Phenylethynyl derivatives as hepatitis c virus inhibitors

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

 

The technical field to which the invention relates.

The invention relates to phenylethylene derivatives, which are inhibitors of the hepatitis C virus (HCV), and to their use, alone or in combination with other inhibitors of HCV, in the treatment or prevention of HCV.

Prior art

HCV is a single stranded (+)RNA virus belonging to the viral familyFlaviviridae, the genus hepatovirus. The viral genome is translated into a single open reading frame encoding a variety of structural and non-structural proteins.

As a consequence of the initial acute infection, most infected patients develop chronic hepatitis due to the fact that HCV replication occurs predominantly in hepatocytes, but without explicit cytopathological manifestations. In particular, the lack of intensive response of T-lymphocytes and a strong tendency of the virus to mutations, likely contribute to the high rate of development of chronic infectious process. Chronic hepatitis may develop in the liver fibrosis leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma, which makes it the main reason for liver transplantation.

There are six major HCV genotypes and more than 50 subtypes, which geograficheskie different distributed. HCV genotype 1 is the genotype, dominant in Europe and the USA. The extensive genetic heterogeneity of HCV causes significant complications in the diagnosis and study of the symptoms of the disease, may explain the difficulties in creating vaccines and the lack of efficacy of current therapy.

Transmission of HCV can occur through contact with infected blood or blood products, for example, due to blood transfusion or intravenous drug administration. The introduction of diagnostic tests used in screening blood, leads to a tendency of lowering the number of cases postinfuzionnaya HCV. Despite the fact that is provided by the slow development of end-stage liver disease, existing infection will remain, posing a serious health problem and economic burden for decades.

Current HCV therapy is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. This combination therapy provides support virologic control more than 40% of patients infected with HCV genotype 1, and approximately 80% of patients infected with HCV genotypes 2 and 3. In addition to the limited efficacy against HCV genotype 1, this combination therapy has significant is obecnie effects and poorly portable many patients. Most side effects include flu-like symptoms, hematologic disorders, and neuropsychiatric symptoms. Therefore, there is a need for more effective, more convenient and better tolerated therapies.

Experience in the use of drugs against HIV, in particular inhibitors of the HIV protease, indicates that sub-optimal pharmacokinetics and complex dosing regimen immediately lead to unintentional errors, compliance with therapeutic recommendations. This, in turn, means that at 24 h, the lowest point of concentration (minimum plasma concentration) for appropriate medications for HIV status often falls below the limit value IC90or ED90for the most part of the day. You should take into account that 24 hour lowest level values at least for the IC50and, more realistically, for IC90or ED90that is very important to deter manifestations "escaped" from drugs mutants. Achieving the required pharmacokinetics and metabolism of drugs, which provide the lowest levels of values, determine the exact prospects for the creation of drugs.

NS5A protein of HCV is located after NS4B protein before and NS5B protein. On stage positrons anionnogo cleavage of viral serine protease NS3/4A protein NS5A is brought to a Mature state in the form of zinc-containing trendmanager phosphorylated protein, present either in the form hypophosphorylation (56-kDa, p56), either in the form hyperphosphorylation (58-kDa, p58) and its variants. NS5A protein of HCV is involved in diverse aspects of the viral life cycle, including viral replication and Assembly of infectious particles, as well as modulation of the environment of its host cell. Despite the fact that the squirrel did not attribute any enzymatic function, it was reported that he interacts with numerous viral and cellular factors.

In a number of patents and patent applications disclosed compounds with inhibitory activity against HCV NS5A. In WO 2006/133326 disclosed derivatives of stilbene, while in WO 2008/021927 and WO 2008/021928 disclosed biphenylene derivatives having inhibitory activity against HCV NS5A. In WO 2008/048589 disclosed derivatives of 4-(phenylethynyl)-1H-pyrazole and their antiviral use. In WO-2010/065668 disclosed 5-(phenylethynyl)-1H-imidazoles and their antiviral activity.

There is a need for inhibitors of HCV, which can overcome the shortcomings of current HCV therapy such as side effects, limited efficacy, the emergence of resistance and lack of adherence, as well as ensuring sustained virologic response.

The present invention relates to a group of inhibiting HCV phenylamine is lnyh derivatives with useful properties, concerning one or more of the following parameters: antiviral efficacy, favorable profile of development of resistance, a reduced level or absence of toxicity and genotoxicity suitable pharmacokinetics and pharmacodynamics, ease of manufacture of the dosage form and the introduction and limited or missing drug-drug interactions with other drugs, namely with other anti-HCV agents.

Compounds of the invention can also be promising due to the fact that they have no activity against other viruses, namely against HIV. HIV-infected patients often suffer from concomitant infections such as HCV. The treatment of such patients with HCV inhibitor, which also inhibits and HIV, can lead to the emergence of resistant HIV strains.

Description of the invention

In one aspect the present invention provides compounds that can be represented by formula I-and

including any possible stereoisomers, where

R represents-CR1R2R3alkylamino, benzylamino, arylamino, aryl, optionally substituted by 1 or 2 substituents selected from halogen and methyl, hetero(C4-7)cycloalkyl;

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

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

R3represents hydrogen or, alternatively, R2and R3together form oxoprop or cyclopropyl;

or their pharmaceutically acceptable salt and/or MES.

In an additional aspect, the invention relates to the use of compounds of formula I as described herein, for inhibiting HCV. Alternatively, it is provided to use for the production of medicines, the compounds of formula I or any subgroup, as specified in this description.

The first variant of implementation of the present invention relates to the compound of formula I

I

or its stereoisomer, where

R and R* represent, each independently, -CR1R2R3C1-4alkylamino, benzylamino, arylamino, the reel, optionally substituted by 1 or 2 substituents selected from halogen and methyl, hetero(C3-6)cycloalkyl; where

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

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

R3represents hydrogen, or

R2and R3together form oxoprop; or

R1and R3together form cyclopropyl;

provided that if one of R or R* represents a-CH(C6H5)N(CH3)2then the other cannot represent-CH(C6H5)NHC(=O)OCH3; and if R and R* are the same, then R1is other than phenyl when R2represents hydroxyl, acetylamino, methoxycarbonylamino ortert-butoxycarbonylamino, and R3represents hydrogen; and R1differs from Csub> 1-4the alkyl when R2represents a C1-4allyloxycarbonyl, and R3represents hydrogen;

or its pharmaceutically acceptable salt or MES.

Subgroups of compounds of formula I are the compounds of formula I, or subgroups of compounds of formula I, as defined herein, where R and R* represent-CR1R2R3or benzylamino; in particular, where R and R* represent-CR1R2R3.

Subgroups of compounds of formula I are the compounds of formula I, or subgroups of compounds of formula I, as defined herein, where R2represents hydrogen, hydroxyl, dimethylamino, acetylamino, methoxycarbonylamino, methylaminoquinoline, piperidine-1-yl or imidazol-1-yl.

