Bis-benzimidazole derivatives as hepatitis c virus inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

 

The technical field to which the invention relates

This invention relates to derivatives of bis-benzimidazole, which are inhibitors of hepatitis C virus (HCV), their synthesis and their use, alone or in combination with other inhibitors of HCV, for the treatment or prevention of HCV.

Prior art

HCV is a single stranded positive RNA virus belonging to the family of virusesFlaviviridaethe genus hepacivirus. The viral genome is translated into a single open reading frame, which encodes a number of structural and nonstructural proteins.

After the initial acute infection, most infected individuals develop chronic hepatitis, because HCV replicates preferentially in hepatocytes, but is not directly cytopathic. In particular, the lack of intensive T-lymphocytic response and high ability of the virus to mutate, apparently, provide a high level of chronic infection. Chronic hepatitis can progress to hepatic fibrosis leading to cirrhosis, liver disease end stage, and HCC (liver cell carcinoma), making it a major cause of liver transplantations.

There are 6 major HCV genotypes and more than 50 subtypes, which are geographically distributed in different ways. HCV type 1, not only is em a predominant genotype in Europe and the USA. Marked genetic heterogeneity of HCV has a high diagnostic and clinical value, as a possible explanation for the difficulties in developing a vaccine and lack of response to treatment.

HCV can be transmitted through contact with infected blood or blood products, for example, after blood transfusion or intravenous drugs. The introduction of the diagnostic tests used for screening blood, caused a downward trend in the occurrence of post-transfusion HCV infection. However, given the slow progression to liver disease end-stage existing infection will remain a major medical and economic problem for decades.

Modern methods of treatment of HCV is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. This combination therapy leads to a reduced virologic response to more than 40% of patients infected with viruses 1 genotype and approximately 80% of patients infected with 2 and 3 genotypes. In addition to limited efficacy against HCV-1 genotype, this combination therapy has significant side effects, including flu-like symptoms, hematologic disorders, and neuropsychiatric symptoms. Thus, there is a need for a more eff is active, more convenient and better tolerated treatments.

Experience with drugs against HIV, and, in particular, HIV protease inhibitors, has shown that suboptimal pharmacokinetics and complex dosing schedules quickly lead to unforeseen problems associated with the mode of treatment. This, in turn, means that the 24-hour minimum concentration minimum plasma concentration) of the respective drugs in the treatment of HIV is often reduced below the threshold IC90or ED90for most of the day. I think that 24 hours is the minimum level at least IC50and, more realistic, IC90or ED90is necessary to slow the emergence of drug-resistant tool mutant forms. Achieving the required pharmacokinetics and metabolism of medicines to ensure such minimum levels is an important task in the development of the medicinal product.

Protein NS5A HCV is below NS4B protein and higher protein NS5B. After post-translational cleavage of the viral serine protease NS3/4A, NS5A Matures in the zinc-containing phosphoprotein of the three domains, which exists either in the form of hypophosphorylated (56-kDa, p56), or hyperphosphorylation forms (58-kDa, p58). NS5A HCV is involved in many aspects of life the military cycle of the virus, including viral replication and Assembly of infectious particles, as well as modulating the environment of its host cell. Although this protein is not attributed to enzymatic function, described that he interacts with numerous viral and cellular factors.

In a number of patents and patent applications described compounds with inhibitory activity against HCV, in particular aimed at NS5A. In WO2006/133326 described derivatives stilbene, and in WO2008/021927 and WO2008/021928 described biphenylene derivative having the activity of inhibiting HCV NS5A. In WO2008/048589 described derivatives of 4-(phenylethynyl)-1H-pyrazole and their antiviral use. In WO2008/070447 described a wide range of inhibiting HCV compounds, including benzimidazole part. As in WO2010/017401, and WO2010/065681 described bis-imidazole inhibitors of HCV NS5A.

There is a need for inhibitors of HCV, which can overcome the shortcomings of modern therapy of HCV, such as side effects, limited efficacy, the emergence of resistance and non-patient treatment, and to improve the response in the form of ongoing viral load.

The present invention relates to a group of inhibiting HCV bis-benzimidazole derivatives with suitable properties for one or more of the following parameters: antiviral efficacy, favorable Pro is ü development of resistance the reduction or absence of toxicity or genotoxicity, favorable pharmacokinetics and pharmacodynamics, simplicity of manufacture and introduction and limited interaction medicinal product is a medicinal product with other medicinal substances, in particular with other anti-HCV, or lack of it.

Compounds according to the invention can also be attractive due to the fact that they lack activity against other viruses, in particular against HIV. HIV-infected patients often suffer from co-infections, such as HCV. The treatment of such patients with HCV inhibitor, which also inhibits HIV can lead to the emergence of resistant HIV strains.

Description of the invention

In one aspect the present invention relates to compounds that can be represented by the formula I:

including any possible stereoisomers, where

R and R' are independently selected from-CR1R2R3, aryl, optionally substituted by 1 or 2 substituents selected from halogen and methyl, and heteros4-7cycloalkyl, where R1selected from C1-4the alkyl, optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; tetrahydropyranyl; phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected and from halogen, C1-4alkoxy, triptoreline, or 2 substituents on adjacent ring atoms form a 1,3-dioxolane group; benzyl, optionally substituted with halogen or methoxy; heteroaryl and heteroaromatic;

R2selected from hydrogen, hydroxyl, amino, mono - and di-C1-4alkylamino, (C3-6cycloalkyl)(C1-4alkyl)amino, C1-4alkylcarboxylic, phenylamino, C1-4allyloxycarbonyl, (C1-4allyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonyl, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidine-1-yl, 3,3-deformability-1-yl, morpholine-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and

R3represents hydrogen or C1-4alkyl, or

CR2R3together form a carbonyl; or

CR1R3forms cyclopropyl group;

and their pharmaceutically acceptable salts and solvate.

The following aspect of the invention relates to the use of compounds of the formula I or their subgroups, as described herein, for inhibiting HCV. An alternative is provided by the use of these compounds for the manufacture of a medicine for inhibiting HCV.

Embodiments of the present invention pertain to compounds of formula (I) or any subgroup, as described herein, where applicable the one or more definitions for R, R', R1, R2and R3as indicated in this document.

Subgroups of compounds of formula I are compounds of formula I, or subgroups of compounds of formula I, as defined herein, where R and R' independently represent-CR1R2R3or aryl, where aryl is a 5-membered heteroaryl; in particular, where R and R' independently represent-CR1R2R3; more specifically, where R and R' represent-CR1R2R3and are equal.

Subgroups of compounds of formula I are compounds of formula I, or subgroups of compounds of formula I, as defined herein, where R2represents a hydroxyl, amino, mono - or di-C1-4alkylamino, C1-4alkylcarboxylic, C1-4allyloxycarbonyl; in particular, R2represents a C1-4alkylcarboxylic or C1-4allyloxycarbonyl.

Subgroups of compounds of formula I are compounds of formula I, or subgroups of compounds of formula I, as defined herein, where R1selected from C1-4of alkyl; phenyl, optionally substituted by 1 or 2 substituents, independently selected from halogen, methyl, methoxy, or 2 substituents on adjacent atoms of the ring form a 1,3-dioxolane group; and heteroaryl. the particular R1selected from branched C3-4of alkyl; phenyl, optionally substituted by 1 Deputy selected from halogen and methyl; and heteroaryl. More specifically, R1selected from branched C3-4of alkyl; phenyl, optionally substituted by 1 Deputy selected from halogen.

