Macrocyclic hepatitis c inhibitors

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

 

The present invention relates to macrocyclic compounds having inhibitory activity against the replication of hepatitis C virus (HCV). In addition, it relates to compositions containing such compounds as active ingredients, and to methods of producing such compounds and compositions.

Worldwide, hepatitis C virus is the leading cause of chronic liver disease and has become the focus of a significant amount of medical research. HCV is a member of the virus familyFlaviviridaeof the genushepacivirusand is closely related to the genusflavivirusthat includes a number of viruses involved in human diseases, such as dengue virus and yellow fever virus, and the familypestivirusanimal viruses that includes the virus diarrhoea bulls (BVDV). HCV is a positive-sense, single-stranded RNA virus with a genome of approximately 9600 grounds. The genome contains both 5'-and 3'-noncoding region, which reproduces the secondary structure of RNA, and the Central open reading frame, which encodes a single polyprotein length of approximately 3010-3030 amino acids. Polyprotein contains products that are encoded by ten genes and generated from polyprotein predecessor as the result of a series of co - and is built to nslation endoproteolytically splits, mediated both host and viral proteases. Viral structural proteins include nuclear nucleocapsid protein and two envelope glycoproteins E1 and E2. Non-structural (NS) proteins cause some vital viral enzymatic functions (helicase, polymerase, protease), and proteins with unknown function. Replication of the viral genome is mediated RNA-dependent RNA polymerase, presents non-structural protein 5b (NS5B). It has been proven that in addition to the polymerase essential for the replication of HCV RNA are functions of viral helicase and protease, both of which are bifunctional NS3 protein. In addition to the serine protease NS3, HCV encodes also metalloproteinases in the NS2 region.

After the initial acute infection, most infected individuals develop chronic hepatitis, because HCV replicates preferentially in hepatocytes, although it is not directly cytopathic. In particular, the lack of sufficiently intense response of T-lymphocytes and high susceptibility of the virus to mutations, presumably, contribute to high propagation speed of chronic infection. Chronic hepatitis can progress to liver fibrosis, leading to end-stage disease to cirrhosis and HCC (hepatocellular carcinoma), that is, the GLA is a major cause of liver transplantation.

There are 6 major HCV genotypes and more than 50 subtypes that are geographically distributed unequally. Type 1 HCV represents a genotype, dominant in Europe and the USA. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, possibly explaining the difficulties in vaccine development and poor response to therapy.

Transmission of HCV can occur through contact with contaminated blood or blood products, for example, after blood transfusion or intravenous drugs. The introduction of diagnostic tests used in the screening of blood leads to the reduction of HCV after transfusion. However, given the slow progress in relation to liver disease end-stage, existing infection will persist for decades, providing major medical and economic burden.

Modern therapy of HCV is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. Such combination therapy results in long-term response to the virus in more than 40% of patients infected with viral genotype 1, and approximately 80% of patients infected with virus genotypes 2 and 3. Along with limited efficacy against HCV type 1 such combination therapy has significant side is ffecti and poorly tolerated by many patients. The main side effects include flu-like symptoms, hematologic disorders, and neuropsychiatric symptoms. Therefore, there is a need for a more efficient, convenient and better tolerated treatments.

Recently as clinical candidates attracted the attention of two peptidomimetic inhibitor of HCV protease, namely, BILN-2061, as described in the application WO00/59929, and VX-950, as described in the application WO03/87092. A number of such inhibitors of HCV protease also described in the scientific and patent literature. Currently, it is already obvious that the continuous introduction of BILN-2061 or VX-950 encourages the selection of HCV mutants that are resistant to the corresponding medicinal product, the so-called mutants, "escaping" from drugs. Such mutants, "escaping" from drugs, have a characteristic mutation in the genome of HCV protease, namely, D168V, D168A and/or A156S. Accordingly, to ensure that failed patients treatment options, additional medicines with other characteristics of resistance and combination therapy with multiple drugs is likely to become the norm in the future, even for the treatment of the first order.

In addition, experience with HIV-medicines and, in particular, inhibitors of the HIV-protease, and makes the penny on the fact, that sub-optimal pharmacokinetics and complex regimens drugs quickly lead to unexpected errors in compliance with the requirements of admission. This, in turn, means that the 24-hour minimum concentration minimum plasma concentration) of the respective drugs in the regimen against HIV often falls below the threshold IC90or ED90for significant segments of the day. It is believed that the 24-hour minimum threshold level of at least IC50and more realistic, IC90or ED90is essential to curbing the growth of the mutants, "escaping" from drugs. Achieving the desired pharmacokinetics and metabolism of medicines to ensure such minimum threshold levels, imposes strict requirements on the creation (design) of drugs. The strong nature of peptidomimetics inhibitors of HCV protease prior art with multiple peptide bonds creates pharmacokinetic difficulties for the effective schemes of receiving the drug.

The necessary inhibitors of HCV, which can overcome the deficiencies in the current HCV therapy such as side effects, limited efficacy, the emergence of resistance and errors in complying with the requirements the deposits in the reception.

Application WO04/072243 relates to macrocyclic inhibitors of serine protease of hepatitis C; pharmaceutical compositions containing the above compounds, intended for administration to a subject suffering from HCV infection; and methods for treating HCV infection in a subject by introducing pharmaceutical compositions containing the said compounds.

The present invention relates to inhibitors of HCV, which have advantages in one or more of the following pharmacological related properties, i.e. activity, low cytotoxicity, improved pharmacokinetics, improved resistance profile, acceptable dosage and reduction techniques.

In addition, the compounds of the present invention have a relatively low molecular weight and is easily synthesized, based on the starting materials, which are commercially available or readily accessible through the procedures of synthesis known in this field.