Subgroups of compounds of formula I are the 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 of the substituents at adjacent ring atoms, form a 1,3-dioxolane group; heteroaryl and heteroaromatic. In particular, heteroaryl represents pyridinyl, namely pyridine-3-yl.

In an additional aspect of the image is the group provides a compound of formula I or its pharmaceutically acceptable salt, hydrate or MES for use in the treatment or prevention of (or in the manufacture of a medicinal product for the treatment or prophylaxis) of HCV infection. Representative genotypes of HCV in the context of treatment or prophylaxis, in accordance with the invention, include genotype 1b (prevalent in Europe) or 1a (predominant in North America). The invention also provides a method of treatment or prevention of HCV infection, namely for cases of genotype 1a or 1b, including an introduction to the needy in this patient a therapeutically effective amount of a compound as defined in this specification.

Stereoisomers pure forms of the compounds and intermediates described in this description are defined as isomers, essentially free from other enantiomeric or diastereoisomeric forms of the same basic molecular structures of these compounds or intermediates. Namely, the term "stereoisomer pure" refers to compounds or intermediate products having a stereoisomeric excess of at least 80% (i.e. at least 90% of one isomer and not more than 10% of the other possible isomers) and to stereoisomeric excess of 100% (i.e. 100% of one isomer and the complete absence of the other), more specifically, pertains to compounds or intermediate products having a stereoisomeric excess of 90% of vplo the ü to 100%, more specifically, having a stereoisomeric excess of 94% up to 100%, and most specifically, to having a stereoisomeric excess of 97% up to 100% or 98% up to 100%. The terms "enantiomerically pure" and "diastereoisomers clean" should be understood in the same way, but in this case as related to the enantiomeric excess and diastereoisomerism surplus, respectively, in the analysis of the mixture.

Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by applying methods known in the art. 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 grape acid, dibenzoylbenzene acid, deoliviera acid and camphorsulfonic acid. Alternatively, the enantiomers can be separated by chromatographic methods using chiral stationary phases. These chemically pure stereoisomeric forms can also be obtained from the corresponding chemically pure stereoisomeric forms of the appropriate starting compounds, provided that the reaction proceeds stereospetsifichno. Preferably, if a particular stereoisomer, a decree of the TES compound synthesized by stereospecific methods of obtaining. For such methods, it is preferable to use enantiomerically pure source materials.

Diastereomeric the racemates of the compounds of formula I can be obtained in a divided form by conventional methods. Suitable physical methods of separation, which can successfully be used are, for example, selective crystallization and chromatography, such as column chromatography or chromatography with supercritical mobile phase.

The compounds of formula I have several centers of chirality. Interest stereogenic centers pyrrolidinone rings, I. e. at the 2-carbon. The configuration in this position may be such, which corresponds to L-Proline, I. e.

,

or this, which corresponds to D-Proline, I. e.

.

In particular, interest compounds of formula I, or subgroups of compounds of formula I, as defined herein, which correspond to the formula I-b:

I-b

Also of interest group configuration-CR1R2R3: if R1selected from C1-4the alkyl, optionally substituted by a methoxy group, a hydroxyl or dimethylaminopropoxy; C3-6cycloalkyl and tetrahydropyranyl, then it is preferable to S-to figurate; if R1selected from phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4alkoxy, triptoreline or 2 of the substituents at adjacent ring atoms, form a 1,3-dioxolane group, and heteroaryl; then preferred is R-configuration.

Pharmaceutically acceptable salt additive include therapeutically active non-toxic forms of the compounds of the formula I or their subgroups in the form of additive salts of acids or bases. Interest and available, i.e. naselenie forms of the compounds of formula I or any subgroup of compounds of formula I, referred to in this specification.

Pharmaceutically acceptable acid additive salts can be obtained by conventional methods, by treating the basic form of a suitable acid. Suitable acids include, for example, inorganic acids such as halogenation acid, for example hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propionic, hydroxyestra, lactic, pyruvic, oxalic (i.e. o), malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic (i.e. hydroxybutanoic acid), grape, lemon, methansulfonate, econsultancy, b is zolsulphonate, p-toluensulfonate, reklamowa, salicylic,p-aminosalicylic, AMOVA and similar acids. In contrast, these salt forms can be converted into the free basic forms by treatment with a suitable base. One compound of formula I, depending on the amount present in the structure of the basic functional groups may form a salt with one, two or more molecules of acid.

The compounds of formula I containing an acidic proton may also be converted into their salt additive bases, in particular in the form of additive metal salts or amine, in the processing of appropriate organic or inorganic bases. Suitable additive salts of the bases include, for example, ammonium salts, salts of alkaline or alkaline-earth metal, for example lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example salt, benzathine, N-methyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine and the like.

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

Some of the which the compounds of formula I can also exist in their tautomeric forms. For example, tautomeric forms amide groups (-C(=O)-NH-) are kinoparty (-C(OH)=N-). Tautomeric forms, although they are not directly referred to in the structural formulas presented in this description are included in the scope of the present invention.

As used herein, "C1-4alkyl" as a group or part of a group, means a saturated, straight or branched chain hydrocarbon groups having from 1 to 4 carbon atoms, such as, for example, 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 from among C1-4Akilov interest C3-4alkyl, i.e., hydrocarbon group with a straight or branched chain 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 is 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 it, means a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms, which together form a cyclic structure. Examples of C3-6cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"C1-4alkoxy" as a group or part of a group means a group of the formula-O-C 1-4alkyl, where C1-4alkyl is as defined above. Examples of C1-4alkoxy are methoxy, ethoxy,n-propoxy or isopropoxy.

The term "halogen" is shared by fluorine, chlorine, bromine and iodine.

As used herein, the term "(=O)" or "oxo" creates a carbonyl functional group for linking to the carbon atom. It should be noted that this atom can only be Deputy in the form of a carbonyl group, when the valence of the atom gives such an opportunity.

As used in this description, for the purpose of definition of the term "aryl" as a group or part of, the values of the aromatic ring structure optionally contains 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. Examples are phenyl, pyridinyl, oxazolyl and the like.

As used herein, the prefix "hetero-" means that the group includes or additionally has at least 1 heteroatom selected from N, O and S, in particular from N and O. for Example, the term "heteroaryl" means an aromatic ring structure, as defined for the term "aryl" includes at least 1 heteroatom selected from N, O and S, in particular from N and O, such as imidazolyl, furanyl, pyridinyl, oxazole and such. Alternatively, the term "heteros4-7cycloalkyl" means a saturated cyclic hydrocarbon group as defined for "C3-6cycloalkyl", optionally containing at least 1 heteroatom selected from N, O and S, in particular from N and O, such as tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and the like.

If the position of the group at the molecular fragment is not precisely specified (for example, the substituent in the phenyl), or a floating connection, then that group may be located at any atom of such a fragment, provided that the resulting structure is chemically stable. If any variables are present in the molecule more than once, each is independent.

Whenever used in this description, the term "compounds of formula I", or "the present compounds" or similar terms means that it covers the compounds of formula I, including any stereoisomeric forms and their pharmaceutically acceptable salt and solvate.

