or

R3represents pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxa is alil, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani or hintline; optionally substituted one, two or three substituents, each of which is independently selected from halogen, cyano, nitro, C1-6of alkyl, hydroxys1-6of alkyl, C1-4alkoxyl1-4of alkyl, C3-7cycloalkyl, C1-6alkylcarboxylic, radical-COOR6, (R5a)(R5b)N-carbonyl, a hydroxyl group, a C1-6alkyloxy, radical (R5a)(R5b)N-, mercapto, C1-6alkylthio or C1-6alkylsulfonyl;

(5-d) R3represents phenyl substituted by one or two radicals selected from nitro, cyano, halogen, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono - or di(C1-4alkyl)methanimidamide, N-hydroxymethylimidazole, oxadiazolyl, isoxazolyl, teinila, pyrrolyl, triazolyl, thiazolyl, furanyl, isoxazolyl and tetrazolyl, where each of these oxadiazolyl, isoxazolyl, teinila, pyrrolyl, triazolyl, thiazolyl, furanyl or isoxazolyl may be optionally substituted C1-4by alkyl;

(5-e) R3represents phenyl substituted by one or two radicals selected from nitro, cyano, halogen, C1-4Ala is lexi, hydroxycarbonyl, aminocarbonyl, mono - or di(C1-4alkyl)methanimidamide, N-hydroxymethylimidazole, oxadiazolyl, isoxazolyl, teinila, pyrrolyl, triazolyl, thiazolyl, furanyl, isoxazolyl or tetrazolyl, where each of these oxadiazolyl, isoxazolyl, teinila, pyrrolyl, triazolyl, thiazolyl, furanyl or isoxazolyl may be optionally substituted C1-4by alkyl;

(5-f) R3represents phenyl, substituted nitro, cyano, halogen, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl;

(5-g) R3represents phenyl, substituted nitro; or

(5-h) R3aon the phenyl ring is in the para-position relative to the nitrogen atom in the condensed pyridine fragment.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where each R4or R5independently represents hydrogen or C1-4alkyl.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where each R5aor R5bindependently represents hydrogen or C1-4alkyl.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup from which dinani formula (I), where R6represents hydrogen or C1-4alkyl.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(6) R7represents hydrogen, C1-6alkyl, optionally substituted aryl or (R4)(R5)N-;

(6-a) R7represents hydrogen, C1-6alkyl, optionally substituted aryl, (R4)(R5)N-, pyrrolidinium, piperidinium, piperazinil, 4-(C1-4alkyl)piperazinil or morpholinyl;

(6-b) R7represents hydrogen, C1-6alkyl, optionally substituted (R4)(R5)N-, pyrrolidinium or piperidinium;

(6-c) R7represents hydrogen, C1-6alkyl, optionally substituted by pyrrolidinyl or piperidinyl.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(7) each aryl independently represents a phenyl, optionally substituted by 1, 2 or 3 substituents, each of which is independently selected from C1-6of alkyl, C1-4alkoxy, cyano and nitro.

Other variants of implementation of the present invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(8) Het is a 5-clandulla system, in which one, two, three or four atoms in the ring are heteroatoms, each of which is individually and independently selected from nitrogen atoms, oxygen and sulfur, and the remaining atoms of the cycle are carbon atoms; and where any nitrogen atom in the ring may be optionally substituted C1-4by alkyl; and any carbon atom in the ring may be optionally and independently substituted Deputy selected from the group comprising C1-4alkyl, C3-7cycloalkyl, halogen, cyano, trifluoromethyl, tsianos1-4alkyl, mono - or di(C1-4alkyl)amino, mono - or di(C1-4alkyl)amino, C3-6alkenyl, isoxazolyl, aryl, hydroxycarbonyl, C1-4alkyloxy-carbonyl, oxo or thio; and where the above-mentioned isoxazolyl may be optionally substituted C1-4by alkyl;

(8-a) Het is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolin, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by a Deputy selected from C1-4of alkyl, C2-6alkenyl, C3-7cycloalkyl, hydroxyl group, mercapto, C1-4alkoxy, halogen, amino, cyano, trifloromethyl, hydroxys1-4of alkyl, tsianos1-4of alkyl, mono - or di(C1-4alkyl)amino, amino-C1-4of alkyl, mono - or di(C1-4alkyl)amino1-4and the Qila, arils1-4of alkyl, amino3-6alkenyl, mono - or di(C1-4alkyl)amino3-6alkenyl, furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C1-4allyloxycarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, C1-4alkylcarboxylic; where any of the above furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl may be optionally substituted C1-4by alkyl;

(8-b) Het is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolin, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by a Deputy selected from C1-4of alkyl, C2-6alkenyl, C3-7cycloalkyl, hydroxyl group, mercapto, C1-4alkoxy, halogen, amino, cyano, trifloromethyl, hydroxys1-4of alkyl, tsianos1-4of alkyl, mono - or di(C1-4alkyl)amino, amino1-4of alkyl, aryls1-4of alkyl, amino3-6alkenyl, mono - or di(C1-4alkyl)amino-C3-6alkenyl, furanyl, teinila, aryl, hydroxycarbonyl, aminocarbonyl, C1-4alkyloxyaryl the sludge, mono - or di(C1-4alkyl)aminocarbonyl, C1-4alkylcarboxylic;

(8-c) Het is furanyl, thienyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by a Deputy selected from C1-4of alkyl, C2-6alkenyl, C3-7cycloalkyl, hydroxyl group, mercapto, C1-4alkoxy, halogen, amino, cyano, trifloromethyl, tsianos1-4of alkyl, aryls1-4of alkyl, amino3-6alkenyl, mono - or di(C1-4alkyl)amino3-6alkenyl, furanyl, teinila, aryl, hydroxycarbonyl, C1-4allyloxycarbonyl, C1-4alkylcarboxylic;

(8-d) Het is furanyl, thienyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by a Deputy selected from C1-4of alkyl, C3-7cycloalkyl, hydroxyl group, mercapto, C1-4alkoxy, halogen, trifloromethyl, tsianos1-4of alkyl, aryls1-4of alkyl, furanyl, teinila, aryl, hydroxycarbonyl, C1-4allyloxycarbonyl, C1-4alkylcarboxylic.

A subgroup of compounds of formula (I), of special interest includes compounds that can be represented by the formula:

where R1, R2, R3aand X take the values described in the definitions of the compounds of formula (I) or any of their sub-groups.

A special subgroup of compounds according to the present invention are the compounds of formula (I) or any of the subgroups defined in the description, where the compound of formula (I) are presented in the form of an acid additive salt, where the salt is preferably selected from triptoreline, fumarata, methanesulfonate, oxalate, acetate and citrate.

Of particular interest are compounds 1, 4, 5, 7 and 8, in particular compound 1, which are presented in table 1 after the experimental part, as well as their salts and possible stereoisomers.