The present invention relates to inhibitors of HCV replication, which can be represented by the formula (I):

and their N-oxides, salts and stereoisomers, in which each dashed line (represented as -----) represents an optional double bond;

Xrepresents N, CH and where X contains a double bond,it represents C;

R1represents-OR11, -NH-SO2R12;

R2represents hydrogen and when X is C or CH,R2can also be a C1-6-alkyl;

R3represents hydrogen, C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl or C3-7-cycloalkyl;

nis 3, 4, 5 or 6;

Wrepresents a heterocycle of the formula

Qrepresents N or CR4;

R4represents hydrogen; phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl;

R5represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl;

one of theR6,R7represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl; while another of theR6,R7represents hydrogen; phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl;

one of theR8,R9,b> R10represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl; while the other two ofR8,R9,R10independently represent hydrogen; phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl;

R11represents hydrogen; aryl; Het; C3-7-cycloalkyl, optionally substituted C1-6-alkyl; or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het;

R12represents aryl; Het; C3-7-cycloalkyl, optionally substituted C1-6-alkyl; or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het;

eacharylas a group or part of a group represents a phenyl, optionally substituted one, two or three substituents selected from halogen, hydroxy, nitro, cyano, carboxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkylsulphonyl, amino, mono - or di-C1-6-alkylamino, azido, mercapto, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkoxy, C3-7-cycloalkyl, pyrrolidinyl, piperidinyl, piperazinil, 4-C -alkylpiperazine, 4-C1-6-acylcarnitine, morpholinyl; where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals; and

eachHetas a group or part of a group is a 5 or 6-membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing from 1 to 4 heteroatoms, each independently selected from nitrogen atoms, oxygen and sulfur, and optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkylsulphonyl, amino, mono - or di-C1-6-alkylamino, azido, mercapto, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkoxy, C3-7-cycloalkyl, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine, 4-C1-6-acylcarnitine, morpholinyl; where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals.

The invention additionally relates to methods of preparing compounds of formula (I),N-oxides, additive salts, Quaternary amines, metal complexes and the stereochemical isomeric forms, their intermediate products, and intermediate products for producing compounds of formula (I).

The invention relates to compounds of formula (I) as such, theirN-oxides, additive salts, Quaternary amines, complexes with metals and their stereochemical isomeric forms, for use as a drug. The invention additionally relates to pharmaceutical compositions containing the above compounds, intended for administration to a subject suffering from HCV infection. The pharmaceutical composition may contain a combination of the above compounds with other agents against HCV.

The invention also relates to the use of compounds of formula (I) orN-oxide, additive salt, Quaternary amine, metal or stereochemical isomeric forms, for the manufacture of a medicinal product intended for inhibiting replication of HCV. Or the invention relates to a method of inhibiting HCV replication in a warm-blooded animal, the said method comprising introducing an effective amount of the compounds of formula (I) orN-oxide, additive salt, Quaternary amine, metal or stereochemical isomeric forms.

Unless otherwise specified, as used above and hereinafter are following the e definition.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "polyhalogen-C1-6-alkyl" as a group or part of a group, for example in polyhalogen-C1-6-alkoxy, is defined as mono - or polyhalogen C1-6-alkyl, in particular C1-6-alkyl, substituted by one, two, three, four, five, six or more halogen atoms, such as methyl or ethyl with one or more fluorine atoms, for example deformity, trifluoromethyl, triptorelin. Preferred is trifluoromethyl. Also included PERFLUORO-C1-6is an alkyl group, which represents C1-6is an alkyl group in which all hydrogen atoms substituted by fluorine atoms, such as pentaverate. In that case, when the alkyl group is attached more than one halogen atom, within the definition polyhalogen-C1-6the alkyl halogen atoms may be the same or different.

Used here, the term "C1-4-alkyl" as a group or part of a group defines saturated hydrocarbon radicals with a straight or branched chain, containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl; "C1-6-alkyl" covers C1-4-alkyl radicals and the higher homologues containing 5 or 6 carbon atoms, such as, for example, 1 pentyl, 2-pentyl, 3-Penta is l, 1-hexyl, 2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 2-ethyl-1-butyl, 3-methyl-2-pentyl etc. Among C1-6is an alkyl group of interest is C1-4-alkyl.

The term "C2-6alkenyl" as a group or part of a group defines hydrocarbon radicals, straight and branched chain, containing saturated carbon-carbon bonds, and, at least one double bond and containing from 2 to 6 carbon atoms, such as, for example, ethynyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl etc. Among C2-6-alkenyl groups of interest represents C2-4alkenyl.

The term "C2-6-quinil" as a group or part of a group defines hydrocarbon radicals, straight and branched chain, containing saturated carbon-carbon bonds, and, at least one triple bond and containing from 2 to 6 carbon atoms, such as, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl etc. Among C2-6-etkinlik groups of interest represents C2-4-quinil.

C3-7-cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

C1-6-alcander determines dwuhvalentnoe hydrocarbon radicals, straight and branched chain, containing from 1 to 6 carbon atoms, such as, for example, methylene, ethylene, 1,3-propandiol, 1,4-butandiol, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl, 1,6-hexandiol etc. Among C1-6-elendilmir groups of interest represents C1-4-alcander.

C1-6-alkoxy means C1-6-alkyloxy, in which C1-6-alkyl has the above value.

Already used herein, the term (=O) or oxo forms a carbonyl fragment when attached to the carbon atom, sulfoxide fragment when attached to the sulfur atom, and sulfanilic fragment, when two mentioned "oxo" attached to the sulfur atom. Whenever the ring or ring system substituted by an oxo-group, the carbon atom to which is connected oxo-group is a saturated carbon atom.