General methods of synthesis

Compounds of the invention where R and R* are the same, can be obtained by acylation phenylethylene skeleton of the formula III with a suitable acid of formula R-C(=O)-OH, where R has the meaning as defined for compounds of formula I or I is th their subgroups.

III

Specified acylation can be carried out by reacting starting materials in the presence of the agent or combination by converting the carboxyl functional groups in the active form, such as an activated ester, mixed anhydride, or acid chloride, or bromohydrin carboxylic acid. General description of such reactions and reagents used in their implementation, can be found in the General guidance 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 an amino group or amide bond formation include the azide method, mixed anhydrides, carbonyl-carboxyl (isobutylparaben), carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide, such asN-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide), the method of activated esters (for example,p-nitrophenyl,p-chlorophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl,N-hydroxysuccinimide and similar esters) method with K-Woodward reagent, 1,1-carbonyldiimidazole method (CDI orN,N'-carbonyldiimidazole) method with phosphorus reagents or oxidation-reduction methods. Some of these m the methods can be improved by adding suitable catalysts, for example, carbodiimide method by adding 1-hydroxybenzotriazole or 4-dimethylaminopyridine (4-DMAP). In addition, the agents of the combination are hexaflurophosphate (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium, either by itself, 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). Such reactions combination can be performed either in solution (liquid phase) or in the solid phase. For the purposes of the present invention the preferred method of acylation is carried out using HATU.

Of combination reaction is preferably carried out in an inert solvent, such as halogenated hydrocarbons, for example dichloromethane, chloroform, bipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide (DMSO), hexamethylphosphorotriamide (HMPT), 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, such as triethylamine, diisopropylethylamine (DIPEA),N-methylmorpholin,N-methylpyrrolidine, 4-DMAP or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction temperature can be in the range from 0°C to 50°C, and the reaction time may range range from 15 minutes to 24 hours

Generationally skeleton of formula III can be obtained according to the synthesis pathway, illustrated in example 1 described in this description. Intermediate compound I-9 is a compound of formula III with (S,S) configuration pyrrolidinone fragments. Alternative compounds of formula III, where the configuration pyrrolidinone fragments does not apply to (S,S) can be obtained using the same path synthesis using N-Boc-Proline another configuration in the synthesis of intermediate I-11.

In an additional aspect, the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I as described herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context refers to an amount that is sufficient to effect as a preventive measure against HCV infection, in order to stabilize or reduce HCV infection in HIV-positive subjects or subjects at risk of infection. In another additional aspect, the invention relates to a method for producing a pharmaceutical composition, as described herein, including thorough mixing pharmaceutically acceptable wear the El with a therapeutically effective amount of the compounds of formula I, as indicated in this specification.

Therefore, the compounds of the present invention or any subgroup can be incorporated into various pharmaceutical forms for the purposes of introduction. Suitable compositions can lead to all songs, usually used to systematically injected drugs. In order to obtain pharmaceutical compositions of the present invention, an effective amount of individual compounds, optionally in the form of additive salt or metal complex as the active ingredient unite with careful mixing with a pharmaceutically acceptable carrier, which can be widely used in a variety of forms, depending on the required for the introduction of forms. These pharmaceutical compositions are desirable in unit dosage form, particularly convenient for oral administration, rectal administration, for insertion through the skin, or parenteral injection. For example, upon receipt of the compositions in oral dosage form can be applied to any commonly used pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid dosage forms such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers, such as to omaly, sugars, kaolin, lubricants, binders, disintegrant and the like in the case of powders, pills, capsules and tablets. Because of the simplicity of the introduction of tablets and capsules are the predominant oral unit dosage forms, in which case, of course, use solid pharmaceutical carriers. For parenteral compositions, as a rule, the carrier will comprise sterile water, at least for the most part, however, may include other ingredients, for example, facilitate solubility. Injectable solutions, for example, can be obtained so that the carrier consisted of a salt solution, a glucose solution or a mixture of saline and glucose solutions. Suspension for injection can also be obtained so that in this case could be a suitable liquid carriers, suspendresume agents and the like. Also included are solid dosage forms intended for conversion immediately before use in liquid dosage forms. In the compositions suitable for injection through the skin, the carrier optionally includes enhancing the penetration of a substance and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, and these additives do not bring tangible is Reden effects on the skin. Compounds of the present invention can also be administered via oral inhalation or insufflation in the form of a solution, suspension or dry powder, using any known in the field of delivery systems.

Particularly preferred is the preparation of the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used in this specification means physically discrete units suitable as disposable dosages, each unit contains a predetermined quantity of active ingredient calculated to cause the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored tablets or coated tablets), capsules, pills, suppositories, sachets of powder, plates, solutions or suspensions for injection and the like and their numerous individual species.

The compounds of formula I are active against HCV and can be used for the treatment and prevention of HCV infection or diseases associated with HCV. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, the last stage C is the disease of the liver and hepatocellular carcinoma. In addition, it is known that some compounds of the present invention is active against mutant strains of HCV. In addition, the compounds of the present invention can have favorable properties in terms of bioavailability, to demonstrate suitable pharmacokinetic profile, including an acceptable half-life, area under the curve (AUC) and the maximum and minimum values of the characteristics, and be characterized by an absence of adverse events, such as insufficient penetration and delay in the tissues.

Antiviral activityin vitroin relation to HCV for compounds of formula I can be tested at the cellular model of HCV in the control system replication based on publishing Lohmann et al. (1999) Science 285:110-113, with the additional modifications described in the publication Krieger et al. (2001) Journal of Virology 75:4614-4624 (included in this description by reference), which further confirmed by the examples in the examples section. This model, despite the fact that is not a fully comprehensive model of HCV infection, is widely used as the most understandable and effective model of Autonomous replication RNA virus, HCV, are currently available. You should take into account that it is important to distinguish compounds that specifically inhibit the function of HCV, such is connected to the th, which cause cytotoxic or cytostatic effect on a model of HCV replication and, consequently, lead to a decrease in the concentration of RNA virus, HCV or concentration of a linked reporter enzyme. Assays known in the field of determination of cytotoxicity at the cellular level, based for example on the activity of mitochondrial enzymes with dyes, fluorescent in redox processes, such as resazurin. Moreover, the inverse screening cells shows the non-selective inhibition of the activity of a linked reporter gene such as luciferase gene of the Firefly. Suitable types of cells can be provided by stable transfection with a gene-reporter luciferase, whose expression depends on the constitutive active gene promoter, and such cells can be used as a reverse screening the selection to exclude non-selective inhibitors.

Due to their antiviral properties, particularly their anti-HCV properties, the compounds of formula I, as specified in this description can be used to inhibit HCV replication, in particular, in the treatment of warm-blooded animals, in particular humans, infected with HCV, and for the prevention of HCV infections. The present invention also relates to a method of treatment, the Oia warm-blooded animal, in particular person infected with HCV or are at risk of HCV infection, including the introduction of anti-HCV effective amount of the compounds of formula I, as specified in this description.