In the first embodiment, R and R' are independently selected from-CR1R2R3, aryl, optionally substituted by 1 or 2 substituents selected from halogen and methyl, and heteros4-7cycloalkyl, where

R1selected from C1-4the alkyl, optionally substituted by methoxy or dimethylamino; phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4alkoxy, triptoreline, or 2 substituents on adjacent atoms of the ring form a 1,3-dioxolane group; benzyl, optionally substituted with halogen or methoxy; heteroaryl and heteroaromatic;

R2selected from hydrogen, hydroxyl, amino, mono - and di-C1-4alkylamino, C1-4alkylcarboxylic, C1-4allyloxycarbonyl, C1-4alkylaminocarbonyl, piperidine-1-yl and imidazol-1-yl; and

R3represents hydrogen, or R1and R3together form oxo or cyclopropyl group; or their pharmaceutically acceptable salt and/or MES.

In the second variant implementation, the value of R and R' are independently selected from-CR 1R2R3, aryl, optionally substituted by 1 or 2 substituents selected from halogen and methyl, and heteros4-7cycloalkyl, where

R1selected from C1-4the alkyl, optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4alkoxy, triptoreline, or 2 substituents on adjacent atoms of the ring form a 1,3-dioxolane group; benzyl, optionally substituted with halogen or methoxy; heteroaryl and heteroaromatic;

R2selected from hydrogen, hydroxyl, amino, mono - and di-C1-4alkylamino, (C3-6cycloalkyl)(C1-4alkyl)amino, C1-4alkylcarboxylic, phenylamino, C1-4allyloxycarbonyl, (C1-4allyloxycarbonyl)(C1-4Alcide)amino, C1-4alkylaminocarbonyl, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidine-1-yl, 3,3-deformability-1-yl, morpholine-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and

R3represents hydrogen or C1-4alkyl, or

CR2R3together form a carbonyl; or

CR1R3forms cyclopropyl group;

and their pharmaceutically acceptable salt and solvate;

provided that (a) when R and R' are identical and represent the th-CR 1R2R3where (a-1) R2represents a C1-4allyloxycarbonyl and R3represents hydrogen, then R1different from unsubstituted C1-4the alkyl, or ethyl substituted by hydroxyl or methoxy; or where (a-2) R2represents methoxycarbonylamino and R3represents hydrogen, then R1different from unsubstituted phenyl; and

(b) when R and R' are different and each independently represents-CR1R2R3where R1represents phenyl or 2-propyl, R2is a dimethylamine and R3represents a hydrogen in the same group-CR1R2R3then in the other group-CR1R2R3R1can't take the value of 2-propyl and R2can't take is methoxycarbonylamino and R3can't take the value of hydrogen.

In the third embodiment, R and R' are independently selected from-CR1R2R3where R1selected from phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4alkoxy, triptoreline, or 2 substituents on adjacent atoms of the ring form a 1,3-dioxolane group;

R2selected from hydroxyl, mono - or di-C2-4alkylamino, (C3-6cycloalkyl)(C1-4alkyl)amino, C1-4al is ylcarbonyl, (C1-4allyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonyl, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidine-1-yl, 3,3-deformability-1-yl, morpholine-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and

R3represents hydrogen or C1-4alkyl, or

CR2R3together form a carbonyl; or

CR1R3forms cyclopropyl group;

and their pharmaceutically acceptable salt and solvate;

In the fourth embodiment, R1selected from heteroaryl and heteroaromatic;

R2selected from hydrogen, mono - or di-C1-4alkylamino, (C3-6cycloalkyl)(C1-4alkyl)amino, C1-4alkylcarboxylic, C1-4allyloxycarbonyl, (C1-4allyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonyl, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidine-1-yl, 3,3-deformability-1-yl, morpholine-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and

R3represents hydrogen;

and their pharmaceutically acceptable salt and solvate.

In the fifth embodiment,

R1represents a C1-4alkyl;

R2selected from C1-4alkylaminocarbonyl or tetrahydro-2-oxo-1(2H)-pyrimidinyl; and

R3represents hydrogen or C1-4alkyl;

and their pharmaceutically acceptable salt and solvate.

In the sixth embodiment,

R1represents a C3-6cycloalkyl;

R2represents hydrogen

and R3represents hydrogen;

and their pharmaceutically acceptable salt and solvate.

The following aspect of the invention relates to a compound of formula I or its pharmaceutically acceptable salt, hydrate or MES for use for the treatment or prevention of (or for the manufacture of a medicinal product for the treatment or prophylaxis) of HCV infection. Typical genotypes of HCV in the context of treatment or prevention according to the invention include, but are not limited to, genotype 1b (prevalent in Europe) and 1a (predominant in North America). The invention relates to a method of treatment or prevention of HCV infection, in particular genotype 1a or 1b, including an introduction to the individual in need, a therapeutically effective amount of a compound as defined herein above.

Pure stereoisomeric forms of the compounds and intermediates used in this document, is defined as isomers, essentially not containing other enantiomeric or diastereoisomeric forms of the same basic molecular structure of the above compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or p is omegaton compounds having a stereoisomeric excess of at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and the absence of another isomer), more specifically, the compounds or intermediate compounds having a stereoisomeric excess of 90% up to 100%, more specifically having a stereoisomeric excess of 94% up to 100% and most specifically having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood similarly, but considering the enantiomeric excess and diastereomeric excess, respectively, of the mixture.

Pure stereoisomeric forms or stereoisomers of the compounds and intermediates of the present invention can be obtained using known in the field of methods. For example, the enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Their examples are tartaric acid, dibenzoyltartaric acid, dItalia acid and camphorsulfonic acid. Alternative enantiomers can be divided chromatographic methods using chiral stationary phases. These pure stereochemical isomeric form can also be obtained from testwuide pure stereoisomeric forms of the appropriate starting materials, provided the reaction proceeds stereospetsifichno. Preferably, if it is desired specific stereoisomer, the specified connection synthesize stereospecific methods of getting. In these methods are primarily used enantiomerically pure starting materials.

Diastereomeric the racemates of the compounds of formula I can be obtained separately by conventional methods. Appropriate methods of physical separation, which can preferably be used are, for example, selective crystallization and chromatography, such as column chromatography or supercritical fluid chromatography.

The compounds of formula have several centers of chirality. Interest stereogenic centers rings pyrrolidine on the 2-carbon atom. The configuration in this position may correspond to L-Proline, i.e.,

or to comply with D-Proline, i.e.,

Of particular interest are compounds of the formula I or their subgroups, as defined herein, which correspond to the formula Ia.

Also of interest is the group configuration-CR4R2R3: when R1selected from C1-4the alkyl, optionally substituted by methoxy, hydroxyl or dimethylamino; C 3-6cycloalkyl and tetrahydropyranyl, then it is preferable to S-configuration; when R1selected from phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4alkoxy, triptoreline, or 2 substituents on adjacent atoms of the ring form a 1,3-dioxolane group; and heteroaryl; then preferred is R-configuration.

Pharmaceutically acceptable salt additive include therapeutically active non-toxic acid and basic additive salt forms of the compounds of formula (I) or their subgroups. Interest free, i.e. naselenie forms of the compounds of formula I or any subgroup of compounds of formula I, referred to in this document.

Pharmaceutically acceptable acid additive salts can conveniently be obtained by treating the basic form of such a suitable acid. Suitable acids include, for example, inorganic acid, such as halogen acids, e.g. hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric acid and so on; or organic acids such as acetic, propionic, hydroxyestra, lactic, pyruvic, oxalic (i.e. o), malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic (i.e. hydroxybutanal the I acid), tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, pamula acid, etc., on the Contrary, these salt forms can be converted by treatment of the corresponding base in the form of a free base.