Compounds according to the present invention show antiretroviral properties, particularly activity against HIV. More specifically, the compounds of formula (I) are inhibitors of HIV reverse transcriptase. In General, the compounds according to the present invention exhibit good selectivity, which is quantified by the ratio between EU50and SS50and show good activity against drug-resistant mutant strains and even against strains multiresistant to medicines. Currently used reverse transcriptase inhibitors (reverse transctiptase - RT) of HIV lose their effectiveness due to mutations that cause changes in the RT-enzyme, resulting in less efficient interaction of the inhibitor with the RT enzyme, the result is e which the virus becomes less sensitive to the RT inhibitor. Mutants, in relation to which RT inhibitors are no longer effective, are called "resistant mutants. The term "polyresistance to medicines" refers to mutants that are resistant to a lot of other inhibitors of HIV RT. The resistance of the mutant to specific HIV RT inhibitor is expressed as the ratio EU50RT HIV inhibitor to the EU50the same HIV RT inhibitor identified using RT wild-type HIV. This relationship is also called "fold change" ("fold change") resistance (FR). Is EU50equal to the number of connections required to protect 50% of the cells from cytopathogenic of the virus.

Many mutants encountered in clinical practice, have a multiplicity of resistance 100 or more in respect of commercially available HIV NNRTIS, such as nevirapine, efavirenz, delavirdine. Clinically relevant mutants of HIV's reverse transcriptase enzyme can be characterized by a mutation in the position code 100, 103 and 181. The term "location code", when used in the description means the position of amino acids in a protein sequence. Mutations at positions 100, 103 and 181 apply to non-nucleoside RT inhibitors.

Of interest are compounds of formula (I) with multiplicity resistance in the range from 0.01 to 100, preferably in the range from 0.1 to 30, valueproposition in the range of from 0.1 to 20, even more preferably in the range from 0.1 to 10, relative to at least one mutant reverse transcriptase of HIV. Of interest are compounds of formula (I) with multiplicity resistance in the range from 0.01 to 100, preferably in the range from 0.1 to 30, more preferably in the range from 0.1 to 20, more preferably in the range from 0.1 to 10 in terms of HIV strains containing at least one or at least two mutations in the amino acid sequence of HIV reverse transcriptase in comparison with the sequence of the wild type at position selected from 100, 103 and 181.

Usually such compounds active against mutant strains that are resistant to currently available NNRTIS, such as nevirapine, efavirenz, delavirdine. Compounds according to the invention interact via a unique mechanism of action in such a way that they are competing NNRT inhibitors and, in addition, show increased activity when combined with the introduction of nucleosidases, such as ATP. Therefore, the compounds according to the present invention can find application in combined drugs against HIV with currently available NNRTIS.

Compounds according to the invention can be used to treat other Zabol the requirements, associated with HIV infection, which include thrombocytopenia, Kaposi's sarcoma and infection of the Central nervous system, characterized by progressive demyelination, which leads to dementia and symptoms, such as progressive dysarthria, ataxia and disorientation. Other diseases that may accompany HIV infection and which can be treated using compounds according to the present invention include peripheral neuropathy, progressive generalized enlarged lymph nodes (progressive generalized lymphadenopathy - PGL) and AIDS-associated complex (AIDS-related complex (ARC).

Due to the presence of favorable pharmacological properties, in particular activity against HIV, the compounds according to the present invention can be used as medicines for the treatment of the aforementioned diseases or to prevent them. The specified application as a medicine or method of treatment includes systemic introduction of subjects infected with HIV, the amount effective for suppressing conditions associated with HIV.

In accordance with an additional aspect of the present invention relates to the compound of formula (I) or any subgroup such compounds for use as drugs. In accordance with another aspect of the present from retina refers to the use of compounds of formula (I) or any subgroup such compounds for the manufacture of a medicinal product for the prevention, treatment or suppression of HIV infection or disease associated with HIV infection.

In accordance with another aspect of the present invention relates to the use of compounds of formula (I) or any subgroup such compounds for the preparation of a medicine for inhibiting the replication of HIV, in particular HIV, containing the mutant reverse transcriptase of HIV, rather multiresistant to medicines mutant reverse transcriptase of HIV.

In accordance with another aspect of the present invention relates to the use of compounds of formula (I) or any subgroup such compounds for the preparation of a medicine for the prevention, treatment or suppression of diseases associated with HIV infection, where the reverse transcriptase of HIV is a mutant, in particular, is a multiresistant to medicines mutant reverse transcriptase of HIV.

The compounds of formula (I) or any subgroup such compounds are also applicable in the way of prevention, treatment or suppression of HIV infection or disease associated with HIV infection, in a mammal, the method comprises the introduction of a given mammal an effective amount of the compounds of formula (I) or any subgroup of compounds.

In accordance with another aspect with the unity of formula (I) or any subgroup applies in the way of prevention, treatment or suppression of infection or disease associated with infection of a mammal mutant HIV, this method includes the introduction of the specified mammal an effective amount of the compounds of formula (I) or any subgroup of compounds.

In accordance with another aspect of the compounds of formula (I) or any subgroup applies in the way of prevention, treatment or suppression of infection or disease associated with infection of the mammalian multidrug-resistant to medicines for HIV, this method includes the introduction of the specified mammal an effective amount of the compounds of formula (I) or any subgroup of compounds.

In accordance with another aspect of the compounds of formula (I) or any subgroup such compounds applicable in the method of inhibiting the replication of HIV, in particular HIV, containing the mutant reverse transcriptase of HIV, rather multiresistant to medicines mutant reverse transcriptase of HIV, this method comprises the administration to a mammal in need, an effective amount of the compounds of formula (I) or any subgroup of compounds.

Preferably a mammal, mentioned in the methods according to the present invention is the man.

Compounds according to the present invention m is may also be useful for inhibiting HIV in experiments ex vivoin samples containing HIV, or is expected to undergo HIV infection. Therefore, the connection can also be used for inhibition of HIV present in the sample of biological fluid that contains or is expected to contain HIV or exposed to HIV.

The following describes the methodologies for the synthesis of compounds according to the present invention. In methods of obtaining described below, the reaction products may be released and, if necessary, further purified according to methods well known in the art, such as, for example, extraction, crystallization, rubbing and chromatography.

The compounds of formula (I) can be obtained as shown in the following diagram, where R1, R2, R3and X take the values defined above.

The original compound (a) can be obtained in accordance with schemes of synthesis disclosed in the patent application WO04/046143. The parent compound, in which R3represents a monocyclic or bicyclic aromatic heterocyclic ring system, can be obtained in a similar way.

The original compound (a) is subjected to interaction with the intermediate product (b) in accordance with the reaction of alkylation with obtaining prom is mediate product (s), which is sequentially subjected to a cyclization reaction to obtain the final product (I). In the intermediate product (b) LG represents a group to delete or predecessor of the deleted group capable ofin situto become removed in a suitable group, such as, for example, an alcohol functional group that undergoes interaction with PCl3, POCl3or is subjected to reaction Mitsunobu using azodicarboxylate/triphenylphosphine to obtain removed the group from Olkiluoto alcohol and then interaction with the appropriate amine. R in the radical-X-R represents hydrogen or a suitable protective group, and X, R1and R2take the values defined above. Suitable protective groups include benzyl, benzyloxycarbonyl, tert-butoxycarbonyl. The group R is removed prior to cyclization of the intermediate product (C). The intermediate product (C) may be subjected to cyclization by adding a base.