The compounds of formula I, as specified in this description can therefore be used as pharmaceuticals, in particular as drugs against HCV. The specified application as a medicine or method of treatment comprises the systemic introduction of infected virus HCV subjects or subjects who are susceptible to HCV infection, the number of medicines that are effective to combat the conditions associated with HCV infection.

The present invention also relates to the use of these compounds in the manufacture of a medicinal product for the treatment or prevention of HCV infection.

In addition, the compounds of the invention may also be of interest due to the fact that they have no activity against other viruses, in particular against HIV. Infected HIV patients often suffer from concomitant infections such as HCV. The treatment of such patients with HCV inhibitor, which also inhibits and HIV, can lead to the emergence of resistant HIV strains.

As a rule, assume that an antiviral effective daily amount of the debtor is about to be from about 0.01 to about 50 mg/kg, or from about 0.02 to about 30 mg/kg of body weight. It may be appropriate to provide the required dose in the form of two, three, four or more subds intervals of time during the day. These subdata can be formulated as 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

The invention also relates to combinations of compounds of formula I, its pharmaceutically acceptable salt or MES and other antiviral compounds, namely another anti-HCV compounds. The term "combination" refers to a product containing (a) compound of formula I, as defined above, and (b) another anti-HCV inhibitor, as a combined medicinal product for simultaneous, separate or sequential use in the treatment of HCV infections.

The combination of the present invention can be used as medicines. Thus, the present invention relates to the use of compounds of formula (I) or any of its subgroups, as defined above, for the production of medicinal when estva, suitable for inhibiting the activity of HCV infected by HCV virus mammals, 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 anti-HCV agent, such as IFN-α, pegylated IFN-α, ribavirin, Albuferon, taribavirin, nitazoxanide, Debio025 or a combination of both.

Other agents that may be combined with the compounds of the present invention include, for example, nucleoside and non-nucleoside polymerase of HCV virus, HIV protease inhibitors, inhibitors of helicase, NS4B inhibitors and agents that functionally inhibit the availability vnutrirezonatornogo site (IRES), and other agents that inhibit cellular connection or HCV viral penetration, broadcast RNA virus, HCV, transcription of virus RNA HCV replication or maturation of HCV, viral Assembly or release. Typical compounds of 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 (HCV NS4A inhibitor protease cofactor), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450, EP-013420 (and representatives of the same genus) and VBY-376; nucleoside inhibitors of HCV polymerase, to the that can be used in 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 all sorts of other nucleosides and nucleotide analogues and inhibitors of HCV, including derivatives such 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)- (link 1) and its complex bis-2-methylpropanoate ether (reference 2). Non-nucleoside HCV polymerase, suitable for use in 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-Dion-16,16-dioxide (reference 3).

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

Examples

Example 1 - Synthesis phenylethylene skeleton of the formula III

Scheme 1

1.1 Obtaining L-Boc-prolinol

Borohydride-methylsulfinyl complex (180 ml) of 1.80 mol) was added dropwise to a solution of N-Boc-L-Proline (300 g, of 1.39 mol) in anhydrous tetrahydrofur is not (THF) (3.0 l), which was cooled to 0°C. When gas evolution ceased, bath with ice was removed and the solution was stirred at 10°C for 18 hours. Thin layer chromatography (TLC) showed that starting material remained and formed the desired product. The solution was cooled to 0°C and slowly added methanol (2.4 l). The solvents were removed under reduced pressure. The residue was again dissolved in dichloromethane (1 l), washed with NaHCO3(500 ml, saturated aqueous solution) and saturated salt solution (500 ml), dried over MgSO4. Solids were removed by filtration and the solvent from the filtrate was removed under reduced pressure, which gave the opportunity to obtain a white solid, 260 g (93%) that was used in the next stage without additional purification.

1.2 Obtaining L-Boc-prolinal, I-1

To a solution of L-Boc-prolinol (100 g, 500 mmol) in CH2Cl2(1.5 l) at 0°C was sequentially added with vigorous stirring 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO; 1.56 g, 10 mmol) and NaBr (5,14 g, 50 mmol). To the resulting mixture was added dropwise a solution of NaHCO3(6 g, 110 mmol, dissolved in 1.5 liters of 6% solution of NaClO) and 6% NaClO in active chlorine (1.5 l, 750 mmol) at 0°C over a period of time of 1 hour. TLC showed that remained of the original substance and that the desired product has formed. The mixture quickly ex who was regionali dichloromethane (2×1.5 l). The organic layers were combined, washed NaHSO4(10%, 1 l) and KI (4%, 200 ml), then Na2S2O3(10%, 1 l) and saturated salt solution (1.5 l), dried over MgSO4solids were removed by filtration and the solvents were removed under reduced pressure, which gave the opportunity to obtain a yellow oil, Boc-prolinal, I-1 (89 g, 92%) that was used in the next stage without additional purification.

1.3 Obtaining an intermediate compound I-2

Aqueous ammonia (25-28%, 200 ml) was added dropwise to a solution of intermediate compound I-1 (89 g of 0.44 mol) and glyoxal (183 ml, 40% solution in water) in 1 l of methanol. The reaction mixture was hermetically closed and carried out the reaction at 10°C. After 16 hours of additional glyoxal (20 ml) and aqueous ammonia (20 ml) was added and the reaction was carried out for an additional 6 hours. The solvents were removed under reduced pressure and the crude substance was re-dissolved in ethyl acetate (1.0 l), washed with water and saturated salt solution, dried over MgSO4solids were removed by filtration and the solvents were removed under reduced pressure. The crude substance was purified column chromatography (silica gel, dichloromethane, then methanol/dichloromethane, 1:70), with 73 g (70%) of intermediate compound I-2 as a white solid.

1H NMR: CDCl3400 MHz δ to 6.95 (s, 2H), 4,82-4,94 (m, 1H), 3,60-3,70 (m, 1H), 3,41-to 3.50 (m, 1H), 2,20-2,39 (m, 1H), 1.91 a-2,03 (m, 3H), of 1.47 (s, 3H), 1,25 (s, 6H).

1.4 Obtain the intermediate compound I-3

To a solution of intermediate compound I-2 (500 g, 2.1 mol) in anhydrous tetrahydrofuran (THF) (1.8 l) and dimethylformamide (DMF; 0.8 l) was added sodium hydride (55 g, 60% dispersion in oil, 2.3 mol) in portions under stirring at 0°C for a period of 4 hours. [2-(trimethylsilyl)ethoxy]methyl chloride (SEM-Cl) (245,8 g, 2.3 mol) was added dropwise at 0°C. the resulting mixture was stirred at 25°C for 14 hours. The reaction was suppressed by addition of water (100 ml). Then the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (2.5 l), washed with water (2 l), saturated salt solution (2 l) and dried over MgSO4solids were removed by filtration and the solvent from the filtrate was removed under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate, 4:1), obtaining oil, 530 g (68%) of intermediate compound I-3.