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

The term "solvate" includes any pharmaceutically acceptable solvate, which the compounds of formula I and their salts are able to form. Such solvate represent, for example, hydrates, alcoholate, for example, ethanolate, propanoate etc.

Some of the compounds of formula I can also exist in tautomeric forms. For example, tautomeric forms an amide (-C(=O)-NH-) groups are kinoparty (-C(OH)=N-). Understood that tautomeric forms, though the e is specified in the structural formula, presented in this document, included in the scope of the present invention.

As used herein, "C1-4alkyl" as a group or part of a group defines a saturated straight or branched hydrocarbon group having from 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl. For the purposes of the present invention among the C1-4Akilov interest C3-4alkali, i.e., straight or branched hydrocarbon group having 3 or 4 carbon atoms, such as 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl. Of particular interest may be branched C3-4alkyl, such as 2-propyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl.

The term "C3-6cycloalkyl" as a group or part of a determines the saturated cyclic hydrocarbon group having 3 to 6 carbon atoms, which together form a cyclic structure. Examples of C3-6cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"C1-4alkoxy" as a group or part of a group means a group of the formula-O-C1-4alkyl, where C1-4alkyl is as defined above. Examples of C1-4alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy.

The term "halogen" awsesome for fluorine, chlorine, bromine and iodine.

As used herein, the term "(=O)" or "oxo" forms a carbonyl group, when it is attached to the carbon atom. It should be noted that the atom can be substituted only by exography, when the valence of the atom allows it.

As used herein "aryl" for the purpose of determining as a group or part of a means an aromatic ring structure, optionally containing one or two heteroatoms selected from N, O and S, in particular from N and O. the Specified aromatic ring structure having 5 or 6 atoms in the ring.

As used herein, the prefix "hetero-" in the definition of the group means that the group contains at least 1 heteroatom selected from N, O and S, in particular N and O. for Example, the term "heteroaryl" means an aromatic ring structure, as defined for the term "aryl", containing at least 1 heteroatom selected from N, O and S, in particular from N and O, for example, furanyl, oxazolyl, pyridinyl. The alternative term "heteros4-7cycloalkyl" means a saturated hydrocarbon group containing at least 1 heteroatom selected from N, O and S, in particular from N and O, for example, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl.

When the position of the group at the molecular part is not specified (for example, Deputy for f the Nile) or presents a flow connection, such a group may be located on any atom of this part, provided that the resulting structure is chemically stable. When a variable is present in the molecule more than once, each definition is independent.

When the term "compounds of formula I", or "the present compounds" or similar terms are used herein, it includes compounds of formula I, including its possible stereoisomeric forms and pharmaceutically acceptable salt and solvate.

General methods of synthesis

Scheme 1

The compounds of formula I, where R and R' are the same, can be obtained by using synthetic reactions illustrated in scheme 1 above. Oxidative cyclization of N-(tert-butoxycarbonyl)-L-prolinal 4-Brabanthal-1,2-diamine leads to a derivative of benzimidazole II, which turns into baranovy ester III in Pd catalyzed conditions in the presence of bis(pinacolato)Debora. Then baranovy ester III is transformed into compound IV by linking with 1,4-diodenta using Suzuki conditions-Maillard. Alternative instead of 1,4-diadesol you can use 1,4-dibromobenzyl. Suitable Pd catalyst is dichloro-((bis-diphenylphosphino)ferrocenyl)palladium(II) (Pd(dppf)Cl2). Compound V obtained after UD is of tert-butoxycarbonyl (Boc) protective group of nitrogen pyrrolidine in acidic conditions, for example, using HCl in isopropanol. Then, the resulting compound V can be transformed into a compound of formula I by acylation of the corresponding acid of the formula R-C(=O)-OH, where R has the values of R and R' are as defined for compounds of formula I or any subgroup.

Specified acylation can be conducted by reaction of starting materials in the presence of the agent of combination reaction or by conversion of the carboxyl functional groups in the active form, such as an active ester, mixed anhydride or chloride, or bromide carboxylic acid. A General description of such reactions and reagents used in them, can be found in General reference books on chemistry of peptides, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev. ed., Springer-Verlag, Berlin, Germany, (1993).

Examples of reactions combination for the acylation of the amino group or the amide bond formation include the azide method, the method of the mixed anhydride coal-carboxylic acid (isobutylparaben), carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide, such as N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide), an active way of ester (e.g. p-nitrophenylthio, p-Hohenlohe, trichloranisole, pentachlorphenol, pentafluorophenyl, N-hydroxyestrogen imido - esters and so on), the way R is agent K Woodword, the way 1,1-carbonyldiimidazole (CDI or N,N'-carbonyldiimidazole), methods of phosphorus reagents or oxidation-reduction methods. Some of these methods can be enhanced by adding suitable catalysts, for example in the way carbodiimide is added 1-hydroxybenzotriazole or 4-DMAP. The following agents reaction combinations are hexaflurophosphate (benzotriazol-1 yloxy)-Tris(dimethylamino)phosphonium either alone or in the presence of 1-hydroxybenzotriazole or 4-DMAP; or tetrafluoroborate 2-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (TBTU), or hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU). These reactions combination can be carried out either in solution phase (liquid phase) or in the solid phase. For the purposes of the present invention the preferred method of acylation is carried out with the use of HATU.

Of combination reaction is preferably carried out in inert solvents, such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO, HMPT, or ethers, such as tetrahydrofuran (THF).

In many cases of combination reaction is carried out in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-METI pyrrolidin, 4-DMAP or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction temperature may be in the range from 0°C to 50°C and the reaction time may be in the range from 15 minutes to 24 hours

Scheme 2

Alternative compounds of formula I, where R and R' are not the same, i.e. the compounds of formula XIII can be obtained using the synthetic route illustrated in scheme 2. Using standard Suzuki conditions-Maillard, it is possible to conduct the reaction mix broowaha of ester III and 1,4-diadesol in conditions comparable to the conditions used for the conversion of III to IV (scheme 1), except that the ratio of 1,4-diadesol and broowaha of ester III is approximately 1 to 1, it is possible above, to obtain monastica VII. Alternative instead of 1,4-diadesol you can use 1,4-dibromobenzyl. Then VII can be subjected to reaction combination with bronovil complex ester VIII. It should be understood that aminosidine group PG on the nitrogen pyrrolidine in baronova complex ester VIII should be selected so that it can be removed under conditions that do not affect the Boc-group, or R-C(=O)-group in the other nitrogen in the molecule. You should also understand that PG may also be an R'-C(=O)-group end of the synthesized compounds of formula I. the Reaction mix VII and VIII can once again about what the contain using standard Suzuki conditions-Maillard, and to get the connection IX. Then from compound IX can selectively remove the protective group to obtain compound X using conditions suitable for removal of the Boc-protective group. For example, when PG is benzyloxycarbonyl or benzyl, Boc-protective group can be selectively removed under standard conditions of removal of the protective group Boc, i.e. by treatment with acid.

Moreover, in the case where PG is benzyloxycarbonyl or benzyl, PG can selectively remove restorative treatment, leaving R-C(=O)-group in compound XI unaffected. Other suitable protective group PG and the appropriate conditions for selective removal of the protective groups can be found in Greene, "Protective groups in organic synthesis", Peter G. M. Wuts, Fourth Edition, Chapter 7: "Protection for the Amino group". Then compound X can be allievate the corresponding acid of the formula R-C(=O)-OH, where R has the values of R, as defined for compounds of formula I or any subgroup. Get the connection XI.