Alternatively, when the substituent R1enter alkyl, hydroxyalkyl or aminoalkyl, the original connection (a) is subjected to interaction with a derivative of glycerol, in which two groups of primary alcohol is protected, for example, acetamino group. The specified derived glycerol is subjected to binding to the nitrogen atom of indole fragment of the original what about the connection (s). Previously entered protective group that is labile in an acid environment, i.e. acetaline functional group is removed by substitution accession acid with obtaining the diol(s). Cyclization after the addition of base results in the formation of compounds (I-a), and adding a suitable reagent for the introduction of the deleted groups, such as methylchloride or tailhold, leads to the transformation of the alcohol functional group in the group that you want. Subsequent substitution reaction with ammonia or mono-, di-substituted amine leads to the formation of compounds of formula (I-b), which are compounds of formula (I), where R1is aminomethyl and R2represents hydrogen. The sequence of these reactions represented by the following diagram, where R3, R4and R5take the values defined above.

The compounds of formula (I) may be subject to transformation into other compounds of formula (I) through various substitutions using techniques known in the art. For example, the compounds of formula (I)containing aromatic Deputy, which is a nitrogroup, may be subject to restoration to the corresponding amino derivatives, which, in turn, can be further prevremeni is.

The compounds of formula (I), where R3substituted with halogen, may be subject to transformation into the corresponding cyano derivative interaction with a suitable cyano-nucleophile, such as copper cyanide (I).

The compounds of formula (I) can also be converted into the corresponding N-oxide forms in accordance with known methods of transformation trisemester nitrogen in N-oxide form. This reaction N-oxidation can usually held in the interaction of the compounds of formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metals or alkaline-earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include nagkalat, such as benzolkarbonovyh nagkalat or halogen-substituted benzolkarbonovyh nagkalat, for example 3-chlorobenzylamino nagkalat, alcamovia nagkalat, for example acetic nagkalat, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Thus, the compounds according to the present is obreteniyu can be used by themselves, but preferably used in the form of pharmaceutical compositions. Therefore, in accordance with another aspect of the present invention relates to pharmaceutical compositions, which as active constituent contain an effective dose of a compound of formula (I) in the mixture with the carrier, which usually can include pharmaceutically innocuous excipients and adjuvants. The pharmaceutical compositions generally contain from 0.1 to 90% (wt.) the compounds of formula (I). The pharmaceutical compositions can be obtained by methods known in the art. To this end, compound of formula (I) together with one or more solid or liquid carriers, which may include pharmaceutical excipients and/or adjuvants, and if necessary, in combination with other pharmaceutical active compounds are introduced into a form suitable for injection or dosage form.

Pharmaceutical preparations containing the compounds according to the present invention may be administered orally, parenterally, for example intravenously, rectally, by inhalation or local methods, and the preferred method of administration depends on the parameters of each particular case, such as a particular disease to be treated. Preferably oral administration.

The special is that the art is known from practice adjuvants, suitable for the desired pharmaceutical preparation. In addition to solvents, glioblastoma additives, the basis for candles, auxiliary additives for tablets and other carriers for active compounds can also be used antioxidants, dispersants, emulsifiers, defoamers, additives that improve the taste, preservatives, soljubilizatory, additives to achieve the effect depot, buffer substances or dyes.

In addition, as a medicinal product can be used in combination of one or more additional antiviral compounds and the compounds of formula (I). Thus, the present invention relates also to a product containing (a) compound of formula (I) and (b) one or more additional antiviral compounds in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of HIV. Various drugs may be combined in one preparation together with pharmaceutically acceptable carriers. These other antiviral compounds may constitute, for example, antiviral drugs, such as suramin, pentamidine, thymopentin, castanospermine, dextran (dextran-sulfate), foscarnet-sodium (trinatriumfosfaat); nucleoside inhibitors of reverse transcriptase inhibitors is (NRTI), for example, zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC (Reverset™), alovudine (MIV-310), amdoxovir (DAPD), elvucitabine (ASN-126443) and the like; non-nucleoside reverse transcriptase inhibitors (NNRTIS), such as delarvidine (DLV), efavirenz (EFV), nevirapine (NVP), capravirine (CPV), calanoid AND TMS, etravirine (TMC), DMS, BMS-561390, DPC-083, and the like; nucleotide reverse transcriptase inhibitors (NtRTI), such as tenofovir (TDF) and getproxyport tenofovir etc.; TIBO derivatives (derivatives of tetrahydroimidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)she thione, for example, (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-ol][1,4]benzodiazepine-2(1H)tion; derivatives of α-APA (α-anilinoquinazoline), for example α-[(2-nitrophenyl)amino]-2,6-dichlorosalicylic and the like; inhibitors of TRANS-activating proteins, such as TAT-inhibitors, e.g. RO-5-3335; REV inhibitors; protease inhibitors, such as ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV), APV (VX-478), TMC-126, BMS-232632, VX-175, DMP-323, DMP-450 (Mozenavir), nelfinavir (AG-1343), atazanavir (BMS 232,632), palinavir, TMC-114, RO033-4649, fosamprenavir (GW433908 or VX-175), P-1946, BMS 186,318, SC-55389a, L-756423, tipranavir (PNU-140690), BILA 1096 BS, U-140690, and the like; inhibitors of introduction of infection, which include fusion inhibitors (e.g., T-20, T-1249), attachment inhibitors and inhibitors, co-receptor; th is DNA include antagonists of CCR5 and CXR4 antagonists (e.g., AMD-3100); examples of inhibitors of introduction of infection are enfuvirtide (ENF), GSK-873140, PRO-542, SCH-417690, TNX-355, maraviroc (UK-427857); inhibitor of maturation, for example, is a PA-457 (Panacos Pharmaceuticals); inhibitors of viral integrase; ribonucleotidic reductase inhibitors (cell inhibitors, such as hydroxyurea, etc.

The combination of medicines may provide a synergistic effect, resulting in viral infection and its associated symptoms can be prevented, significantly reduced or completely removed.

Compounds according to the present invention can also be administered in combination with immunomodulators (e.g., bropirimine, an antibody against alpha-interferon in human, IL-2, mentionedearlier, interferon-alpha and naltrexone), antibiotics (e.g., pentamidine-isocyanato (pentamidine isothiorate)), cytokines (e.g., Th2), modulators of cytokines, chemokines or modulators chemokines, chemokine receptors (e.g., CCR5, CXCR4), modulators of chemokine receptors or hormones (e.g. growth hormone) to facilitate, suppress or eliminate HIV infection and its symptoms. This combined therapeutic treatment with various drugs can be performed simultaneously, sequentially or independently from each other. Alternatively, this combination is s may be the same drug, whereby the active ingredients are released from the drug at the same time or separately.