1.5 Obtain the intermediate compound I-4

To a solution of intermediate compound I-3 (530 g, 1.44 mol) in dichloromethane (2 l) was addedN-bromosuccinimide (NBS; 256 g, 1.44 mol) in portions under stirring at -10°C over a period of time, avego 4 hours. The mixture was stirred for 14 hours at 20°C. the Reaction mixture was washed with water (2 l), saturated salt solution (2 l) and dried over MgSO4solids were removed by filtration, and the solvent from the filtrate was removed under reduced pressure. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate, 10:1). Fractions with the target substance were combined and the solvents were removed under reduced pressure, which gave the opportunity to obtain a yellow oil, 460 g (71%) of intermediate compound I-4.

1.6 Obtaining an intermediate compound I-5

A mixture of intermediate compound I-4 (272 g, 609,2 mmol), trimethylsilylacetamide (TMS-acetylene; 77,8 g, 792 mmol), Pd(OAc)2(13,7 g, 60,9 mmol) and triphenylphosphine (Ph3P; 31,9 g, the level of 121.8 mmol) in triethylamine (TEA, 2 l) was stirred at 80°C for 18 hours in an atmosphere of N2. Then TMS-acetylene (41.7 g, 426,3 mmol) was added after cooling to 20°C. the resulting mixture was then stirred at 80°C for 8 hours in an atmosphere of N2. Then the reaction mixture was filtered through diatomaceous earth and the solvent from the filtrate was removed under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate, 30:1 to 10:1) twice to obtain 98 g (34,7%) of intermediate compound I-5 as a brown solid.

1H is Mr: CDCl 3400 MHz δ 6.87 in (s, 1H), 5,16-the 5.65 (m, 1H), br4.61-to 4.87 (m, 2H), 3,24-of 3.42 (m, 4H), 1,64-of 2.21 (m, 4H), 1,02-1,17 (d, 9H), 0,59-to 0.73 (m, 2H), of 0.01 (s, 9H), -0,35 (s, 9H).

1.7 Obtain the intermediate compound I-8

Intermediate compound I-5 (55 g, 118,6 mmol), intermediate compound I-13 (68 g, 130,46 mmol), CuI (of 2.26 g, up 11,86 mmol) and TEA (36 g, 355,79 mmol) were combined in DMF (500 ml), then after the reaction mixture was barbotirovany N2and added PdCl2(Ph3P)2(8,32 g, up 11,86 mmol) in an atmosphere of N2. The mixture was heated to 70°C and kept bubbling N2. Tetra-n-butylammonium (TBAF; 1M in THF, 118 ml, 118 mmol) was added via injection syringe for 10 hours. The reaction mixture was diluted with water (1 l) and was extracted with a mixture of petroleum ether and ethyl acetate (1:1 (by vol.:vol.), 2×500 ml). The combined organic layers were washed with water and saturated salt solution, dried over MgSO4solids were removed by filtration and the solvent from the filtrate was removed under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 2:1), to obtain 35 g of the crude product with a purity of 80%, and again was purified preparative HPLC, to obtain 19.2 g (19.4%) of intermediate compound I-8 in the form of a yellow solid.

1H NMR: CDC13400 MHz δ 7,70-7,72 (d, J=8.0 Hz, 2H), 7,49-7,51 (d, J=8.0 Hz, 2H), 7,14-7,20 (m, 2H), 5,38-5,90 (m, 2H), 4,875,19 (m, 4H), 3,50-3,70 (m, 8H), 1.91 a-a 2.36 (m, 8H), to 1.21 to 1.47 (m, 18H), of 0.85 to 0.97 (m, 4H), of 0.01 (s, 18H).

1.8 Getting I-9

Intermediate compound I-9 (53,9 g, a 64.6 mmol) was dissolved in methanol (250 ml) was added a mixture of HCl/methanol (250 ml, 4M). The mixture was stirred at 60°C for 18 hours. They removed 80% of the solvent was added acetonitrile (200 ml). The resulting mixture was stirred at 60°C for 2 hours. The resulting solid was isolated by filtration and dried in vacuum, obtaining of 25.2 g (75.2 per cent) of solid substances in the form of cleaners containing hydrochloride salt.

1H NMR: 400 MHz, MeOD δ of 7.97 (s, 1H), 7,85-7,87 (d, J=8,2 Hz, 2H), 7,66-to 7.68 (d, J=8,2 Hz, 2H), 7.62mm (s, 1H), 4,90-5,19 (m, 2H), 3,50-3,60 (m, 4H), 2,16 was 2.76 (m, 8H).

1.9 the production of intermediate compound I-11

N,N-Diisopropylethylamine a (80.0 g of 0.62 mol) was added dropwise during 30 minutes to a mixture of 2-amino-1-(4-bromophenyl)ethanone (50 g, 0.2 mol), hexaflurophosphate 2-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethylurea (hydroxide (carboxymethyl)trimethylammonium, inner salt) (HATU; 53 g, 0.21 mol), N-Boc-L-Proline (43,0 g, 0.2 mol) in dimethylformamide (DMF) (600 ml). The reaction mixture was stirred at 5°C for 1 hour. The most volatile components were removed in vacuo and the resulting residue was distributed between ethyl acetate (600 ml) and water (300 ml). The organic layer was washed with saturated aqueous rest the rum NaHCO 3(500 ml) and saturated salt solution (500 ml), dried over MgSO4solids were removed by filtration, the solvent from the filtrate was removed under reduced pressure. The crude product was purified column chromatography (silica gel, petroleum ether/ethyl acetate, 3:1 to 1:1), obtaining a pale yellow solid, 60 g (62%) of intermediate compound I-11.

1H NMR: CDC13400 MHz δ a 7.85 (d, J=8,4 Hz, 2H), 7,66 (d, J=8,4 Hz, 2H), 4,67-4,80 (m, 2H), 4,33-to 4.41 (m, 1H), 3,42-of 3.53 (m, 2H), 2,19-2,31 (m, 2H), 1,90-2,00 (m, 2H), 1,50 (s, 9H).

1.10 Retrieving I-12

A mixture of intermediate compound I-11 (60 g, 0.14 mol) and ammonium acetate (89 g, 1.4 mol) in xylene (800 ml) was heated at the boil under reflux for 16 hours. The reaction mixture was distributed between ethyl acetate (700 ml) and a saturated solution of NaHCO3(500 ml). The layers were separated and the aqueous layer was extracted with additional ethyl acetate (2×300 ml). The organic layers were combined, washed with saturated salt solution (500 ml), dried over MgSO4solids were removed by filtration and the solvent from the filtrate was evaporated under reduced pressure. The resulting substance was recrystallized from a mixture of ethyl acetate/petroleum ether, which gave the opportunity to obtain a yellow solid I-12, 25 g (43%).

1H NMR (400 MHz, MeOD) δ memorial plaques of 1.23 (s, 6H), 1,46 (who, 3H), of 1.84-2.10 (m, 3H), of 2.36 (m, J=5,80 Hz, 1H), 3,50 (m, J=the 10.40, 5,10 Hz, 1H), 3,60-to 3.73 (m, 1H), 4,94-5,00 (m, 1H), 7,28-7,39 (m, 1H), 7,49 (d, J=of 8.28 Hz, 2H), to 7.61 (d, J=8,03 Hz, 2H).