The radical Het represents a heterocycle, which is specified in this description and the claims. Examples of Het include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, piperazinil, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, teasingly, isothiazolin, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl etc. Among the radicals Het interest those radicals Het, which are what I unsaturated, in particular radicals having aromatic character. Of additional interest are those radicals Het, which contain one or two nitrogen atom.

Each of the radicals Het mentioned in this and the following paragraphs are optional and can be replaced by some number and type of substituents mentioned in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I). Some of the radicals Het mentioned in this and the following paragraphs can be substituted by one, two or three hydroxy substituents. Such hydroxy-substituted rings may occur in the form of its tautomeric forms, containing ketogroup. For example, 3-hydroxypyridinone fragment can meet in their tautomeric form 2H-pyridazin-3-one. When Het represents piperazinil, it is preferably substituted in its position 4 Deputy attached to the 4-nitrogen via a carbon atom, such as 4-C1-6-alkyl, 4-polyhalogen-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl, C1-6-alkylcarboxylic, C3-7-cycloalkyl.

Interest radicals Het include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, piperazinil, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 12,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl or any of such heterocycles condensed with a benzene ring, such as indolyl, indazoles (in particular 1H-indazole), indolinyl, chinoline, tetrahydroquinolines (in particular, 1,2,3,4-tetrahydroquinoline), ethenolysis, tetrahydroisoquinolines (in particular, 1,2,3,4-tetrahydroisoquinoline), hintline, phthalazine, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzoxadiazole, benzothiadiazole, benzofuranyl, benzothiazol.

The radicals Het pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, piperazinil, 4-substituted piperazinil preferably attached through its nitrogen atom (i.e. 1-pyrrolidinyl, 1-piperidinyl, 4-thiomorpholine, 4-morpholinyl, 1-piperazinil, 4-substituted 1-piperazinil).

It should be noted that the provisions of the radicals in any molecular fragment specified in the definitions may be located on this fragment anywhere, provided that it is chemically stable.

If not stated otherwise, the radicals used in the definitions of the variables include all possible isomers. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1 pencil, 2-pentyl and 3-pentyl.

When any variable in any component element occurs more on the aqueous times, each definition is independent.

Whenever in the future uses the term "compounds of formula (I)," or "the present compounds"or similar terms, this means that they include the compounds of formula (I), their prodrugs,N-oxides, additive salts, Quaternary amines, complexes with metals and stereochemical isomeric form. One of the embodiments of the invention includes compounds of formula (I) or any specified here subgroup of compounds of formula (I), andN-oxides, salts in the form of their possible stereoisomeric forms. Another variant of implementation includes the compounds of formula (I) or any specified here subgroup of compounds of formula (I), and salts in the form of their possible stereoisomeric forms.

The compounds of formula (I) have several centers of chirality and exist in the form of stereochemical isomeric forms. Used here, the term "stereochemical isomeric form" defines all possible compounds consisting of the same atoms connected in the same sequence of relationships, but having different three-dimensional structures, which are not mutually replaceable and which the compounds of formula (I) may possess.

With reference to the examples to denote the absolute configuration of chiral atom in the Deputy applies (R) or (S), connect the s is considered as a whole and without interrupting the Deputy.

If not mentioned, or indicates otherwise, the chemical name of the compounds comprises a mixture of all possible stereochemical isomeric forms, which mentioned the connection can have. The above mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the above-mentioned compounds. Of course, all stereochemical isomeric forms of the compounds of the present invention in pure form and mixed with each other should be included in the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates mentioned herein, are defined as isomers, essentially not containing other enantiomeric or diastereoisomeric forms of the same basic molecular structure of the above-mentioned compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate products containing excess stereoisomer, at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers) until the excess stereoisomer 100% (i.e. 100% of one isomer and the absence of another isomer), more specifically, to compounds or intermediate products containing excess stereoisomer from 90% up to 100%, even more specifically, containing excess stereoisomer from 94% up to 100% and is the most concrete, containing excess stereoisomer from 97% up to 100%. The terms "enantiomerically pure" and "diastereomers net" in the matter under discussion should be understood in a similar way, but in this case they refer, respectively, to the enantiomer excess and surplus of the diastereoisomer mixture.

Pure stereoisomeric forms of the compounds and intermediates in this invention can be obtained by applying known in this field procedures. For example, the enantiomers can be separated from each other by using the selective crystallization of their diastereomeric salts with optically active acids or bases. Their examples are tartaric acid, dibenzoyltartaric acid, ditawarkannya acid and camphorsulfacid. Alternative enantiomers can be separated using chromatographic methods using chiral stationary phase. Mentioned pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that is stereospecific reaction. If you want a specific stereoisomer, preferably the above-mentioned compound to synthesize using stereospecific methods of obtaining. These methods are mainly used enantiomerically pure starting materials.

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

For some of the compounds of formula (I), their prodrugs,N-oxides, salts, solvate, Quaternary amines or metal complexes and intermediates used for their production, the absolute stereochemical configuration was not experimentally determined. The person skilled in the art is able to determine the absolute configuration of these compounds, using known in the field methods, such as, for example, x-ray diffraction method.

Also of course that the present invention includes all isotopes of atoms occurring in the present compounds. Isotopes include those atoms have the same atomic number but different mass number. As a conventional example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Used throughout this text the term "prodrug" means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the received result of the biotransformation product of the derivative in the body ( in vivo) is an active drug, which is defined in the compounds of formula (I). Here are included the link to the article authors Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pp. 13-15), describes prodrugs in General. Prodrugs preferably have excellent water solubility, increased bioavailability and metabolism in the body (in vivo) easily converted into active inhibitors. Prodrugs of the compounds of the present invention can be obtained by modifying present in the connection of functional groups so that the modification was cut to source connection, either using normal manipulation, either in the body (in vivo).