To connect XI, when PG represents -(C=O)-R', compound XI coincides with compound XIII. When PG represents aminosidine group PG can be removed under conditions that are compatible with -(C=O)-R, for example by hydrogenation, when PG is a benzyl or benzyloxycarbonyl, or basic conditions, such as diethylamine, the case, when PG represents fluorenylmethoxycarbonyl, to obtain the compounds XII. Other methods of selective removal of the protective groups can be found in the directory Greene.

In the case when -(C=O)-R incompatible with the terms of the removal of the protective group PG, you can use the path presented in figure 5, where the protective group PG is selected so that it was compatible with the Boc group.

Compound XII can be converted into compound XIII acylation, similar to the conversion of XIV to XV, V I and X in XI, and as described for the conversion of V to I according to the scheme 1.

Scheme 3

Scheme 4

Baranovy ester VIII can be obtained in at least two different ways, as illustrated in schemes 3 and 4. When PG represents a protective group such as benzyloxycarbonyl, fluorenylmethoxycarbonyl, benzyl or other suitable protective group PG, as described in the Handbook Greene, the compound can be synthesized by the methods used for the synthesis of intermediate compounds II and IIa (see example 2), and broowaha of ester III, starting with a suitably protected derivative of pyrrolidine. When PG represents -(C=O)-R', the connection can be obtained from the intermediate compound (II), as presented in CX is IU 4, by removing the protective group of the nitrogen of Proline in acidic conditions, such as HCl, for example, in iPrOH, or triperoxonane acid to obtain compound XIV, with the subsequent condensation reaction under standard acylation conditions, such as the use of HATU in the presence of a base such as DIPEA. Next, the resulting bromide XV can be converted into Bronevoy acid VIII (where PG represents -(C=O)-R'), such as the conversion of II to III.

Scheme 5

Alternatively, as shown in figure 5, the protective group of compound IX can be removed under conditions that are compatible with the Boc protecting group, e.g. by hydrogenation, when PG is a benzyl or benzyloxycarbonyl, or basic conditions, such as diethylamine, when PG represents fluorenylmethoxycarbonyl, to obtain the compound XVI. Other methods of selective removal of the protective groups can be found in the directory Greene. In this case, the connection of the XVI coincides with compound X, and PG is a Boc. In this case, the removal of the protective group from the XI-XII can be carried out in conditions similar to the conversion of II to XIV and IV V.

The synthesis methods described above in schemes 1-5, also can be performed using racemic Proline derivatives or derivatives of D-Proline instead of L-Proline. So about what atom, it is possible to obtain the compounds of formula I with an alternate stereochemistry.

In the following aspect the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I, as described in the present description, and pharmaceutically acceptable carrier. Therapeutically effective amount is an amount sufficient to stabilize or reduce HCV infection in infected individuals, or the amount sufficient for the prevention of HCV infection in individuals with risk of infection. The following aspect of this invention relates to a method for producing a pharmaceutical composition, as described in the present description, which includes mixing into a homogeneous mixture pharmaceutically acceptable carrier with a therapeutically effective amount of the compounds of formula I, as described in the present description.

Thus, for the purposes of introducing the compounds of the present invention or any subgroup can be made in the form of various pharmaceutical forms. As suitable compositions can be called all compositions usually employed for systemic administration of drugs. To obtain pharmaceutical compositions of the present invention, an effective amount of a specific soedinitionotcanne in the form of additive salt or complex with the metal as the active ingredient is mixed into a homogeneous mixture with a pharmaceutically acceptable carrier, which can be in various forms depending on the desired form of the drug for injection. Preferably, these pharmaceutical compositions were presented in unit dosage form, in particular for oral, rectal, subcutaneous administration, or for parenteral injection. For example, to obtain compositions in oral dosage form can be used with any conventional pharmaceutical environment, such as water, glycols, oils, alcohols, etc., in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja substances, etc., in the case of powders, pills, capsules and tablets. Due to the simplicity of the introduction of tablets and capsules represent the most preferred oral unit dosage forms, in which case typically use solid pharmaceutical carriers. In the case of parenteral compositions, the carrier typically contains sterile water constituting at least a large part of it, although it may include other ingredients, for example, to ensure solubility. For example, you can get injectable solutions, in which the medium contains a salt solution, a glucose solution or a mixture with the left solution and glucose solution. You can also get injectable suspension, in which case you can use a suitable liquid carriers, suspendresume substances, etc. are Also provided by the drugs in solid form that must be turned, immediately before use, to liquid form. In the compositions suitable for percutaneous administration, the carrier optionally contain reinforcing the permeability of the substance and/or a suitable wetting agent, optionally combined with suitable additives of any structure in small proportions that do not have significant adverse effects on the skin. Compounds of the present invention can also be entered via oral inhalation or insufflation in the form of a solution, suspension or dry powder, using any of the known in the field of systems for the delivery.

Particularly preferred is the preparation of the above-mentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used in the present description, the unit dosage form refers to physically discrete units suitable as single doses, where each unit contains a certain amount of active ingredient calculated to provide the desired therapeutic effect, compatible with the IDT with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including rough or coated tablets), capsules, pills, suppositories, packets of powder, wafers, injectable solutions or suspensions, etc., and their individual types.

The compounds of formula I exhibit activity against HCV, and can be used for treatment or prevention of HCV infection or disease due to HCV. Disease due to HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, liver disease end-stage hepatic cell carcinoma. Moreover, some compounds of the present invention it is known that they are active against mutant strains of HCV. In addition, the compounds according to the present may have attractive properties from the point of view of bioavailability, demonstrated a favorable pharmacokinetic profile, including an acceptable half-life, AUC (area under the curve) and the maximum and minimum values, and devoid of adverse effects, such as lack of rapid onset of action and retained in the tissues.

Antiviral activity of the compounds of formula I against HCVin vitrotested in the cellular system with HCV replicon based on Lohmann et al. (1999) Science 285:110-113, with additional modifications described by Krieger et al. (2001) Journal of Virology 7: 4614-4624, which are further illustrated in the Examples section. Although this model is not a complete model of HCV infection, this model is widely distributed as the most reliable and effective model of Autonomous replication of HCV RNA, are currently available. Compounds with activity against HCV in this cellular model, considered as candidates for further development for the treatment of HCV infection in mammals. It will be clear that it is important to distinguish compounds that are specific impede the functioning of HCV, from compounds, which have a cytotoxic or cytostatic effects in the model replicon HCV, and consequently lead to a reduction in HCV RNA or concentration associated reporter enzyme. In this area known methods of analysis for assessing cellular cytotoxicity based on, for example, the activity of mitochondrial enzymes using fluorogenic redox dyes such as resazurin. Moreover, there are ways of screening counting cells for evaluation of selective inhibition of the activity of a linked reporter gene such as luciferase gene fireflies. Suitable types of cells can be adapted by stable transfection of reporter luciferase gene, expression of which depends on the Constitution is utive active promoter of the gene such cells can be used as a method of screening calculation to eliminate non-selective inhibitors.

Due to the properties against HCV, the compounds of formula I or their subgroups, as described in this document are suitable for inhibiting replication of HCV, in particular for the treatment of warm-blooded animals, in particular humans, infected with HCV, and for the prevention of HCV infections in warm-blooded animals, in particular humans. Moreover, the present invention relates to a method of treating a warm-blooded animal, in particular human infected with HCV or have the risk of HCV infection, and this method includes the introduction of a therapeutically or prophylactically effective amount of the compounds of formula I, as defined in the present document above.

Thus, the compounds of formula I as described herein, can be used as a medicine, in particular as a drug against HCV. The specified application as a medicine or method of treatment comprises the systemic introduction of HCV infected individuals or susceptible to HCV infection individuals amount effective to alleviate or prevent symptoms and conditions associated with HCV infection.