1.11 Retrieving intermediate compound I-13

To a solution of intermediate compound I-12 (212 g, 540,4 mmol) in anhydrous tetrahydrofuran (THF) (1.6 l) and dimethylformamide (DMF) (0.8 l) was added sodium hydride (14,27 g, 60% dispersion in oil, 540,4 mol) in portions under stirring at 0°C over a period of time equal to 4 hours. SEM-Cl (90,1 g, 540,4 mol) was then added dropwise at 0°C. the resulting mixture was stirred at 25°C for 14 hours. The reaction was suppressed by addition of water (100 ml). The solvent was removed in vacuum and the residue was dissolved in ethyl acetate (2 l), washed with water, saturated salt solution and dried over MgSO4solids were removed by filtration and the solvent from the filtrate was removed under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 4:1), to obtain yellow solids, 200 g, which was recrystallized from 1 l of petroleum ether, which gave the opportunity to obtain a white powder, 150 g (53,4%) of intermediate compound I-13.

1H NMR: DMSO 400 MHz δ 7,76 (s, 1H), 7,69-7,71 (d, J=8,4 Hz, 2H), 7,54-7,56 (d, J=8,4 Hz, 2H), 4,87-5,69 (m, 3H), 3,41 is 3.57 (m, 4H), 1,81-2,47 (m, 4H), 1,14-to 1.38 (d, 9H), 0,87-0,98 (m, 2H), of 0.01 (s, 9H).

Example 2 - Synthesis of compounds of formula I

2.1 connection 2

Into a flask of 20 ml were placed intermediate compound I-9 (259 mg, 0.5 mmol), 3-pyridyloxy acid (171 mg, 1.25 mmol), HATU (475 mg, 1.25 mmol), N,N-diisopropylethylamine (DIPEA; 0,826 ml, 5 mmol) in DMF (5 ml) and the mixture was shaken for 15 hours. Liquid chromatography-mass spectrometry (IHMS) showed complete conversion to the target product. The solvent was removed under reduced pressure and the residue was purified using strong effects for cation-exchanger column SCX SPE (5 g sorbent, 20 cm3). The column was washed with methanol (2 volumes), then it inflicted connection in the residual DMF. Impurities were suirable methanol (4 volume) and then the product was washed from the column, elwira 7M solution of ammonia in methanol (2 volumes). The solvent and excess ammonia was removed by evaporation in a vacuum. Compound 2 was isolated as a yellow powder.

1H NMR (400 MHz, Chloroform-d) δ memorial plaques of 1.13 (d, J=6,44 Hz, 2H), 2.06 to 2,22 (m, 4H), 2,30-2,52 (m, 2H), 3,50 (s, 4H), 3,53-of 3.78 (m, 6H), 3,62-3,62 (m, 0H), 5,17 is 5.28 (m, 2H), 7,18 (s, 1H), 7,21 (s, 1H), 7,28-7,33 (m, 3H), 7,49 (d, J=7,80 Hz, 2H), 7,63 (d, J=to 7.61 Hz, 2H), and 8.50 (d, J=1,95 Hz, 2H), 8,55 (dt, J=3,17, the 1.44 Hz, 3H).

Alternatively, isolation and purification of the reaction product can be carried out as follows. Added CH2Cl2to the residue and the resulting solution was washed with saturated solution of NaHCO3. The organic phase sushi is whether over anhydrous Na 2SO4, filtered and concentrated in vacuum. The compound was then purified column chromatography on silica gel (0-10% MeOH in CH2Cl2) or preparative HPLC.

Getting connections 4

Obtaining and cleaning specified in the title compound 4 was carried out following the method described in example 2.1 (connection 2), using 2-cyclohexyloxy acid in the first stage of the reaction.

1H NMR (400 MHz, Chloroform-d) δ memorial plaques to 0.97 (d, J=13,07 Hz, 8H), 1,09-to 1.21 (m, 2H), 1,22-to 1.37 (m, 5H), 1.69 in (m, 9H), 1,83-of 1.93 (m, 2H), 2,01-2,12 (m, 4H), 2,15 is 2.43 (m, 6H), 3,49-3,61 (m, 4H), 5,11-of 5.34 (m, 2H), 7,12-7,24 (m, 2H), was 7.36-7,56 (m, 2H), 7,65-7,81 (m, 2H).

The connection 21

Obtaining and cleaning specified in the title compound 21 was carried out following the method described in example 2.1 (connection 2), using (S)-2-(dimethylamino)-3-methylbutanoyl acid in the first stage of the reaction.

1H NMR (400 MHz, Chloroform-d) δ M. D. 0,65-of 0.79 (m, 5H), and 1.00 (d, J=6,63 Hz, 12H), 1,99-of 2.23 (m, 6H), 2,42 (d, J=3,71 Hz, 12H), 2.95 and-3,03 (m, 2H), 3.04 from-3,18 (m, 1H), 3,53-3,71 (m, 4H), 5,28-of 5.45 (m, 2H), 7,15-7,25 (m, 2H), 7,51 (d, J=8,39 Hz, 2H), 7.68 per-7,80 (m, 2H).

The connection 28

Obtaining and cleaning specified in the title compound 28 was carried out following the method described in example 2.1 (connection 2), using (S)-2-(methoxycarbonylamino)-3-IU inputanalog acid in the first stage of the reaction.

1H NMR (400 MHz, DMSO-d6) δ memorial plaques of 0.77 to 0.92 (m, 4H), of 1.03 (d, J=6,05 Hz, 12H), 1,19-of 1.30 (m, 2H), 1,83-2,05 (m, 6H), 2.06 to 2,22 (m, 2H), 3,53 (s, 6H), 3,56-the 3.65 (m, 2H), 3,68-a 3.87 (m, 1H), Android 4.04 (m, J=11,10 Hz, 1H), 4,98-5,02 (m, 1H), of 5.06 (m, J=3,50 Hz, 1H), 7,28 (s, 1H), 7,30 (s, 1H), 7,42 (m, 2H), 7,50-to 7.59 (m, 2H), 7,71 (m, 2H).

The connection 32

Obtaining and cleaning specified in the title compound 32 was carried out following the method described in example 2.1 (connection 2), using (R)-2-acetamido-2-phenylacetic acid in the first stage of the reaction.

1H NMR (400 MHz, Chloroform-d) δ M. D. 1,41 (user.s, 2H), 1.91 a (user.s, 2H), 1,98 is 2.10 (m, 6H), 2,86-of 3.06 (m, 3H), 3,09-to 3.35 (m, 3H), 3,53-3,88 (m, 4H), 5,16-5,33 (m, 2H), 5,62 (d, J=6,44 Hz, 1H), 5,71-of 5.83 (m, 1H), 6,58 of 6.68 (m, 1H), 6,69-to 6.88 (m, 1H), 7,30 (d, J=2,54 Hz, 2H), 7,37-to 7.61 (m, 12H), 7,63-7,87 (m, 2H).