Preferred are pharmaceutically acceptable ester prodrug that is hydrolyzed in the body (in vivo) and are derived from those compounds of the formula (I), which contain a hydroxy or carboxyl group. Hydrolyzable in the body (in vivo) ester is an ester which is hydrolysed in the human or animal with the formation of the original acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy groups include complex C1-6-alkoxymethyl esters, for example ethoxymethylene, complex C1-6-alkanoyloxy esters, such as complex pivaloyloxymethyl, telegrafie esters, complex C3-8-cycloalkylcarbonyl-C1-6-alkalemia esters, for example 1-cyclohexyloxycarbonyloxy; complex of 1,3-dioxolan-2-animecrave esters, for example 5-methyl-1,3-dioxolan-2-animationy; and complex C1-6-alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethylene, which can be used to form the compounds of this invention at any carboxy group.

Hydrolyzable in the body (in vivo) ester compounds of formula (I)containing a hydroxy group includes inorganic esters such as esters of phosphoric acid, a simple α-aryloxyalkyl ethers and related compounds which as a result of the hydrolysis of ester in the body (in vivo) decompose, giving the original hydroxy group. Examples of simple α-aryloxyalkyl esters include acetoxymethyl and 2,2-dimethylphenylacetate. The choice is hydrolyzable in the body (in vivo) of ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (for more complex alkalicarbonate esters), dialkylamino and N-(dialkylaminoalkyl)-N-allylcarbamate (to get to the of ramatou), dialkylaminoalkyl and carboxyethyl. Examples of the substituents on the benzoyl include morpholino and piperazinone connected to the ring nitrogen atom via a methylene group in position 3 or 4 sensornogo rings.

Salts of compounds of formula (I) for therapeutic use are those salts in which the counterion is pharmaceutically acceptable. However, it also can be used salts of acids and bases, which are not pharmaceutically acceptable, for example, to get or purification of pharmaceutically acceptable compounds. All salts are pharmaceutically acceptable or not included in the scope of the present invention.

Of course, that the above-mentioned pharmaceutically acceptable additive salts of acids and bases contain therapeutically active, non-toxic form of additive salts of acids and bases, which are capable of forming compounds of formula (I). Pharmaceutically acceptable additive, acid 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, for example hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, e.g. the measures acetic, propanoic, hydroxyestra (glycolic acid), lactic, pyruvic, oxalic (i.e. o), malonic, succinic (i.e. butanedioate), maleic, fumaric, malic (i.e. hydroxybutyrate), tartaric, citric, methansulfonate, econsultancy, benzolsulfonat,p-toluensulfonate, reklamowa, salicylic,p-aminosalicylic, AMOVA and the like acid.

On the other hand, this form of salts by treatment with a suitable base can be converted into the form of a free base.

The compounds of formula (I)containing an acidic proton, by treatment with appropriate organic and inorganic bases can also be converted to form their additive salts with non-toxic metals or amines. Form of suitable basic salts include, for example, ammonium salts, salts of alkali and alkaline earth metals, such as lithium salts, sodium, potassium, magnesium, calcium and the like, salts with organic bases, such as benzathine salt,N-methyl-D-glucamine, geranamine and salts with amino acids such as, for example, arginine, lysine, etc.

Used above, the term additive salt also includes a solvate, which the compounds of formula (I)and their salts are able to form. Such solvate represent, for example, hydrates, alcohol what you etc.

Used above, the term "Quaternary amine" defines the Quaternary ammonium salt, which is able to form compounds of formula (I) in the interaction of atoms of the basic nitrogen compounds of formula (I) and a suitable quarternizing agent, such as, for example, optionally substituted alkylhalogenide, aryl halides or arylalkylamine, such as methyliodide or benzylated. You can also use other reagents with suitable leaving groups, such as alkylarylsulfonate, alkylarylsulfonate and alkyl-p-toluensulfonate. Quaternary amine contains positively charged nitrogen atom. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, triptorelin and acetate. Selected counterion can be entered using ion-exchange resins.

Assume thatNoxide forms of the present compounds include the compounds of formula (I)in which one or more atoms of nitrogen oxidized to the so-calledN-oxide.

It should be noted that the compounds of formula (I) can form a connection with the metals to be hepatoblastoma and complexing properties, and can therefore exist in the form of metal complexes or chelates metals. Of course, that such metilirovannye derivatives of compounds of formula (I) subject to the inclusion in this volume is the future of invention.

Some of the compounds of formula (I) can also exist in their tautomeric form. Of course, such forms, although implicitly indicated in the above formula, should be included in the scope of the present invention.

As mentioned above, the compounds of formula (I) contain several centers of asymmetry. In order more effectively to refer to each of these centers of asymmetry, will apply the numbering system indicated in the following structural formula.

Centers of asymmetry are in positions 1, 4 and 6 of the macrocycle, as well as on the carbon atom 3'a 5-membered ring, the carbon atom 2'when the substituent R2represents a C1-6-alkyl, and the carbon atom 1'when X represents CH. Each of these centers of asymmetry may occur in their R or S-configuration.

The stereochemistry at position 1 preferably corresponds to the stereochemistry configuration of L-amino acids, i.e. the stereochemistry of L-Proline.

When X represents CH, 2 carbonyl groups, replacing the cyclopentane ring in positions 1'5'preferably are located in theTRANS-configuration. Carbonyl substituent in position 5'preferably is in the configuration that meets the configuration of L-Proline. Carbonyl group, C is mesousa (cyclopentane ring) in positions 1 '5'preferably reside in the structure of the following formula, as shown below:

The compounds of formula (I) include cyclopropyl group, which is presented below in the structural fragment:

in which C7represents the carbon atom in position 7, and the carbon atoms in position 4 and 6 are asymmetric carbon atoms cyclopropanol rings.