Compounds according to the present invention can also be administered in combination with modulators of absorption by the body after drug administration by the patient. Such modulators include compounds that affect the metabolism cytochromes, such as cytochrome P450. It is known that there are several cytochrome P450 isoenzymes, one of which is cytochrome P450 3A4. Ritonavir is an example of the modulator absorption through cytochrome P450. Such combination therapy in various preparations may be administered simultaneously, sequentially or independently from each other. Alternatively, such a combination may be administered as a single drug, causing the active ingredients are released from the drug at the same time or separately. Such a modulator can be entered in the quantity equal to the number of compounds according to the present invention, or in varying proportions relative to the compounds according to the present invention. Preferably the mass ratio of such a modulator and compounds according to the present invention (modulator:connection according to the present invention) is 1:1, more preferably is 1:3 or less, a suitable ratio is aspect] is the solution of 1:10 or less a more appropriate ratio is 1:30 or below.

To obtain forms for oral administration of the compounds according to the present invention are mixed with suitable additives, such as excipients, stabilizers or inert diluents, and are introduced by standard methods into suitable forms of administration, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert carriers are gumarabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the drug may be provided in the form of dry and as wet 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. As an additional auxiliary ingredients forms for other routes of administration can also be used glycols and polypropylenglycol.

For subcutaneous or intravenous administration, the active compounds, if necessary, with other commonly used substances such as soljubilizatory, emulsifiers or other auxiliary additives which, are introduced into a solution, suspension or emulsion. The compounds of formula (I) can also lyophilisates, and received lyophilizate can be used, for example, to obtain preparations for injection or infusion. Suitable solvents are, for example, water, saline solution or alcohols, such as ethanol, propanol, glycerol, as well as solutions of sugars such as glucose or mannitol, or alternatively, a mixture of the mentioned solvents.

Suitable pharmaceutical preparations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of formula (I) or their physiologically absorbable pharmaceutically acceptable salts in a solvent such as ethanol or water, or mixtures of such solvents. If necessary, the product may also contain other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, as well as propellants. Such preparations usually contain the active compound in a concentration in the range from about 0.1 to 50%, in particular from about 0.3 to 3% (wt.).

To improve the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions may preferably be used α-, β - or γ-cyclodextrins or their derivatives. In addition to the CSO, jointly applied solvents, such as alcohols, can improve the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions. When receiving water compositions additive salts of the compounds according to the present invention are more stable because of their increased solubility in water.

Appropriate cyclodextrins are α-, β - or γ-cyclodextrins (CDS)or ethers and mixed ethers, where one or more hydroxyl groups anhydroglucose fragments cyclodextrin substituted With1-6the alkyl, in particular the stands, ethyl or isopropyl, e.g. disordered methylated β-CD; hydraxis1-6alkyl-, in particular hydroxyethyl-, hydroxypropyl - or hydroxybutyl-; carboxy1-6the alkyl, in particular carboxymethyl or carboxyethyl; C1-6alkylcarboxylic, particularly acetyl; C1-6allyloxycarbonyl1-6the alkyl or carboxy1-6alkalosis1-6the alkyl, in particular carboxyphenoxypropane or carboxitherapy; C1-6alkylcarboxylic1-6the alkyl, in particular 2-acetoxypropionyl. Deserve special attention as complexing agents and/or β-CD, disordered methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-D and (2 carboxymethoxy)propyl-β-CD, in particular, 2-hydroxypropyl-β-CD (NR-β-CD).

The term "simple mixed ether" means derivative of cyclodextrin in which at least two hydroxyl groups of the cyclodextrin tarifitsirovana different groups, such as, for example, hydroxypropyl and hydroxyethyl.

Noteworthy way to get the drug on the basis of the compounds according to the present invention in combination with cyclodextrin or its derivatives has been described in EP-A-721331. Despite the fact that the products described in this document was obtained with active ingredients that have fungicidal activity, they are equally of interest and to obtain preparations of the compounds according to the present invention. The drugs described in this publication, are particularly suitable for oral administration and include the fungicide 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 alcohol co-solvent, which greatly simplifies the obtaining of the composition. These drugs can give a more pleasant taste with pharmaceutically acceptable sweeteners and/or flavorings.

Other convenient ways of increasing the solubility of the compounds according to the present is the first invention in the pharmaceutical compositions described in the publications WO 94/05263, WO 98/42318, EP-A-499299 and WO 97/44014, which are introduced in this description by reference.

More specifically, the compounds according to the present invention can be administered in a pharmaceutical composition comprising a therapeutically effective amount of particles forming a solid dispersion comprising (a) compound of formula (I) and (b) one or more pharmaceutically acceptable water-soluble polymers.

The term "solid dispersion" refers to the system in the solid state (as opposed to liquid or gaseous state)comprising at least two components, where one component is distributed more or less evenly in another component or components. When this variance component is a stable chemically and physically uniform or homogenous throughout the volume of the system or consists of one phase, as defined in thermodynamics, such a solid dispersion is called a "solid solution". Solid solutions are preferred physical system, since forming their components usually are biologically digestible for organisms in which they are inserted.

The term "solid dispersion" also includes dispersion, which are less homogeneous in terms of volume than solid solutions. Such dispersions are not chemically and physically uniform replycount more than one phase.

Water-soluble polymer in the particles is typically a polymer with an apparent viscosity in the range from 1 to 100 MPa·s when dissolved in 2% aqueous solution at the solution temperature of 20°C.

Preferred water-soluble polymers are hydroxypropylmethylcellulose or a receiver array. A receiver array with a degree methoxy-substitution in the range of from about 0.8 to about 2.5 molar hydroxypropyl-substitution in the range of from about 0.05 to about 3,0 usually are water-soluble. The term "degree methoxy-substitution" refers to the average number of groups of simple methyl ester present in each anhydroglucose fragment molecules of cellulose. The term molar hydroxypropyl-substitution refers to the average number of moles of propylene oxide, are reacted with each anhydroglucose fragment molecules of cellulose.

Particles that are listed in the above definitions, can be obtained by obtaining a solid dispersion of the components and then optionally grinding or milling the obtained dispersion. There are different ways of getting solid dispersions, including melt extrusion, spray drying and evaporation of the solution, and preferred is a method of melt extrusion.

It may be convenient to prepare the preparation of the compounds according to the SNO present invention in the form of nanoparticles, containing 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 as surface modifiers applicable compounds that are physically held on the surface of antiretroviral funds, but do not form chemical bonds with him.