The connection 36

Obtaining and cleaning specified in the title compound 36 was carried out following the method described in example 2.1 (connection 2), using (S)-3-methyl-2-(3-methylurea)butane acid in the first stage of the reaction.

1H NMR (400 MHz, DMSO-d6) δ M. D. 0,71-0,83 (m, 7H), 0,84-of 0.95 (m, 5H), 1,75-2,04 (m, 7H), 2,13 (user.s, 3H), 2,52-2,60 (m, 12H), 3,44 (DD, J=6,63, 3,71 Hz, 2H), 3,67-a-3.84 (m, 2H), 4,13-the 4.29 (m, 2H), 4,96-5,12 (m, 2H), 5,90 (m, J=4,70 Hz, 1H), 6,02 (d, J=8,98 Hz, 1H), 7,43 (d, J=6,24 Hz, 2H), 7,72 (d, J=to 7.61 Hz, 2H).

The connection 37

Obtaining and cleaning specified in the header is connected to the I 37 was carried out, following the method described in example 2.1 (connection 2), using (R)-2-phenyl-2-(piperidine-1-yl)acetic acid in the first stage of the reaction.

1H NMR (400 MHz, DMSO-d6) δ M. D. 1,04-of 1.56 (m, 15H), 1.70 to 2,03 (m, 8H), 2,10 (user.s, 2H), 2,20-of 2.44 (m, 9H), 3,80-was 4.02 (m, 1H), 4,28 (s, 2H), 4,84-of 5.05 (m, 1H), 6.87 in (d, J=6,24 Hz, 1H), 7,14 (m, J=3,50 Hz, 2H), 7.23 percent-of 7.48 (m, 10H), 7,56 (user.s, 1H), 7,76 (d, J=6,44 Hz, 2H).

2.1 Obtain compound 3

In the flask of 10 ml were placed intermediate compound I-9 (200 mg, 0,386 mmol), N,N-diisopropylethylamine (0,638 ml, 3,859 mmol), phenylisocyanate (0,126 ml, 1,158 mmol). The flask was shaken overnight at room temperature. The solvents were removed under reduced pressure, the residue was dissolved in dichloromethane (1 ml) and was purified column chromatography on silica gel using a gradient from dichloromethane to 10% methanol in dichloromethane. The best fractions were combined and the solvents were removed under reduced pressure, which gave the opportunity to obtain the pure product 3.

All compounds were characterized using LC/MS. Used the following methods LC/MS:

The way A: The instrument Waters Acquity UPLC equipped with spectrophotometric detector (PDA range 210-400 nm), and a Waters SQD with the ionization source operating in two modes ES+/-. The used column was a Halo C18, 2.7 μm, and 2.1×50 mm, and was supported operating temperature 50°C. the Gradient of the 95% aqueous formic acid (0.1 percent)/5% acetonitrile to 100% acetonitrile linearly changed over a period of time, equal to 1.5 minutes was maintained for 0.6 minutes, then used a 100% aqueous formic acid (0.1%) for 0.5 minutes. The flow rate was 0.6 ml/min

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

The method C: Instruments Waters Acquity UPLC equipped with spectrophotometric detector (PDA range 210-400 nm), and a Waters SQD with the ionization source operating in two modes, ES+/-. The used column was a XS Strategy of 1.7 μm, and 2.1×20 mm, and was supported operating temperature 50°C. a Gradient from 100% aqueous formic acid (0.1%) to 100% acetonitrile linearly changed over a period of time equal to 1.5 minutes was maintained for 0.6 minutes, then used a 100% aqueous formic acid (0.1%) for 0.5 minutes. The flow rate was 0.6 ml/min

Table 1
The compounds of formula I
Conn. No. R-C(=O)*=R*-C(=O)*
* The designation of the point of attachment of the radical
Exact mass calculatedThe observed mass (M+H+)Rt (min) [method]
1608,296090,80 [A]
2610,286110,48 [A]
3610,286110,76 [A]

4620,386211,00 [A]
5696,276970,65 [A]
6 636,256370,87 [A]
7764,257650,79 [A]
8568,285690,62 [A]
9638,316390,57 [A]
10568,285690,62 [A]
11616,306170,56 [A]
12776,25777of 1.03 [A]
13740,2774114672,306730,95 [A]
15640,286410,75 [A]
16696,346970,92 [A]
17802,478030,72 [A]
18762,307630,68 [A]
19654,446550,60 [A]

20754,32755 0,84 [A]
21626,416270,57 [A]
22560,225610,69 [A]
23582,255830,67 [A]
24582,255830,61 [A]
25616,246170,83 [A]
26740,337410,62 [A]
27618,276190,74 [A]
28 686,356870,76 [A]
29542,315430,62 [A]
30638,316390,79 [A]
31750,447510,62 [A]
32722,337234,11 [B]
33640,286410,72 [A]
34714,397150,85 [A]

35 654,296552,63 [B]
36684,396853,62 [B]
37775,017761,85 [B]
38686,816890,60 [A]
39630,706310,52 [A]
40658,766590,55 [A]

Example 3 Biological activity of the compounds of formula I

Analysis of replication

The compounds of formula (I) were tested for their inhibitory activity in the process of replication of the HCV virus. Cell analysis was based on the gene expression in the composition bicistronic design, as described in the Lohmann et al. (1999) Science vol. 285 pp. 110-113, using the modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, strategy multipurpose screening.

Essentially, the method was as follows.

Analyses used consistently transtitional cell line Huh-7 luc/neo (hereinafter in this description referred to as Huh-Luc). This cell line contains coding RNA expressed bicistronic design, including NS3-NS5B region of the wild type nematanthus HCV type Ib received broadcast vnutrirezonatornogo available site (IRES) of the virus encephalomyocarditis (EMCV) in front of the area reporter gene (FfL-luciferase), and a portion of a gene of breeding marker (neoR, neomycinphosphotransferase). On limiting design 5' and 3' ends are NTR (noncoding sites) of the genome of HCV genotype 1b. A functioning culture of cells containing the replicon in the presence of G418 (neoRdepends on the replication of RNA virus HCV. Stable transfetsirovannyh the replicon cells, which is expressed HCV RNA with a high level of Autonomous replication, encodes, among other things, luciferase, was used for screening of antiviral compounds.

Containing the replicon cells were sown in 384-well plates in the presence of the test and control compounds are added to different to what ncentrate. Further incubation was performed for three days, HCV replication was determined by measuring luciferase activity (using standard substrates and reagents for analysis of luciferase and microplate Visualizer Perkin Elmer ViewLux™ ultraHTS). Containing the replicon cells in the control cultures had a high level of luciferase gene expression in the absence of any inhibitor. Inhibitory activity of compounds against luciferase activity was monitored in cells Huh-Luc, ensuring curve dose-response for each test compound. Then the expected value EC50that represent the number of connections required to reduce the level of detectable luciferase activity by 50%, or, more specifically, are the ability to genetically associated with HCV replicon RNA replication.