Despite other possible centers of asymmetry, in other segments of the compounds of formula (I), the presence of two such centers of asymmetry means that the compounds can exist as mixtures of diastereomers, such as diastereomers of the compounds of formula (I), in which the carbon atom in position 7 has the configuration orSYNwith respect to the carbonyl, orShin-relative to the amide, as shown below.

One of the embodiments of the invention relates to compounds of formula (I), in which the carbon atom in position 7 hasSYN-configuration with respect to the carbonyl. Another variant embodiment of the invention relates to compounds of formula (I), in which the configuration at the carbon atom in position 4 represents the R-configuration. A specific subgroup of compounds is the second of the formula (I) are compounds, in which the carbon atom in position 7 hasSYN-configuration with respect to the carbonyl in which the configuration at the carbon atom in position 4 represents the R-configuration.

The compounds of formula (I) may include polynomy balance (when X represents N or cyclopentenyl or cyclopentadienyl balance (when X represents CH or C). Preferred are the compounds of formula (I), in which the substituent in position 1 (or 5'and Deputy W at position 3'areTRANS-configuration. Of particular interest are compounds of formula (I), which in position 1 have a configuration corresponding to L-Proline and Deputy W at position 3' is inTRANS-configuration with respect to the position 1. Preferably the compounds of formula (I) have the stereochemistry as indicated below in structural formulas (I-a) and (I-b):

One of the embodiments of the present invention relates to compounds of formula (I), or formula (I-a), or any subgroup of compounds of formula (I)in which one or more of the following conditions:

(a) R2represents hydrogen;

(b) X represents nitrogen;

(c) between carbon atoms 7 and 8 present the double bond.

One of the embodiments of the present imaging the acquisition relates to compounds of formula (I) or formula (I-a), (I-b), or any subgroup of compounds of formula (I)in which one or more of the following conditions:

(a) R2represents hydrogen;

(b) X represents CH;

(c) between carbon atoms 7 and 8 present the double bond.

Particular subgroups of compounds of formula (I) are subgroups, represented by the following structural formulas:

Among the compounds of formula (I-c) and (I-d) of particular interest are compounds having the stereochemical configuration of the compounds of formula (I-a) and (I-b), respectively.

The double bond between carbon atoms 7 and 8 in the compounds of formula (I) or any subgroup of compounds of formula (I) can be inCIS-orTRANSconfiguration. Preferably the double bond between carbon atoms 7 and 8 is inCIS-configuration, which is depicted in formula (I-c) and (I-d).

In the compounds of formula (I) or any subgroup of compounds of formula (I) between carbon atoms 1'and 2'may contain a double bond, which is shown below in the formula (I-e).

Another particular subgroup of compounds of formula (I) are compounds represented by the following structural formulas:

Among the compounds is of oral (I-f), (I-g) or (I-h) special interest are compounds having the stereochemical configuration of the compounds of formula (I-a) and (I-b).

In formulas (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) and (I-h), where applicable, W, X, n, R1, R2and R3have the values listed in the definitions of the compounds of formula (I) or in any of these subgroups of compounds of formula (I).

Of course, it should be understood that the above specified subgroups of compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or (I-h)and any other specified here subgroups, also include any prodrugs,N-oxides, additive salts, Quaternary amines, complexes with metals and stereochemical isomeric forms of such compounds.

When n is 2, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds ethandiyl. When n is 3, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds propandiol. When n is 4, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds butandiol. When n is 5, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponding to pentangelo. When n is 6, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds hexandiol. Compounds in which n is 4 or 5 represent a particular subgroup of compounds of formula (I).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), in which

(a) R1represents a group-OR11in particular the group in which R11represents a C1-6-alkyl, such as methyl, ethyl ortert-butyl, and most preferably when R11represents hydrogen; or

(b) R1represents a group-NHS(=O)2R12in particular the group in which R12represents a C1-6-alkyl, C3-C7-cycloalkyl or aryl, for example, in which R12represents methyl, cyclopropyl or phenyl; or

(c) R1represents a group-NHS(=O)2R12in particular the group in which R12represents a C3-7-cycloalkyl, substituted C1-6-alkyl, preferably where R12is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which are substituted C1-4-alkyl, i.e. stands, ethyl, propylene, isopropyl, bootrom,tert-bootrom or isobutyl.

To anitelea embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), in which R1represents-NHS(=O)2R12in particular, in which R12is cyclopropyl, substituted C1-4-alkyl, i.e. stands, ethyl, propylene or isopropyl.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents-NHS(=O)2R12in particular, in which R12is a 1-methylcyclopropyl.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), in which

(a) R2represents hydrogen;

(b) R2represents a C1-6-alkyl, preferably methyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), in which

(a) X represents N, C (X attached via a double bond) or CH (X is attached via a single bond, and R2represents hydrogen;

(b) X represents C (X attached via a double bond), and R2represents a C1-6-alkyl, preferably methyl.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), W is

(a) R3represents hydrogen;

(b) R3represents a C1-6-alkyl;

(d) R3represents a C1-6-alkoxy-C1-6-alkyl or C3-7-cycloalkyl.

Preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R3represents hydrogen or C1-6-alkyl, more preferably hydrogen or methyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which W represents a

andR5represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which W represents a

andR5represents phenyl, 3-methoxyphenyl, 3,4-acid, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.

Other subgroups of the compounds of formula (I) include those compounds of formula (I) or any specified here subgroup of compounds of formula (I)in which W represents the FDS is th

in whichR6represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl; and

R7represents hydrogen; phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl.