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

Compounds according to the present invention may be incorporated in hydrophilic polymers, and this mixture can be applied as a film coating on a small granules. In accordance with one embodiment of the present invention these granules include a Central, rounded or spherical) core, a film coating of a hydrophilic polymer and antiretroviral means and the sealing layer of polymer coating. Materials suitable for use as cores in the granules, are the RA is generated, provided, these materials are pharmaceutically acceptable and have the appropriate size and hardness. Examples of such materials are polymers, inorganic substances, organic substances and sugars and their derivatives. Thus obtained granules with the coatings have good bioavailability and are suitable for the preparation of dosage forms for oral administration.

The route of administration may depend on the condition of the subject, concomitant treatment, etc.

Another aspect of the present invention relates to a collection or container containing the compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit reverse transcriptase of HIV, the growth of HIV or the presence of both these properties. This aspect of the invention may find application in the study of pharmaceuticals.

Compounds according to the present invention can be used in research, including the control of the resistance phenotype, for example the well-known studies of recombinants in the clinical treatment of diseases characterized by the development of resistance, such as HIV-associated diseases. Specific applicable control system d is istinnosti is the study of recombinant, known as the Antivirogram®. Antivirogram® is a highly automated, high-performance analysis method of the second generation, which can quantify the sensitivity, particularly viral sensitivity to compounds according to the present invention (see Hertogs K.,et al. Antimicrob Agents Chemother,1998; 42(2):269-276, which is put into the description by reference).

It should be noted that the compounds according to the present invention may include chemically active fragments, capable of forming covalent bonds with localized sites, so the join will be characterized by longer periods of retention in tissues and longer half-lives. The term "reactive group", when used in the present description, refers to chemical groups that can form covalent bond. Reactive groups are usually stable in the aquatic environment and are a carboxyl group, a phosphoryl or a standard acyl group as the group of ester or mixed anhydride, or imidate or maleimide that ways to form a covalent bond with functional groups such as amino group, hydroxyl group or Tolna group on the target site, such as blood components, such as al the IOR techniques. Compounds according to the present invention can connect with maleimido or its derivatives with the formation of conjugates.

The dose of the compounds according to the present invention or their physiologically absorbable(s) salt(s), subject to the introduction, depends on each case and, as a rule, to achieve the optimal effect in each individual case should be assigned with consideration of the States of the individual. Thus, it depends, surely, on the frequency of administration and strength, and duration of action of the compounds used in each case for therapeutic treatment or prevention, from nature and severity of the infection and symptoms, as well as gender, age, weight of the human or animal to be treated, together used drugs and individual responsiveness of the human or animal to be treated, and to treat any condition (acute or chronic) is applied therapeutic agent, or it is used for prophylaxis. The daily dose of the compounds of formula (I) in the case of the introduction of patient weighing approximately 75 kg is from 1 mg to 3 g, preferably in the range from 3 mg to 1 g, more preferably in the range of from 5 mg to 0.5 g Dose may be in the form of a separate single dose or divided into several, for example two, the ri or four, separate doses.

Examples

The following examples illustrate the compounds of formula (I), processes for their preparation and pharmacological properties and should not be construed as limiting the scope of the present invention.

Example 1

A mixture of intermediate A (2,558 mmol, 845 mg), glycidol (2 equiv., 5,117 mmol, 379 mg) and diisopropylcarbodiimide (2 equiv., 5,117 mmol, 1035 mg) are mixed in DMF (10 ml). The reaction mixture was cooled in an ice bath and to the mixture is added triphenylphosphine (2 equiv., 5,117 mmol, 1342 mg). The reaction mixture was stirred at room temperature overnight. To the mixture add pyrrolidine (20 equiv., 51,166 mmol, 3639 mg) and the reaction mixture was stirred at 50°C for 4 hours. To the mixture is added water (25 ml)causing precipitation of the reaction product. The precipitate is collected by filtration and washed successively with water, ethanol and diisopropyl ether, resulting in the intermediate product B (1060 mg, yield = 91%, purity (LC) >95%).

A mixture of intermediate B (0,1639 mmol, 75 mg) in DMF (3 ml) is stirred with cooling in an ice bath for 15 minutes. Then added to the mixture of tert-piperonyl sodium (1.5 EQ., 0,2459 mmol, of 27.6 mg) and the reaction mixture was stirred over night at room temperature. To the mixture is added water (5 ml), obtained with the feature is extracted with dichloromethane and the organic phase is washed with saturated salt solution. After drying (MgSO4) the organic phase is concentrated, receiving compound 1 (73 mg, yield = 94%, purity (LC) >95%);1H NMR (δ, DMSO-D6): 8,72 (1H, USS), of 8.47 (2H, d, J=8.7 Hz), 7,79 (2H, d, J=8.7 Hz), 7,66 (1H, d, J=8,4 Hz), 7,37 (1H, t, J=7,7 Hz), 6,92 (1H, t, J=7,7 Hz), of 6.31 (1H, d, J=8,3 Hz)to 4.33 (2H, t, J≈5 Hz), 3,86 (2H, t, J≈5 Hz).

Example 2

To a solution of intermediate A (7.87 mmol, 2600 mg) in DMF (50 ml) was added with stirring sodium hydride (3.00 equiv., 23,62 mmol, 945 mg, 60%) and the resulting mixture is heated for one hour at 60°C. After cooling to room temperature, to the mixture of N-tBoc-2-chloroethylamine (2.00 equiv., 15,74 mmol, 2828 mg), the mixture is heated to 60°C and maintained at the specified temperature for 3 hours. The reaction product precipitated from solution by addition of water and the precipitated precipitate is collected by filtration. The precipitate is washed with isopropanol and diisopropyl ether, obtaining compound 2 (1213 mg, yield = 41%, purity (LC)=93%);1H NMR (δ, DMSO-D6): 8,48 (2H, d, J=8,8 Hz), 7,78 (2H, d, J=8,8 Hz), 7,63 (1H, d, J=8.5 Hz), was 7.36 (1H, t, J≈8 Hz), 6.90 to (1H, t, J≈8 Hz), of 6.26 (1H, d, J=8,2 Hz), to 4.38 (2H, t, J≈5 Hz), of 3.97 (2H, t, J≈5 Hz), 3,62 (3H, s).

To a solution of compound 2 (0,269 mmol, 100 mg) in DMF (10 ml) add methyliodide (1.50 equiv., 0,404 mmol, 57 mg) and potassium carbonate (2.00 equiv., 0,538 mmol, 74 mg). The resulting mixture was refluxed for 2.5 hours. The reaction mixture is cooled to room so the temperature, the product precipitated from solution by addition of water and the precipitated precipitate is collected by filtration. The precipitate is washed with isopropanol and diisopropyl ether, receiving connection 3 (44 mg, yield = 42%, purity = 98%).