Table 2
Connect., No.R-C(=O)-=R*-C(=O)-EC50(µm)
10,00026
2 0,0015
30,81
40,13
50,0048
60,018
70,057
80,56
9<0,00048
100,018
110,25

120,29
13 0,76
140,093
150,00069
161,03
170,00011
180,000091
190,11
200,000020
21being 0.036
220,031
233,95
24 1,0058

251,023
260,00095
270,018
280,000036
290,28
300,00077
310,00026
32<0,00048
330,00022
340,00008
350,068
360,00069

370,00003
380,0054
39>0,98
400,00023

1. The compound of the formula I

or a stereoisomer, where
R and R, each independently, represents-CR1R2R3C1-4alkylamino, benzylamino, C6-10arylamino, heteros4-7cycloalkyl containing 1 heteroatom selected from O; where
R1selected from C1-4of alkyl; phenyl, optionally substituted by 1, 2 or 3 substituents, independently selected from halogen, C1-4of alkyl, C1-4alkoxy, triptoreline or 2 of the substituents at adjacent ring atoms, form a 1,3-dioxolane group; benzyl, n is necessarily substituted with halogen or methoxy; phenylsulfonyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroaromatic containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl;
R2selected from hydrogen, hydroxyl, CI-C1-4alkylamino, C1-4alkylcarboxylic, C1-4allyloxycarbonyl, C1-4alkylaminocarbonyl, piperidine-1-yl or imidazol-1-yl;
R3represents hydrogen or, alternatively,
R2and R3together form oxoprop; or
R1and R3together form cyclopropyl;
provided that if one of R or R* represents a - CH(C6H5)N(CH3)2then the other cannot represent - CH(C6H5)NHC(=O)OCH3; and if R and R* are the same, then R1is other than phenyl when R2represents hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3represents hydrogen; and R1differs from C1-4the alkyl when R2represents a C1-4allyloxycarbonyl, and R3represents hydrogen;
or its pharmaceutically acceptable salt or MES.

2. Connection on p. 1, where R and R* represent-CR1R2R3or benzylamino.

3. Connection on p. 2, where R and R* represent the a-CR 1R2R3.

4. Connection under item 1 or 3, where R2represents hydrogen, hydroxyl, dimethylamino, acetylamino, methoxycarbonylamino, methylaminoquinoline, piperidine-1-yl or imidazol-1-yl.

5. Connection under item 1 or 3, where R1selected from C1-4of alkyl; phenyl, optionally substituted by 1 or 2 substituents, independently selected from halogen, methyl, methoxy or 2 of the substituents at adjacent ring atoms, form a 1,3-dioxolane group; heteroaryl and heteroaromatic.

6. Connection on p. 5, where heteroaryl represents pyridinyl.

7. Connection on p. 1, where the compound represented by formula I-b

8. Pharmaceutical composition for prevention or treatment of HCV infection in a mammal, containing the compound as defined in any of paragraphs.1-7, and a pharmaceutically acceptable carrier.

9. The use of compounds according to any one of paragraphs.1-7 for the prevention or treatment of HCV infection in mammals.



 

Same patents:

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: medicine, pharmaceutics.

SUBSTANCE: invention relates to piridazine derivatives of formula II

,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

EFFECT: compounds of formula II demonstrate inhibiting effect with respect to proteinkinases such as c-met, ron, or ALK, or chimeric proteins, and can be useful for treatment of disorders, associated with abnormal activity of proteinkinases, such as cancer.

7 cl, 1 tbl, 30 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: medicine, pharmaceutics.

SUBSTANCE: invention relates to the derivatives of pyrimidine with formula I, where Z is a carbon atom or a nitrogen atom; Y is a carbon atom or a nitrogen atom, where one of the Z and Y is a nitrogen atom; A, D and E are chosen from the carbon atom and nitrogen atom; R1 is hydrogen or methyl, when D is a carbon atom; R2 is hydrogen or an amine group; R3 is hydrogen, methyl, trifluoromethyl or (C0-C1) alkylaryl; R5 is hydrogen or methyl; L-R4 is chosen from: and R6 is chosen from hydrogen and methyl; R7 is chosen from hydrogen, methyl, (C1-C4)alkyl-OH and (CO)OCH3, R7a and R7b are independently chosen from hydrogen and methyl; R8 is chosen from halogen, hydrogen, hydroxy, (CO)OH, (CO)OCH3, O(C1-C4) alkyl, O(C1-C4)alkyl(C6-C10)aryl, O(C1-C4)alkyl(C2-C9)heterocyclyl, O(EtO)1-3(C1-C4)alkyl and OCF3; and R11 is chosen from hydrogen, methyl and O(C1-C4) alkyl. The invention also relates to a pharmaceutical formulation for curing of cancer which contains the compounds with the formula I, to the usage of the compounds with the formula I to produce a medicinal agent and pharmaceutical formulation and to the cancer curing method.

EFFECT: compounds with the formula I aimed at cancer curing.

20 cl, 3 tbl, 109 ex

Diaryl ethers // 2528231

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), to its possible stereoisomers, or to its pharmaceutically acceptable salts, where R and R1, independently on each other, represent benzoyl, substituted with one substituent, each of which is independently selected from halogen or -C(=O)-Het, where Het is optionally substituted with two substituents, independently selected from C1-4alkyl, or a group of formula -C(=O)-CH(Rx)-R6, C1-6alkyloxycarbonyl, a group of formula R8-O-C(=O)-HN-CH(R7)-C(=O)- or -C(=O)-C(=O)-phenyl; R6 represents C1-4alkyl, C3-6cycloalkyl, benzyl or phenyl, where phenyl can be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, C1-6alkyl, methoxy, trifluoromethoxy, or two substituents at adjacent atoms of the ring together with a phenyl ring form benzodioxol, and where C1-4alkyl is substituted with diC1-6alkylamino, phenylsulphonyl, Het, and where benzyl is substituted with one substituent, each of which is independently selected from halogen, methoxy; Rx is selected from hydrogen, hydroxyl, diC1-6alkylamino, imidazolyl, Het represents a heterocyclic group, containing one or two heteroatoms, selected from O and N, and containing 5-6 atoms in a ring, where the said heterocyclic ring is bound with the carbonyl carbon atom through the ring carbon atom and where at least one of the said heteroatoms is adjacent to the said ring carbon atom, R2 and R3, independently on each other represent hydrogen; R4 and R5, independently on each other represent hydrogen or methoxy; each R7 independently represents phenyl or C1-4alkyl optionally substituted with methoxy; and R8 represents C1-4alkyl. The invention also relates to particular compounds and a pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel compounds, useful as HCV inhibitors.

11 cl, 4 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of bis(2,4,7,8,9-pentamethyldipyrrolylmethen-3-yl)methane dihydrobromide as fluorescent zinc (ii) cation sensor.

EFFECT: invention will make it possible to increase fluorescent activity of heterocyclic organic compound with respect to zinc (II) ion in presence of other ions of metals.

1 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

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