Other subgroups of the compounds of formula (I) include those compounds of formula (I) or any specified here subgroup of compounds of formula (I)in which W represents a

in whichR6represents phenyl,m-methoxyphenyl, 2-pyridyl, 3-pyridyl or 2-thiazolyl; and

R7represents phenyl,p-methoxyphenyl or 4-ethoxyphenyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which W represents a

in whichR4represents hydrogen; phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl; and

R5represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, it is certainly substituted C 1-6-alkyl; or pyridyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which W represents a

in which one of theR8,R9,R10represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl; while the other two ofR8,R9,R10independently represent hydrogen; phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which W represents a

in whichR8represents hydrogen, 4-methoxyphenyl or phenyl;

in whichR9represents hydrogen, phenyl, 4-methoxyphenyl, 3-pyridyl or thiazol-2-yl;

in whichR10represents hydrogen, phenyl, 3-pyridyl or thiazol-2-yl;

in which in the same molecule each of the three deputiesR8R9R10independently represents hydrogen.

Options implemented is tvline the invention relates to compounds of formula (I) or any subgroup of compounds of formula (I), in which W represents a

in whichR5represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; thiazolyl, optionally substituted C1-6-alkyl; or pyridyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which W represents a

andR5represents phenyl, 3-methoxyphenyl, 3,4-acid, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or thiazol-2-yl.

The compounds of formula (I) consist of three structural elements P1, P2, P3. Structural element P1 further comprises an end portion P1'. Carbonyl group, lower in the compound (I-c) are marked with an asterisk, may be part of either a structural element P2, or structural element P3. Chemical considerations structural element P2 of the compounds of formula (I)in which X represents C, includes a carbonyl group attached at position 1'.

The connection of the structural elements P1 to P2, P2 to P3 and P1 with P1'(when R1represents-NH-SO2R12) provides for the formation of amide linkages. The connection elements P1 and P3 involves the formation of double bond. Sedimentextrakten elements P1, P2 and P3 to obtain the compounds (I-i) or (I-j) can be performed in any particular sequence. One of the stages involves cyclization, which is formed macrocycle.

Below are the compound (I-i), which are compounds of formula (I), in which the carbon atoms C7 and C8 are connected by a double bond, and the compound (I-j), which are compounds of formula (I), in which the carbon atoms C7 and C8 are connected by a single bond.

The compounds of formula (I-j) can be obtained from corresponding compounds of formula (I-i) by restoring the double bond in the macrocycle.

Of course, as described in further synthesis procedure should be applicable equally to the racemates, pure stereochemical intermediate products or final products, or any mixtures of stereoisomers. The racemates or mixtures of stereoisomers can be divided into stereoisomeric forms at any stage of the synthesis procedures. In one variant of the invention, the intermediate products and final products have the stereochemistry indicated above for compounds of formula (I-a) and (I-b).

In one of the embodiments of the invention the compound (I-i) receive, forming a first amide bond, and then forming a double bond between P3 and P1, with concomitant cyclization to the macrocycle.

In preferably the m variant of the invention, the compounds (I), in which the relationship between carbon atoms C7 and C8 is a double bond and which are the above compounds of formula (I-i)can be obtained, as outlined in the following reaction scheme:

The formation of the macrocycle can be done by using the metathesis reaction of olefins in the presence of a suitable metal catalyst, such as, for example, a catalyst based on EN reported in the publications: S.J. Miller, H.E. Blackwell, R.H. Grubbs,J. Am. Chem. Soc.118, (1996), 9606-9614; Kingsbury J.S., J.P.A. Harrity, Bonitatebus P.J., A.H. Hoveyda,J. Am. Chem. Soc.121, (1999), 791-799; and Huang and others,J. Am. Chem. Soc.121, (1999), 2674-2678; for example, the catalyst of the Hoveyda-verification (Hoveyda-Grubbs).

You can apply sustainable air ruthenium catalysts, such as chloride bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-illiterately (Neolyst M1®or dichloride, bis(tricyclohexylphosphine)-[(phenylthio)methylene]ruthenium (IV). Other catalysts that can be used are catalysts of the verification of the first and second generation, i.e. benzylidene-bis(tricyclohexylphosphine)dichloroethane and (1,3-bis-(2,4,6-trimetilfenil)-2-imidazolidinone)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium, respectively. Of particular interest are the catalysts Hoveyda-verification of the first and second generation, which represent dichloro(o -isopropoxyaniline)(tricyclohexylphosphine)-ruthenium(II) and 1,3-bis-(2,4,6-trimetilfenil)-2-imidazolidinone)dichloro(o-isopropoxyaniline)ruthenium, respectively. For this reaction it is possible to use other catalysts containing other transition metals such as Mo.

The metathesis reaction can be carried out in a suitable solvent, such as ethers, for example THF, dioxane; halogenated hydrocarbons such as dichloromethane, CHCl3, 1,2-dichloroethane and the like, Such reaction is carried out at elevated temperatures in an atmosphere of nitrogen.

The compounds of formula (I), in which the relationship between carbon atoms C7 and C8 in the macrocycle is a single bond, i.e. compounds of formula (I-i)can be obtained from compounds of formula (I-j) by restoring the double bond C7-C8 in the compounds of formula (I-i). Such recovery can be performed using catalytic hydrogenation with hydrogen in the presence of a catalyst based on noble metals such as Pt, Pd, Rh, Ru or Raney Nickel. Interest is Rh on alumina. The hydrogenation reaction is preferably carried out in a solvent such as an alcohol, such as methanol, ethanol, or in a simple ether, such as THF, or their mixtures. Such solvents or mixtures of solvents can also be added water.