Example 3

A mixture of intermediate A (0,606 mmol, 200 mg), potassium carbonate (2 EQ., to 1.21 mmol, 167 mg), biomethanol (2 EQ., to 1.21 mmol, 151 mg) and tetrabutylammonium iodide (2 EQ., to 1.21 mmol, 447 mg) in dry DMF (4 ml) heated to 70°C in an atmosphere of N2and maintained under these conditions for 48 hours. After cooling to room temperature the reaction mixture was concentrated and the residue distributed between ethyl acetate (200 ml) and water (100 ml). The organic layer is dried (Na2SO4) and concentrate. The crude residue is purified column chromatography on silica gel (elution: CH2Cl2/AcOEt/petroleum ether, 7:1:2)to give intermediate product B in the form of a yellow powder (120 mg, yield = 53%, purity (LC) >95%).

To a solution of intermediate product (0,134 mmol, 50 mg) in dry DMF (2 ml) at room temperature in an atmosphere of N2add tert-piperonyl potassium (1.2 EQ., 0,160 mmol, 18 mg). The mixture was incubated for 30 minutes at room temperature, then acidified to pH 5 with acetic acid and partitioned between water (30 ml) and ethyl acetate (150 ml). The organic layer is dried (Na2 SO4) and concentrate. The residue is purified column chromatography on silica gel (elution: CH2Cl2/AcOEt/MeOH, 5:4:1)to give compound 4 as yellow powder (5.1 mg, yield = 10%, purity (LC) >95%).

Example 4

A mixture of intermediate A (1,51 mmol, 500 mg), potassium carbonate (2 EQ., 3.03 mmol, 418 mg), 3-bromopropane-1,2-diol (2 EQ., 3.03 mmol, 469 mg) and tetrabutylammonium iodide (1 EQ., is 1.51 mmol, 580 mg) in dry DMF (10 ml) heated to 90°C in an atmosphere of N2and maintained under these conditions for 2 hours. After cooling to room temperature the reaction mixture was concentrated and the residue distributed between ethyl acetate (200 ml) and water (100 ml). The organic layer is dried (Na2SO4) and concentrate. The crude residue is purified column chromatography on silica gel (elution: CH2Cl2/THF, 2:1)to give compound 5 in the form of a yellow powder (6.5 mg, yield = 1.1%of,purity (LC)>95%).

The following table presents a list of examples of compounds according to the present invention, which is obtained in accordance with methods similar to those described in the above schemes of synthesis.

Table 1

In the above table, the symbolshows the et connection, through which the moiety is connected with the remainder of the molecule.

The compounds according to the present invention, identified by the connection number under which each of them are shown in table 1, with the corresponding NMR data:

Connection 7

1H NMR (δ, DMSO-D6): charged 8.52 (2H, d, J=9.0 Hz), 7,88-to 7.84 (2H, m), 7,74 (1H, d, J=8,2 Hz), 7,46 (1H, t, J=8 Hz), 6,97 (1H, t, J=8 Hz), 6,37 (1H, d, J=8,2 Hz), 5,22-of 5.15 (1H, m), 4,74-4,69 (1H, m), or 4.31-4.26 deaths (1H, m), 2,98-2,95 (2H, m), 2,67-2,61 (4H, m), 1.04 million of 1.00 (6H, m).

Connection 9

1H NMR (δ, DMSO-D6): charged 8.52 (2H, d, J=8.6 Hz), 7,89-7,83 (2H, m), 7,74 (1H, d, J=8.5 Hz), was 7.45 (1H, t, J=8 Hz), 6,97 (1H, t, J=8 Hz), 6,37 (1H, d, J=8,3 Hz), 5,14-5,08 (1H, m), 4,67-to 4.62 (1H, m), 4,37-4,32 (1H, m), 3,11-2,89 (4H, m), 1,03-a 1.01 (12H, m).

Connection 10

1H NMR (δ, DMSO-D6): 8,53 (2H, d, J=8,8 Hz), 7,88-to 7.84 (2H, m), 7,74 (1H, d, J=8.5 Hz), 7,46 (1H, t, J=8 Hz), 6,97 (1H, t, J=8 Hz), 6,37 (1H, d, J=8,2 Hz), from 5.29 with 5.22 (1H, m), 4.80 to the 4.75 (1H, m), 4,25-4,17 (1H, m), 2,88-2,82 (2H, m), 2,33 (6H, c).

These studies antiviral activity

Compounds according to the present invention is subjected to testing to determine their antiviral activity in cell test, which is carried out in accordance with the following method.

HIV-positive or false-infected MT4 cells incubated for five days in the presence of inhibitor used in various concentrations. At the final stage of the incubation period of the breeding VI the condition in the control cultures in the absence of any inhibitor affects all HIV-infected cells. Cell viability determined by determining the concentration of MTT (methylthiotetrazole - yellow water-soluble dye-based tetrazole), which turns into a purple insoluble in water formazan in mitochondria only under the condition that the cells are alive. In the process of solubilization of the resulting crystals formazan isopropanol observe the absorption solution light with a wavelength of 540 nm. The absorption intensity is directly proportional to the number of surviving cells after five days of incubation. Inhibitory activity of compounds evaluated in virus infected cells and expressed as EU50. This value is equal to the number of connections required to protect 50% of the cells from cytopathogenic of the virus. The toxicity of compounds to determine false positive cells and expressed as CC50equal concentrations of compounds inhibiting cell growth by 50%. Index selectivity the selectivity values index - SI) (ratio CC50/EC50) gives a measure of the selectivity of antiviral action of the inhibitor against HIV.

The following table 2 shows values of EC50in respect of the strain HIV-LAI wild type for a number of compounds according to the present invention.

Table 2
Connection # EC50(µm)
10,34
23,05
31,88
40,51
50,74
6of 9.30
70,27
80,37
94,51
101,96
110,16

Drugs

Capsules

Compound 1 dissolved in a mixture of ethanol and methylene chloride and hypromellose (receiver array) 5 MPa·s is dissolved in ethanol. Both solution are mixed so that the ratio of wt./wt. the compound/polymer equal to 1/3, and the resulting mixture was spray dried in a standard spray drying apparatus. The powder obtained by spray drying (solid dispersion), fill capsules. The number of drugs introduced into one of the capsules is, pick up in such a way that it is in the range from 50 to 100 mg depending on the size of the used capsules. In accordance with the same methodology can be obtained drugs in capsule form other compounds of formula (I).

Coated tablets in film form

Obtain core tablets

A mixture of 1000 g of compound 1, 2280 g of lactose and 1000 g of starch are thoroughly mixed and then moisturize with a solution of 25 g of sodium dodecyl sulfate and 50 g of polyvinylpyrrolidone in about 1000 ml of water. The wetted powder mixture is passed through a sieve, dried, and sift again. Then add 1000 g of microcrystalline cellulose and 75 g of hydrogenated vegetable oil. The whole mixture was thoroughly mixed and pressed into tablets, receiving 10,000 tablets, each containing 100 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 add 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 was added to a solution of cellulose derivatives, then added to the mixture of 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye and the resulting mixture is homogenized. Core tablets cover prigot is undertaken thus mixture in the apparatus for obtaining coverage.

In accordance with this method can be obtained drugs in tablet form other compounds of formula (I).