The present invention t is the train refers to the application of the presented compounds for the manufacture of a medicine for treatment or prevention of HCV infection.

Mainly, it is envisaged that effective antiviral daily amount may be from about 0.01 to about 50 mg/kg, or from about 0.02 to about 30 mg/kg of body weight. May be suitable introduction of the required dose as one, two, three, four or more subds appropriate intervals throughout the day. These subdata can be made in the form of a unit dosage forms, for example, containing from about 1 to about 1000 mg, or from about 1 to about 500 mg, or from about 1 to about 100 mg, or from about 2 to about 50 mg of the active ingredient in a unit dosage form.

Combination therapy

Also the present invention relates to combinations of compounds of formula I, its pharmaceutically acceptable salt or MES, and other antiviral compounds, in particular other compounds against HCV. The term "combination" refers to a product containing modulating (a) a compound of formula I, as defined herein above, and (b) another inhibitor against HCV as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections.

The combination of the present invention can use the TB as medicines. Thus, the present invention relates to the use of compounds of formula (I) or its sub-groups, as defined above, for the manufacture of a medicinal product, suitable for inhibiting HCV activity in a mammal infected with HCV viruses, where the specified drug used in combination therapy, and the specified combination therapy, in particular, includes the compound of formula (I) and at least one other agent against HCV, such as IFN-α, pegylated IFN-α, ribavirin, Albuferon, taribavirin, nitazoxanide Debio025 or a combination of both.

Other tools which can be combined with the compounds of the present invention, include, for example, nucleoside and non-nucleoside HCV polymerase inhibitors protease inhibitors helicase, NS4B inhibitors and tools that functionally inhibit the part of the internal landing ribosomes (IRES) and other tools that inhibit the attachment of HCV to the cell or virus entry into, broadcast HCV RNA, the transcription of HCV RNA replication or maturation of HCV, Assembly, or release of virus. Specific compounds within these classes include inhibitors of HCV protease, such as telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC435350 (TMC435), MK-7009, BI-201335, BI-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095, GS 9256, VX-985, IDX-375 (ingebi the EOS cofactor NS4A protease of HCV), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450, EP-013420 (and related compounds) and VBY-376; nucleoside inhibitors of HCV polymerase, suitable for the invention include R7128, PSI-7851, PSI 7977, IDX-189, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other analogs of nucleosides and nucleotides and inhibitors of HCV, including inhibitors obtained as 2'-C-methyl-modified nucleosides, 4'-Aza-modified nucleosides, and 7'-deaza-modified nucleosides, for example, 4-amino-1-[5-azido-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl]pyrimidine-2(1H)-he (link 1) and bis-2-methylpropanoate ester (reference 2). Non-nucleoside HCV polymerase suitable for the invention include HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728, GL-60667, ABT-072, AZD-2795 and 13-cyclohexyl-3-methoxy-17,23-dimethyl-7H-10,6-(methanomicrobiales)indolo[2,1-a][2]benzazepin-14.24 from-dione 16,16-dioxide (reference 3).

The following examples are provided to illustrate the invention and they should not be construed as limiting its scope.

EXAMPLES

Example 1 - synthesis of compound V

1.1 Obtain the intermediate compound (II)

To a solution of 4-Brabanthal-1,2-diamine (170 grams of 0.91 mol) in ethanol (2 l) was added (S)-tert-butyl-2-formylpyridine-1-carboxylate (258 g, 1.3 mol) at 25°C. the mixture was heated to 60°C for 24 hours, TLC showed that the reaction was completed. The solution was concentrated and the crude product was purified column chromatography (petroleum ether: ethyl acetate 10:1 to 2:1) to give 215 g II in the form of a yellow solid.

1H-NMR: CDCl3400 MHz

δ 7.95 is to 7.4 (m, 3H), 5,35-a 5.25 (m, 1H), 3,85-3,70 (m, 1H), 3,6-of 3.45 (m, 1H), 2,6-of 2.45 (m, 1H), 2,20-of 1.95 (m, 3H), 1,48-to 1.38 (m, 5H), 1,2-1,1 (m, 4H).

1.2 Obtaining an intermediate compound III

To a mixture of II (200 g, 546 mmol), potassium acetate (160,8 g of 1.64 mol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (416 g of 1.64 mol) in DMF (3 l) was added Pd(dppf)Cl2(20 g) in a gaseous nitrogen. The reaction mixture was stirred at 85°C for 15 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, the solids were removed by filtration and the solvent of filtrate was removed under reduced pressure. The residue was purified column chromatography on silica gel (petroleum ether: ethyl acetate 10:1 to 2:1) to obtain 125 g of III in the form of a white solid (contains 15% Bronevoy acid).

1.3 Obtaining an intermediate compound IV

To a solution of 1,4-diadesol (1.7 g, 5,15 mmol), III (6 g, 14.4 mmol) and K2CO3(2.14 g, a 15.5 mmol) in a mixture of dioxane-H2O (50 ml, 5:1) was added Pd(dppf)Cl2(300 mg) in a nitrogen atmosphere. The mixture was heated to 85°C min is of 15 hours. The mixture was cooled to room temperature, concentrated, added water and the mixture was extracted with ethyl acetate, dried over magnesium sulfate, the solids were removed by filtration and the solvent of filtrate was removed under reduced pressure. The crude product was purified by reversed-phase HPLC to obtain 2 g, 96% (IV).

1H-NMR: d-methanol 400 MHz

δ 7,84-of 7.70 (m, 6H), to 7.67-7,52 (m, 4H), 5,15-4,99 (m, 2H), 3,70-a 3.83 (m, 2H), 3,62-to 3.52 (m, 2H), 2,54 to 2.35 (m, 2H), 2,19-of 1.93 (m, 6H), 1,44-and 1.54 (m, 6H), 1,12-1,25 (m, 12H).

1.4 Obtain intermediate compound V

A 20-ml flask were placed IV (500 mg), dichloromethane (3 ml) and HCl in isopropanol (3 ml from 5 to 6 M solution, Acros). This mixture was allowed to mix for 4 hours at room temperature, LCMS confirmed complete metamorphosis in V. the Solvent was removed by azeotropic distillation under reduced pressure with toluene and methanol to obtain a yellowish-brown solid, which was used as is in the next stage.

Example 2 - Getting IIA, benzylamino intermediate compounds

A solution of 10 g of L-Proline and KOH (10 g) in 120 ml of isopropanol was stirred at 40°C, then drip added benzylchloride (13,5 ml). The reaction mixture was stirred for additional 6 hours, then neutralize with concentrated HCl to pH 5-6. Reactionuses was extracted with CH 2Cl2(3×70 ml), the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, the solids were removed by filtration and the solvent of filtrate was removed under reduced pressure. The residue was treated with acetone to obtain N-benzylbromide (15 g).

N-Antipolis (10.2 g, 50 mmol) and triethylamine (50 mmol) was dissolved in THF (250 ml) and cooled to 0°C. To this solution droplets were added ethylchloride (ClCOOEt, 50 mmol) over 15 minutes and was stirred for an additional 30 minutes. To this solution was added 4-Brabanthal-1,2-diamine (75 mmol) for 15 minutes. The reaction mixture was stirred at 0°C for 1 hour, then allowed it to reach room temperature and was stirred for 16 hours, and then boiled under reflux for 3 hours. After completion of the reaction the mixture was cooled to room temperature and was diluted with ethyl acetate (3×70 ml). The organic layers were combined, dried (magnesium sulfate), the solids were removed by filtration and the solvent of the filtrate is evaporated under reduced pressure. The residue was purified column chromatography (hexane/ethyl acetate: 7/3) to obtain 11 g of the intermediate compound.