GRU is PU R 1can be attached to the structural element P1 at any stage of the synthesis, i.e. before or after the cyclization, or before or after the cyclization and recovery, as described above. The compounds of formula (I)in which R1represents-NHSO2R12[mentioned compounds represented by formula (I-k-1)]can be obtained by joining the group R1to P1 through education between the two fragments of the amide bond. Similarly the compounds of formula (I)in which R1represents-OR11, that is, the compound (I-k-2), can be obtained by joining the group R1to P1 through education ester bonds. In one of the embodiments of the invention group OR11introduced at the last stage of the synthesis of compounds (I), as briefly outlined in the following schemes of reactions, in which G represents a group:

Intermediate (2a) can be associated with the amine (2b) through the formation of amide, such as any described in further procedures for the formation of amide linkages. In particular, (2a) can be processed by condensing agent, such asN,N'-carbonyl diimidazol (CDI) or hexaphosphate benzotriazol-1 iloxi-Tris-pyrrolidinone (commercially available under the trade the brand PyBOP ®), in a solvent like THF, followed by reaction with the desired sulfonamide (2b) in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or diisopropylethylamine. Intermediate (2a) can be associated with alcohol (2c) via the formation of ester. For example, (2a) and (2c) are subjected to interaction with removal of water or physically, for example by azeotropic removal of water, or chemically, using a dehydrating agent. Intermediate (2a) can also be converted into an activated form, for example the acid chloride (G-CO-Cl) or a mixed anhydrate acids (G-CO-O-CO-R, where R represents, for example, C1-4is alkyl or benzyl), and then subjected to interaction with alcohol (2c). The formation of esters is preferably carried out in the presence of a base such as a carbonate of an alkali metal or hydrogen carbonate, such as sodium bicarbonate or potassium, or in the presence of a tertiary amine, such as amines, mentioned here in connection with the reaction of formation of amides, in particular trialkylamine, for example, triethylamine. Solvents that can be used in the reaction of formation of esters include ethers such as THF; halogenated hydrocarbons such as dichloromethane, CH2Cl2; hydrocarbons such as toluene; polar APRO is traditional solvents, such as DMF, DMSO, DMA; and the like solvents.

The compounds of formula (I)in which R3represents hydrogen (mentioned compounds represented by formula (I-1))can also be obtained by removal of the protective group PG from a corresponding nitrogen-protected intermediate (3a), as shown in the following reaction scheme. The protective group PG, in particular, is any one of nitrogen-protecting groups mentioned hereinafter, and can be removed with the use of procedures, also referred to in the future:

Raw materials (3a) in the above reaction can be obtained by following the procedures for obtaining compounds of formula (I), but using intermediate products in which the group R3is a PG.

The compounds of formula (I) can also be obtained by reacting intermediate (4a) with a heterocycle (4b), as outlined in the following reaction scheme, in which the various radicals have the following values:

Y in (4a) represents hydroxy or a leaving group such as halide, for example bromide or chloride, or arylsulfonyl group, such as mesilate, triflate or tosylate etc.

In one of the embodiments of the invention the reaction of (4a) with (4b) represents the reaction of O-arily the tion, and Y represents a leaving group. In particular, this reaction is carried out in the presence of a base, preferably a strong base, in a reaction-inert solvent, for example in one of the solvents mentioned in the case of formation of amide linkages. In one of the embodiments of the invention, the source material (4a) subject to interaction with (4b) in the presence of a base which is strong enough to take the hydrogen from the hydroxy group, for example, is an alkali-based alkali metal hydride such as LiH or NaH or alcoholate of an alkali metal, such as methylate or sodium ethylate or potassium,tert-butyl potassium, in a reaction inert solvent, type dipolar aprotic solvent such as DMA, DMF and the like, the resulting alcoholate is subjected to interaction with alleroisk agent (4b), in which, as mentioned above, Y represents a leaving group. The transformation of (4a) in (I) with the use of this type of reaction O-arilirovaniya does not change the stereochemical configuration at the carbon atom that carries a Y or W-group.

Alternative reaction (4a) with (4b) can also be carried out using the reaction of Mitsunobu (Mitsunobu, 1981, Synthesis, January, 1-28; Rano and others, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak, etc., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter and others, Tetrahedron Lett., 1994, 35, 27, 4705-4706). This reaction includes the processing of the intermediate product (4a), in which Y represents hydroxyl, the compound (4b) in the presence of triphenylphosphine and an activating agent, such as dialkyldithiocarbamate, such as diethylazodicarboxylate (DEAD), diisopropylcarbodiimide (DIAD) or the like by the reaction of Mitsunobu change the stereochemical configuration at the carbon atom that carries a Y or W-group.

The raw materials W-H (4b) can be obtained from known or commercially available products. Tetrazole can be obtained by reacting commercially available nitrile compounds with sodium azide. Derivatives of triazole can be obtained through reaction of alkyne compounds and trimethylsilane. Applicable connection alkynes either available commercially, or they can be obtained, for example, according to the reaction Sonogashira (Sonogashira), i.e. the reaction of the primary alkyne, arylalkenes and triethylamine in the presence of PdCl2(PPh)3and CuI, as described, for example, in A. Elangovan, Y.H. Wang, T.I. Ho,Org. Lett,2003, 5, 1841-1844. Deputy W may also change when it is attached to the structural element P2, either before or after bonding of the structural element P2 with other structural elements P1 and P3.

Additional alternatives for linking group W with a structural element P2 in obtaining compounds of formula (I) described in the application WO 2004/072243.

Alternatively, to obtain compounds of the Fort the uly (I) first, to form amide bond between the structural elements P2 and P1, with the subsequent binding of the structural element P3 fragment P1 in P1-P2, and the subsequent formation of urethane or ester bonds between P3 and fragment P2 P2-P1-P3 with concomitant closure of the loop.

Another alternative method of synthesis is the formation of amide linkages between the structural elements P2 and P3 with the subsequent binding of the structural element P1 to P3 fragment in P3-P2 and education at the end of the amide bond between P1 and P2 in P1-P3-P2 with concomitant closure of the loop.