1. The compound of the formula

its salts,
where R1and R2each independently represents hydrogen or C1-10alkyl which may be optionally substituted by a Deputy selected from the group comprising hydroxyl group, NR4R5pyrrolidinyl, piperidinyl, morpholinyl;
R3represents a radical of the formula

where n is 1;
R3arepresents nitro;
X represents-NR7- or-O-;
R4and R5each independently represents a C1-6alkyl;
R7represents hydrogen, C1-6alkyl, optionally substituted by pyrrolidinyl.

2. The compound according to claim 1, where R1represents hydrogen.

3. The compound according to claim 1 or 2, where R2represents hydrogen, C1-6alkyl, optionally substituted hydroxyl group, di-C1-4alkylamino, pyrrolidinyl, piperidinyl or morpholinyl.

4. The use of compounds according to any one of claims 1 to 3 for the preparation of drugs for the treatment of retroviral diseases.

5. Pharmaceutical composition having antiviral activity and comprising effective amounts of the compounds of formula (I) according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

6. A method of obtaining a pharmaceutical composition according to claim 5, characterized by thorough mixing of the carrier with the active ingredient.

7. The method of obtaining chemical compounds according to any one of claims 1 to 3, characterized in that the starting material (a) is subjected to interaction with the intermediate product (b) in accordance with the alkylation reaction to obtain an intermediate product (s)that subsequently undergoes cyclization to obtain the compounds (I):

where in the intermediate product (b) LG represents a group to delete or predecessor of the deleted group, which in situ can be transformed into a suitable removable group, and R represents hydrogen or a suitable protective group; and, if necessary, the conversion of compounds of formula (I) into other compounds of formula (I) with another substitution, using the methods of transforming functional groups; and, if necessary, obtaining salt forms of the compounds of formula (I) processing mesolevel form acid or base.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (1a) or its pharmaceutically acceptable salt, esters or imides where A is a thiophenyl group containing, probably, substitution, the thiophenyl group A containing, probably, substitution with one or several groups as follows: alkyl, halo or arylalkyl, Y is O, S or NR2 where R2 is hydrogen or alkyl group containing 1 to 6 carbon atoms, and R1 is an non-ramified alkyl group containing 6 to 25 carbon atoms, ramified alkyl group containing 6 to 25 carbon atoms, aryl alkyl group where the alkyl group contains 2 to 25 carbon atoms or phenyl group containing substitution with one or several groups as follows: phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR16- phenyl, NR16CO-phenyl or NR16 -phenyl containing, probably, substitution where R16 is hydrogen or alkyl group containing 1 to 4 carbon atoms, the groups phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR-phenyl or NR-phenyl containing, probably, substitution with one or several groups as follows: halo, alkyl, alkylhalo or phenyl group containing substitution with one or several groups or alkyl groups provided the above compound is not 5-methyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on, 6-amyl-2-(4-chlorophenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on or 6-amyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on Invention also relates to method of obtaining compounds of the formula (Ia) or (IIa), to pharmaceutical compound and application, as well as cosmetic technique.

EFFECT: obtaining of new biologically active compounds and pharmaceutical compounds based on them.

27 cl, 4 ex, 1 tbl

The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received

The invention relates to new compounds of the formula (I) in which R1represents a group of formula (Ia) or (IB), in which either R7represents an optionally protected hydroxy-group, alloctype, halogen, -OR10where R10represents lower alkyl, optionally protected-O(CH2)mHE, where m = 2 to 4, or-ОСОNН2and R7ais hydrogen, or R7and R7atogether represent oxoprop, R8represents a hydroxy or methoxy group, and R9- hydroxy - or alloctype; R2- hydrogen, alloctype or optionally protected hydroxy-group, and between the two carbon atoms connected by the dotted line, there is a simple or a double bond; R3is methyl, ethyl, n-propyl or allyl; or R4represents hydrogen or a hydroxy-group, and R4ais hydrogen, or R4and R4atogether represent oxoprop; or R5represents a hydroxy-group, and R5ais hydrogen, or R5and R5atogether represent oxoprop; and a represents a group of formula-CH(OR6)-CH2-(CH2)nor-CH= CH-(CH2)n- associated with carbon atom (CH2

The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received

The invention relates to a new process for the preparation of 9-amino-20/S/-camptothecin formula /I/

< / BR>
which is a well-known anti-cancer agent: Wani, etc

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula , where X is -O-; values of Ar, R1-R5, R11 are given in the formula of invention. The said compounds have inhibitory effect on HIV reverse transcriptase. The invention also relates to a pharmaceutical composition containing the invented compounds or their pharmaceutically acceptable salts.

EFFECT: obtaining new compounds and a pharmaceutical composition containing said compounds.

8 cl, 61 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: there are described salts of 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB). Particularly, there is disclosed production process, pharmaceutical estimation and bioavailability estimation in vivo of N-methyl-D-glucamine salt and alkali salt. The pharmaceutical compositions containing these salt forms are used in methods of treating HIV infection and related diseases. There is also described method for preparing DBS salts.

EFFECT: improved clinical effectiveness.

12 cl, 5 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing HIV protease inhibitor atazanavir sulphate in form of Form A crystals, which involves reacting a solution of a free base of atazanavir in an organic solvent in which atazanavir sulphate is virtually insoluble, at temperature ranging from 35°C to 55°C with a first portion of concentrated sulphuric acid in an amount sufficient for reaction with less than approximately 15 wt % free base of atazanavir, addition of nucleating centres of Form A atazanavir sulphate crystals, addition of an additional amount of concentrated sulphuric acid in several steps, where the acid is added at increasing rate to form atazanavir sulphate crystals and drying the atazanavir sulphate to form Form A crystals. A method of producing atazanavir sulphate in form of Form C crystals is also proposed.

EFFECT: improved method.

20 cl, 11 dwg, 6 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical composition, suitable for peroral introduction in form of solid medicinal form, which contains efficient amount of main salt of formula compound and composition with controlled rate of release, which contains solubilising agent, gel-forming agent and eater-soluble filler.

EFFECT: compositions are suitable for application in inhibiting of HIV integrase, treatment and prevention of HIV infection, and in treatment, prevention and retardation of AIDS development.

15 cl, 4 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,,,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

FIELD: medicine.

SUBSTANCE: present invention concerns lysine compounds of formula (I) or its pharmaceutically acceptable salts, a based pharmaceutical compositions and application for treatment or prevention of HIV-infection. The compounds of formula (I) where n is equal to 3 or 4, where X and Y identical or different are chosen from the group consisting of H, F, Cl, Br, I and -NR4R5, where R6 is chosen from the group consisting of unbranched alkyl group, containing 1 to 6 carbon atoms, and branched alkyl group containing 3 to 6 carbon atoms, where R3 is chosen from the group consisting of the group of formula R3A-CO-, and R3a is chosen from the group consisting of unbranched or branched alkyl group containing 1 to 6 carbon atoms, alkyloxygroup containing 1 to 6 carbon atoms, and 4-morpholinyl, where R4 and R5 are identical and represent H, where R2 is chosen from the group consisting of diphenylmethyl group, naphthyl-1-CH2-group, and naphthyl-2-CH2-group, where X' and Y' are identical and represent H, and where R1 is chosen from the group consisting of from (HO)2P(O) and (MO)2P(O), where M represents alkaline metal.