11 g of the intermediate was dissolved in acetic acid (50 ml) at 20°C and was stirred for 15 hours. The solvent was removed under reduced pressure is, and then added NaHCO3(saturated aqueous, 200 ml). The resulting mixture was extracted with ethyl acetate (3×80 ml). The combined organic layers were concentrated and the residue was purified column chromatography to obtain 3 g of IIA.

Example 3 - synthesis of compounds of formula I

3.1 get No connection. 1

To a solution of V (400 mg, 0.77 mmol) in DMF (10 ml) was added DIPEA (0.5 ml, 3 mmol), HATU (0.73 g, 1.9 mmol) and phenylacetic acid (2.2 EQ, 230 mg, 1.7 mmol). The mixture was stirred for 2 hours at room temperature, and then purified by solid-phase extraction (Waters PoraPak CX 60cc, washed with 3 volumes of methanol before use). Put the crude reaction mixture, washed with methanol (4 volume), and then suirable 7 M ammonia in methanol (solution from Aldrich, 4 volume). The eluate was evaporated under reduced pressure to obtain a yellowish-brown foam. To obtain a pure solid substance was added HCl (3 ml, 5 to 6 M in isopropanol, Acros), and then the solvent was removed by azeotropic distillation with toluene to obtain a yellowish brown solid.

LCMS (M+H) m/z=685 for VI, having the formula C44H40N6O2

Alternative clearing and processing of the reaction mixture can be performed as follows: add CH2Cl2, washed with saturated NaHCO3to dry organizes the phase with Na 2SO4, filter, and concentrate in vacuo. Then the residue purified by chromatography on silica gel (0-10% MeOH in CH2Cl2) or preparative HPLC.

3.2 Obtaining compounds 2-62

Connection 2-62, are shown in table 1, was synthesized using the method for compound 1 described in example 3.1, using the appropriate carboxylic acid of formula R-C(=O)-OH.

All connections okharakterizovali using LC/MS. Used the following methods LC/MS:

Method A: system Waters Acquity UPLC equipped with a PDA detector (range 210-400 nm) and a Waters SQD with dual mode ion source ES+/-. The used column was a Halo C18, 2.7 microns, and 2.1×50 mm, and kept at 50°C. a Gradient from 95% aqueous formic acid (0.1 percent)/5% acetonitrile to 100% acetonitrile was passed within 1.5 minutes, kept for 0.6 minutes, and then returned to 100% aqueous solution of formic acid (0.1%) for 0.5 minutes. The flow rate was 0.6 ml/min

Method B: liquid chromatography: Waters Alliance 2695, UV detector: Waters 996 PDA, range: 210-400 nm; detector mass: Waters ZQ, ion source: ES+, ES-. Used column: SunFire C18 3.5 microns of 4.6×100 mm, mobile phase A: 10 mm NH4OOCH+0,1% HCOOH in H2O; mobile phase B: CH3OH; column temperature: 50°C; flow rate: 1.5 ml/min. While gradient (min) [%A/%B]: 0 [65/35] to 7[5/95 to 9.6[5/95] to 9.8[65/35] to 12 [65/35].

Method C: the system Waters Acquity UPLC equipped with a PDA detector (range 210-400 nm) and a Waters SQD with dual mode ion source ES+/-. The used column was a XS Strategy of 1.7 MK, 2,1×20 mm, and kept at 50°C. a Gradient from 100% aqueous formic acid (0.1%) to 100% acetonitrile was passed within 1.5 minutes, then held for 0.6 minutes, and then returned to 100% aqueous solution of formic acid (0.1 per cent) for 0.5 minutes. The flow rate was 0.6 ml/min

Method D: XTerra MS C182,5 MK of 4.6×50 mm; mobile phase A: 10 mm NH4OOCH+0,1% HCOOH in H2O; mobile phase B: CH3OH; column temperature: 50°C; flow rate: 1.5 ml/min; gradient (min) [%A/%B]: 0 [65/35] to 3.8 [5/95] 5.5[5/95] to 5.6[65/35] to 7 [65/35].

Some compounds okharakterizovali using1H-NMR:

Connection 2:1H-NMR (400 MHz, DMSO-d6, described the main isomer): 12,14-12,30 (2H, m), 7,70-a 7.85 (6H, m), 7,44 to 7.62 (4H, m), from 7.24 (2H, d, J=8.0 Hz), 5,15 is 5.28 (2H, m), 4.26 deaths-of 4.38 (2H, m), 3,81-3,98 (4H, m), of 3.56 (6H, s), 3,47-of 3.54 (2H, m), 3,20 (6H, s), 2,15 of-2.32 (4H, m), 2,15 of-2.32 (4H, m) of 1.09 (6H, d, J=6.0 Hz).

Compound 30:1H-NMR (400 MHz, DMSO-d6, described the main isomer): 12,13-12,77 25 (2H, m), 7,73-7,80 (6H, m), 7,47-of 7.60 (4H, m), 7,32 (2H, d, J=8.6 Hz), 5,17-5,24 (2H, m), 4,05-to 4.15 (2H, m), 3,80-3,91 (4H, m), 3,55 (6H, s), 2,18-2,31 (4H, m), 1,87 and 2.13 (6H, m), the 0.80 to 0.92 (12H, m).

The connection 40:1H-NMR (400 MHz, DMSO-d6, described the main isomer): 12,13-12,25 (2H, m), 7,42-7,87 (12H, m), 5,12-5,26 2H, m), 3,97-4,07 (2H, m), 3,69-to 3.89 (4H, m), 3,55 (6H, s), 2,15-2,31 (4H, m), 1,89 with 2.14 (4H, m), of 1.05 to 1.19 (2H, m) 0,31-0,50 (8H, m).

Table 1
The compounds of formula I

Biological examples, the activity of the compounds of formula I against HCV

Analysis of replicons

The compounds of formula (I) were investigated for inhibitory activity in the HCV replicon. This cell analysis is based on bicistronic expressing constructs, as described in Lohmann et al. (1999) Science vol. 285 pp. 110-113 with modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, the strategy of screening multiple targets. In essence, the method was as follows.

Essentially, the method was as follows.

In the analysis used consistently transtitional cell line Huh-7 luc/neo (hereafter in this document referred to as Huh-Luc). This cell line contains RNA encoding bicistronic expressing a construct that contains lots NS3-NS5B HCV type 1b wild-type transmitted from the internal binding site of the ribosome (IRES) virus encephalomyocarditis (EMCV), with the previous reporter plot (FfL-luciferase), and site selective marker (neoR, neomycinphosphotransferase). The design was funkysouls 5' and 3'-NTR (untranslated region) of the HCV type 1b. The culture of cells with replicon in the presence of G418 (neoRdepends on the replication of HCV RNA. For screening antiviral joint is used consistently transfetsirovannyh the replicon cells that Express HCV RNA that replicates autonomously and at a high level and which encodes, in particular, the luciferase.

Cells with replicon were placed in 384-well plates in the presence of the test and control compounds, which were added in various concentrations. After incubation for three days was determined by the replication of HCV by analysis of luciferase activity (using standard substrates and reagents for analysis of luciferase and imaging devices microplate Perkin Elmer ViewLuxTmultraHTS). Cells with replicon in the control cultures had high expression of luciferase in the absence of any inhibitor. Monitoring inhibitory activity of compounds against luciferase activity were performed on cells Huh-Luc, receiving curve "dose-effect" for each of the tested compounds. Then calculate the values of EC50which corresponds to the number of connections required to reduce the level of detectable luciferase activity by 50%, or more specifically, the ability of genetically related replicon HCV RNA replication.

Results

Table 2 presents the results of the analysis of replicon obtained for compounds of the examples above.

Studies of combinations of inhibitors

In a preferred embodiment, the combination of compounds described herein with another tool, which changes the replication of the HCV virus may act synergistically or antagonistically. Interaction of compounds can be analyzed various mechanistic and empirical methods.

One approach to the analysis of such combinations is carried out using a three-dimensional graphs and calculating synergistic amounts held by MacSynergyTMII model-based Bliss Independency model (Dr. Mark Pritchard, University of Alabama, Tuscaloosa, AL). Essentially, the compounds described herein in combination with another agent that alters viral replication of HCV, called acting synergistically or have a synergistic effect when the values stated in nm2% (vol synergy) is from 25 to 50 nm2% (a small, but significant amount of Ciner the AI), between 50 and 100 nm2% (moderate synergy) or more than 100 nm2% (strong synergy).

In certain embodiments of the implementation of the connection 2 is combined with a compound that inhibits replication of hepatitis C. Examples of such compounds include inhibitors of proteases (TMC435350) or polymerase inhibitor (inhibitor-based nucleosides: link 1; non-nucleoside: reference 3). The experiment was arranged in a "checkerboard" when one drug was titrated horizontally, and the other was titrated vertically on the cells Huh-Luc, containing stable transfetsirovannyh the replicon HCV type 1b. Each two-way combination was carried out in four copies and analyzed using software MacSynergyTMII to obtain the amounts of interest synergy/antagonism (expressed as nm2%).

In MacSynergyTMII theoretical calculations additive interactions are obtained from the curves of "dose-effect" for each individual connection. Then the calculated additive surface is subtracted from the experimental surface with the receiving surface of synergy. Only additive interaction can lead to a horizontal plane at the level of 0%. Peak above the plane of 0% indicates synergy, and a decrease below the plane of 0% refers to the antagonism. 95% confidence interval for the EC the pilot surfaces "dose-effect" was calculated to assess the statistical significance of synergy or antagonism.

The combination was tested in the concentration range mentioned in table 3. The volumes obtained using MacSynergyTMII when combining compound 2 with TMC435350, reference compound 1 or the reference compound 3 are small, moderate or vysokoenergeticheskie respectively. Given that the range of volumes synergy obtained at a 95% confidence interval for independence in Bliss for combinations with TMC435350 and reference compound 1, covers the ranges of volume, defined as synergistic and independent in Bliss, tested these combinations are considered to have effect from the additive to synergistic. In combination with the reference compound 3 this range of volumes synergy is synergistic (table 4). In all cases did not observe significant antagonism.

Table 3
Tested range of compounds
ConnectionThe concentration range nm
Connection 20,250-0,024
TMC43535075,0 to 7.2
Reference compound 136000,0-3400,0
The standard of the second connection 3 600,0-57,0

Table 4
The amount of synergy/antagonism in combination, obtained using MacSynergyTMII

*NS="not significant", as it was designated MacSynergyTMII

1. The compound of formula I:

including any possible stereoisomers, where
R and R' are independently selected from-CR1R2R3, phenyl, substituted 1 Deputy selected from halogen; and tetrahydrofuranyl, where
R1selected from C1-4the alkyl, optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4alkoxy, triptoreline, or 2 substituents on adjacent ring atoms form a 1,3-dioxolane group; benzyl, substituted with halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl and indolylmethane;
R2selected from hydrogen, hydroxyl, CI-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarboxylic, phenylamino,1-4allyloxycarbonyl, (C1-4allyloxycarbonyl) (the 1-4alkyl)amino, C1-4alkylaminocarbonyl, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidine-1-yl, 3,3-deformability-1-yl, morpholine-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and
R3represents hydrogen or C1-4alkyl, or
CR2R3together form a carbonyl; or
CR1R3forms cyclopropyl group;
and its pharmaceutically acceptable salt and solvate;
provided that (a) when R and R' are identical and represent-CR1R2R3where
(a-1) R2represents a C1-4allyloxycarbonyl and R3represents hydrogen, then R1different from unsubstituted With1-4the alkyl or ethyl, substituted by hydroxyl or methoxy; or where
(a-2) R2represents methoxycarbonylamino and R3represents hydrogen, then R1different from unsubstituted phenyl; and,
(b) when R and R' are different and each independently represents-CR1R2R3where R1represents phenyl or 2-propyl, R2represents a dimethylamino and R3represents a hydrogen in the same group-CR1R2R3then in the other group-CR1R2R3R1can't take is 2-propyl, and R2can't take the value methyloxime is arylamino, and R3can't take the value of hydrogen.

2. The compound of formula I under item 1, where
R and R' are independently selected from-CR1R2R3where
R1selected from phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4alkoxy, triptoreline, or 2 substituents on adjacent atoms of the ring form a 1,3-dioxolane group;
R2selected from hydroxyl, CI-C2-4alkylamino, (C3-6cycloalkyl)(C1-4alkyl)amino, C1-4alkylcarboxylic, (C1-4allyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonyl, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidine-1-yl, 3,3-deformability-1-yl, morpholine-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and
R3represents hydrogen or C1-4alkyl or CR2R3together form a carbonyl; or CR1R3forms cyclopropyl group;
and its pharmaceutically acceptable salt and solvate.

3. The compound of formula I under item 1, where
R1selected from pyridinyl, indolyl, pyridinylmethyl and indolylmethane;
R2selected from hydrogen, CI-C1-4alkylamino, (C3-6cycloalkyl)(C1-4alkyl)amino, C1-4alkylcarboxylic,1-4allyloxycarbonyl, (C1-4allyloxycarbonyl)(C1-4alkyl)amino, C1-4alnilam is decarbonylation, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidine-1-yl, 3,3-deformability-1-yl, morpholine-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and
R3represents hydrogen;
and its pharmaceutically acceptable salt and solvate.

4. The compound of formula I under item 1, where
R1represents a C1-4alkyl;
R2selected from C1-4alkylaminocarbonyl and tetrahydro-2-oxo-1(2H)-pyrimidinyl; and
R3represents hydrogen or C1-4alkyl;
and its pharmaceutically acceptable salt and solvate.

5. The compound of formula I under item 1, where
R1represents a C3-6cycloalkyl;
R2represents hydrogen
and R3represents hydrogen;
and its pharmaceutically acceptable salt and solvate.

6. Connection on p. 1, where R and R' are the same.

7. Connection on p. 1, where the compound has formula Ia

8. Pharmaceutical composition having inhibitory activity against hepatitis C virus containing the compound according to any one of paragraphs.1-7 and a pharmaceutically acceptable carrier.