EFFECT: lysine compounds representing effective inhibitors of aspartyl-protease.

15 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely medical products for HIV/AIDS infection therapy. There is offered application of Glimurid as a drug for HIV-infection treatment.

EFFECT: application of said drug ensures to increase the clinical effectiveness due to viral load reduction and immunocorrection.

1 ex, 2 dwg

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: salts of di- and/or trinicotinates of glycyrrhizic acid are inhibitors of human immunodeficiency virus reproduction, including salts of di- and/or trinicotinates of glycyrrhizic acid.

EFFECT: derivatives of glycyrrhizic acid display properties of highly efficient and water-soluble inhibitor of human immunodeficiency virus reproduction.

2 cl, 5 ex, 2 tbl, 2 dwg

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention proposes application of (1R)-1-[({(2R)-2-amino-3-[(8S)-8-(cyclohexyl-methyl)-2-phenyl-5.6-dihydromidazo[1.2-a]pyrazin-7(8H)-yl]-3-oxopropyl}ditio)methyl]-2-[(8S)-8-(cyclohexylmethyl)-2-phenyl-5.6-dihydromidazo[1,2-a]pyrazin-7(8H)-yl]-2-oxoethylamine and pharmaceutically acceptable salts thereof for obtaining a remedy for pain prevention or management. In particular, pains provoked by neuropathy and/or inflammation, other chronic diseases: cancer, radiculopathies, painful obesity, migraine, chronic diseases, fibromailgia, algoneurodistrophy, or complex local pain syndrome, brain vascular diseases, arthrosis, arthritis, diabetic neuropathies or neuropathies due to HIV, sciatica, painful muscle contractions, intoxication, scalds, posthepeic neuralgias, thalamus disease or disseminated sclerosis, or pre- and/or postsurgical pains.

EFFECT: reduction of pain sensitivity threshold at hyperalgesia and at taxol induced neuropathy.

7 cl, 4 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of modulating expression of a target gene induced by β-catenin using an agent which increases linkage of p300 with β-catenin and reduces linkage of CBP with β-catenin, involving bringing a composition containing β-catenin, CBP and p300, where β-catenin is more likely linked to CBP than p300, into contact with an agent in an amount which is effective for changing the probability of linking β-catenin to CBP compared to p300, where the said agent is a compound with a structure selected from formula (I), or its stereoisomers: where A represents -(C=O)-, B represents -(CHR4)-, D represents -(C=O)-, E represents -(ZR6)-, G represents -(XR7)n-> W represents (C=O)NH-, X represents nitrogen or CH, Z represents CH, n = 0 or 1. Values of substitutes R1 and R2 are indicated in the formula of invention. The invention also relates to a composition for modulating expression of a target gene induced by β-catenin.

EFFECT: novel compounds have useful biological properties.

9 cl, 7 tbl, 30 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention concerns compounds of general formula I or to their pharmaceutically acceptable salts, where X1 - CH; X2 - N or CH; Q1 represents ,

where X11 - CH or C-halogen; X12 - CH, C-halogen or C-CF3; X13 - CH; X14 - C-E11, and E11 represents C0-10alkyl or C0-10alkoxy; X15 - CH or N; X16 - N or N+ -0; G1 - phenyl or 5-6-members unsaturated ring containing one heteroatom N or S; R1 - C0-10alkyl, cycloC3-10alkyl or piperidinyl, any of which is optionally substituted with 1-2 independent substitutes G11, or R1 represents phenyl; G11 is chosen from: OR21 where R21 represents C0-10alkyl; -oxo; -cycloC3-8alkyl; -C0-10alkyl optionally substituted with group N(C0-10alkyl)(C0-10alkyl) wherein C0-10alkyl is optionally substituted with group N(C0-10alkyl)C(O)C0-10alkyl; group OR2221, where R2221 - C0-10alkyl; group N(C0-10alkyl)C(O)C0-10alkyl; group N(C0-10alkyl)SO2(C0-10alkyl); group -N(C0-10alkyl)C(O)N(C0-10alkyl)(C0-10alkyl); group -N(C0-10alkyl)C(=O)R3331, where R3331 - C1-10alkoxy C1-10alkyl or tetrahydrofuranyl; -N(R21)R31 where R21 and R31 independently represent C0-10alkyl optionally substituted with thiophenyl, morphlinyl, furanyl; cycloC3-8alkyl; C1-10alkoxyC1-10alkyl; tetrahydropyranyl; piperidylC0-10alkyl; or piperidyl optionally substituted with C0-10alkyl; or R21 and R31 optionally taken together with nitrogen atom whereto attached, form 3-10-members saturated ring optionally substituted with one or more independent substitutes G1111, and optionally including one or more heteroatoms different from nitrogen whereto R21 and R31 are attached; where G1111 - C0-10alkyl optionally substituted with group OR77 where R77 - C0-10alkyl, or G1111 represents C1-10alkoxyC1-10alkyl, pirimidinyl, pyrazinyl, imidazolylmethyl; C(O)N(R21)R31 where R21 and R31 independently represent C0-10alkyl; -C(O)O(C0-10alkyl); -C(O) C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or halogen; -heterocyclylC0-10alkyl where heterocyclyl represents 4-6-members saturated ring containing 1 or 2 heteroatoms, independently chosen from N, O or S optionally substituted with a substitute chosen from: 1) OR2221, where R2221 - pyrimidinyl or C0-10lkyl; 2) C(O)OR2221, where R2221 - C0-10alkyl or phenyl-C0-10alkyl; 3) C(O)C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or C1-10alkoxy C1-10alkyl; 4) C(O)N(C0-10alkyl)(C0-10alkyl); 5) S(O)2C0-10alkyl; 6) SO2N(C0-10alkyl)(C0-10alkyl); 7) -NR2221R3331, where R2221 and R3331 taken together with nitrogen atom whereto attached, form pyrrolidinyl; or G11 represents C, which taken together with carbon whereto attached, forms C=C double bond substituted with R5 and G111 where R5 and G111 are hydrogens. The invention also specifically concerns cys-3-[8-amino-1-(2-phenylquinoline-7-yl)-imidazo[1,5-α]pyrazine-3-yl]-1-methl-cyclobutanole or its pharmaceutically acceptable salt. The specified compounds and their pharmaceutically acceptable salts are applicable in treatment of conditions mediated by activity IGF-1R proteinkinase, particularly angiogenesis, vascular permeability, immune response, cell apoptosis, tumour growth or inflammation. The invention also concerns a pharmaceutical composition.

EFFECT: improved efficiency of the composition and method of treatment.

14 cl, 3 tbl, 171 ex

Up!