9. The compound according to any one of paragraphs.1-7 or the pharmaceutical composition under item 8 for use for the prevention or treatment of HCV infection in a mammal.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new macrocyclic compounds of formula

or their tautomer, pharmaceutically acceptable salt, solvate or ester, wherein: X represents O or NR; Y represents -O-(CH2)mCOOR or -O-(CH2)mCON(R)2, wherein groups related to a nitrogen atom, can be in a Z- or E-configuration; R1 and R2 independently represent hydrogen or halogen; R3, R4, R5, R6, R7, R8, R9 and R10 independently represent hydrogen, alkyl, OR, -O(CH2)mC(O)(CH2)pN(R)2, -O(CH2)mN(R)C(O)(CH2)pOR, -(CH2)mN3 or -O(CH2)mN3; and each R independently represents R11, hydrogen, alkyl, alkylamino, dialkylamino, alkoxycarbonyl, phenyl or a protective group; or two R on the same nitrogen are taken together with nitrogen for producing a 5-6-merous heterocyclic or heteroaryl ring; wherein the group contains more than one substitute R; wherein R is optionally substituted, and each R can be identical or different, and wherein the protective group is specified in ethoxymethyl, methoxymethyl, tert-butyldimethylsilyl (TBS), phenylmethylsilyl, trimethylsilyl (TMS), 2-trimethylsilyl ethoxymethyl (SEM), 2-trimethylsilylethyl, benzyl and substituted benzyl; R11 represents a group

,

wherein Z represents an inorganic or organic counter-ion specified in a halogen, -O-alkyl, toluene sulphonate, methylsulphonate, sulphonate, phosphate, formiate or carboxylate; n represents 0, 1 or 2; m and p independently represent 0, 1 or 2; and dashed lines mean either a single, or a double bond, wherein the necessary conditions of the valence are observed by additional hydrogen atoms; and wherein in formula I′, when n represents 1, and X represents O, and the double bond is present between the carbon atoms having R9 and R10, then at least one of R5, R6, R7, R8, R9 or R10 are other than hydrogen; and wherein in formula I′, when n represents 1, and X represents O, and the bond between the carbon atoms having R9 and R10, represents the single bond, then at least one of R5, R6, R7 or R8 is other than hydrogen. The invention also refers to pharmaceutical compositions containing these compounds, using them and methods of treating diseases mediated by kinases and a heat-shock protein 90 HSP90.

EFFECT: preparing the new macrocyclic compounds.

28 cl, 5 dwg, 3 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new phenylamide or pyridylamide derivatives of formula

or their acceptable salts, wherein A1 is CR12 or N; A2 is CR13 or N; R1 and R2 are independently specified in hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup; R12 and R13 are independently specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino group and C1-7-alkylsulphanyl; R3 is specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, cyano group, C3-7-cycloalkyl, five-merous heteroaryl and phenyl; R4 is specified in methyl and ethyl; or R3 and R4 together represent -X-(CR14R15)n- and form a part of the ring, wherein X is specified in -CR16R17-, O, S, C=O; R14 and R15 are independently specified in hydrogen or C1-7-alkyl; R16 and R17 are independently specified in hydrogen, C1-7-alkoxycarbonyl, heterocyclyl substituted by two groups specified in a halogen, or R16 and R17 together with an atom C, which they are attached to, form =CH2 group; or X is specified in a group NR18; R14 and R15 are hydrogen; R18 is specified in hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarbonyloxy-C1-7-alkyl, phenyl, wherein phenyl is unsubstituted, phenylcarbonyl, wherein phenyl is substituted by C1-7-alkoxycarbonyl, and phenylsulphonyl, wherein phenyl is substituted by carboxyl-C1-7-alkyl, or R18 and R14 together represent -(CH2)3- and form a part of the ring, or R18 together with R14 and R15 represent -CH=CH-CH= and form a part of the ring; and n has the value of 1, 2 or 3; B1 represents N or CR19 and B2 represents N or CR20, provided no more than one of B1 and B2 represents N; and R19 and R20 are independently specified in a group consisting of hydrogen and halogen-C1-7-alkyl; R5 and R6 are independently specified in a group consisting of hydrogen, halogen and cyano group; and one-three, provided R4 represents methyl or ethyl, two of the residues R7, R8, R9, R10 and R11 are specified in C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxygroup, cyano group, C1-7-alkoxycarbonyl, hydroxy-C3-7-alkynyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkynyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl-carbonyl, wherein phenyl is unsubstituted, phenyl-C1-7-alkyl, wherein phenyl is substituted by 1-2 groups specified in a halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-alkynyl, wherein phenyl is substituted by 2 groups specified in halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidine carbonyl-C1-7-alkyl, wherein pyrrolidinyl is substituted by carboxyl, and the other R7, R8, R9, R10 and R11 represent hydrogen; the term 'heteroaryl' means an aromatic 5-merous ring containing one or two atoms specified in nitrogen or oxygen; the term 'heterocyclyl' means a saturated 4-merous ring, which can contain one atom specified in nitrogen or oxygen. Besides, the invention refers to a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new compounds possessing the GPBAR1 agonist activity.

21 cl, 1 tbl, 190 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 and R2 have the following values: (i) R1 and R2 together form =O; (ii) R1 and R2 together with carbon atom, which they are bound with, form duoxacycloalkyl; R1 represents hydrogen or halogen; and R2 represents halogen; (iv) R1 represents C1-6alkyl, where alkyl is optionally substituted with cyano, -RxS(O)qRv or -RxNRyRz; and R2 represents hydrogen; (v) R1 represents -OR12 or -NR13R14; and R2 represents hydrogen, deutero or phenyl, which is optionally substituted with halogen; R3 represents hydrogen, halogen, C1-6alkyl, cyano, halogen C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy; R4 and R5 represent hydrogen; R6 is independently selected from halogen, C1-6alkyl, halogenC1-6alkyl, -RxOR18 and -RxS(O)qRv; R7 independently represents halogen or -RxORw; R12 is selected from hydrogen and C1-6alkyl, R13 represents hydrogen; R14 is selected from hydrogen, C3-10cycloalkyl, -C(O)Rv and -C(O)ORw; R18 represents hydrogen, C1-6alkyl, or pyperidinyl, where R18 is optionally substituted with 1-3 Q1 groups, each Q1 is independenly selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl; Rx independently represents C1-6alkylene or simple bond; Rv and Rw represent hydrogen or C1-6alkyl; Ry and Rz represent hydrogen; n has value 0-4; p has value 0-5; and each q independently has value 0, 1 or 2. Invention also relates to compounds of formula (II) , where substituents have values, given in the invention formula, to pharmaceutical composition, possessing inhibiting activity with respect to JAK kinases, containing compounds of formula (I) or (II), methods of treating JAK-modulated disease, and application of compounds of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) as inhibitors of JAK kinases.

32 cl, 6 dwg, 2 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a preparation which inhibits microbial growth, which includes an arylamide compound as an active compound and kleptose or captisol.

EFFECT: methods of producing the preparation, use and method of treating microbial infections are disclosed.

21 cl, 5 dwg, 11 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula I and its pharmaceutically acceptable salt, wherein if a chemical valency permits, i represents 1 or 2, R1 represents H; a linear (C1-C4) alkyl group, R2 represents H, Cl or F, X represents either N, or CR3, R3 represents H; halogen; a linear (C1-C4) alkyl or (C1-C4) alkoxyl group, Y represents Z represents O or NRx, Rx represents H or a linear or branched (C1-C4) alkyl, k is equal to 2, 3 or 4, n and p independently represents 2, and a sum of n+p cannot exceed 4, T represents H or a linear (C1-C4) alkyl group; T′ represents a linear C1-C3 alkyl chain substituted by either (C1-C6)-dialkylaminogroup, or a 5-6-merous saturated heterocycle containing one nitrogen atom and optionally containing the second heteroatom specified in O, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; or a 5-merous saturated heterocycle containing one nitrogen atom, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; r represents zero, 1; R′ represents di(C1-C4)alkylamino, (C1-C4)alkoxy; except for the compounds specified in the clause. The invention also refers to a pharmaceutical composition based on the compound of formula (I), using the compound of formula (I) and to a method of treating diseases, in which the hedgehog signalling pathway modulation is effective.

EFFECT: there are prepared new heterocyclic compounds possessing t effective biological properties.

20 cl, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

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