Structural elements P1 and P3 can be attached to the sequence P1-P3. If necessary, you can restore the double bond connecting P1 and P3. Thus formed, the sequence of P1-P3, or restored, or not, can be associated with a structural element P2, and thus formed a sequence of P1-P3-P2 then collisional through the formation of amide linkages.

Structural elements P1 and P3 in any of the previous approaches can be connected with the formation of a double bond, for example, through reaction of metathesis of olefins, described later, or by using a reaction type of reaction the Wittig. If necessary, the thus formed double bond can be restored, just as described above for the conversion of (I-i) (I-j). The double bond can also be restored at a later stage, voltage is emer, after adding a third structural element or after the formation of the macrocycle. Structural elements P2 and P1 are connected with the formation of amide linkages, and P3 and P2 are connected with formation of carbamate or ether complex.

The end part P1' can be associated with a structural element P1 at any stage of the synthesis of compounds of formula (I), for example, before or after bonding of structural elements P2 and P1; before or after bonding of the structural element P3 with P1; or before or after closure of the loop.

You can first obtain a separate structural elements and then link them together or, alternatively, can be linked together predecessors structural elements and change them at a later stage to the desired molecular structure.

In order to avoid side reactions, it is possible to protect functional groups in each of the structural elements.

The formation of amide bonds can be performed using standard procedures, such as procedures for linking amino acids in the synthesis of peptides. The latter involves dehydrating the combination of a carboxyl group of one reagent with the amino group of another reagent with the formation of the linking amide bond. The formation of the amide bond can be accomplished by reacting starting materials in the presence of condensing Agay the TA or by converting the carboxyl functional groups in the active form, such as an active ester, mixed anhydride or acid chloride or bromohydrin carboxylic acids. A General description of such reactions combination and used reagents 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 with amide bond formation include the azide method of synthesis, the method of mixed anhydrides of coal-carboxylic acid (using isobutylphthalate), carbodiimide method (using dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide, such asN-ethyl-N'-[(3-dimethylamino)propyl]carbodiimide), the method of activated esters (for example,p-nitrophenyloctyl,p-hlorfenilovy, trichloranisole, pentachlorphenol, pentafluorophenyl,N-hydroxysuccinimide and the like esters), the method using K-Woodward reagent, 1,1-carbonyldiimidazole (CDI or N,N'-carbonyldiimidazole) method, a method using phosphorus reagents or oxidation-reduction methods. Some of these methods can be improved by adding suitable catalysts, for example, carbodiimide method by adding 1-hydroxybenzotriazole, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or 4-DMP. Additional condensing agents 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, or hexaphosphateabout-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea. Such reactions combination can be performed either in solution (liquid phase)or in the solid phase.

Preferably the formation of amide linkages carried out using N-ethoxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEDQ) or N-isobutylketone-2-isobutoxy-1,2-dihydroquinoline (IIDQ). In contrast to the classical anhydrous way EEDQ and IIDQ not require any base or low temperature reactions. Typically, the procedure involves the interaction of equimolar amounts of carboxylic and amine components in an organic solvent (you can use a large variety of solvents). Then add excess EEDQ or IIDQ and enable the mixture mixed at room temperature.

Of combination reaction is preferably carried out in an inert solvent, such as halogenated hydrocarbons, for example dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO, HMPT, ethers, is 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 may be in the range from 0°C to 50°C, and the time of interaction can range from 15 minutes to 24 hours.

Functional groups in the structural elements, which are joined together, it is possible to protect to prevent unwanted connections. Suitable protective groups which can be used are listed, for example, in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1999) and "The Peptides: Analysis, Synthesis, Biology", t 3, Academic Press, New York (1987).

The carboxyl group can be protected in the form of ester, which can be removed, while receiving carboxylic acid. Protective groups which can be used include: 1) complex alkalemia esters, such as methyl, trimethylsilyloxy andtert-butyl; 2) complex arylalkylamine esters, such as benzyl and substituted benzyl; or 3) esters that can be removed using a weak base or a weak reductant, such as a complex trichlorethylene and peacelove esters.

The amino group can be protected with the help of various N-protecting groups, such as:

1) acyl who groupings, such as formyl, TRIFLUOROACETYL, phthalyl andp-toluensulfonyl;

2) aromatic urethane groups, such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc);

3) aliphatic urethane groups, such astert-butyloxycarbonyl (Boc), etoxycarbonyl, diisopropylperoxydicarbonate and allyloxycarbonyl;

4) cyclic allylcarbamate groups, such as cyclopentanecarbonyl and adamantanecarbonyl;

5) alkyl groups such as triphenylmethyl, benzyl or substituted benzyl, such as 4-methoxybenzyl;

6) trialkylsilyl, such as trimethylsilyl ortert-Bu-dimethylallyl; and

7) tiradera groups, such as phenylthiocarbamyl and datasection.

Aminosidine groups of interest are Boc and Fmoc-group.

Preferably aminosidine group is removed before the next stage combination. Removal of the N-protective group can be performed following well-known in this field procedures. When applied Boc-group selection methods lies in the choice of triperoxonane acid, pure or in dichloromethane, or HCl in dioxane or ethyl acetate. The resulting ammonium salt is then neutralized either before combination, or in the process of its realization using basic solutions, such as aqueous buffers Il the tertiary amines in dichloromethane, or acetonitrile, or dimethylformamide. When used with Fmoc-group, the choice of reagents includes a piperidine or substituted piperidine in dimethylformamide, although you can apply any secondary amine. Removing the protection is carried out at a temperature from 0°C to room temperature, usually about 15-25°C or 20-22°C.

Other functional groups that can interfere in the reaction of a combination of structural elements can also be protected. For example, hydroxyl groups can be protected in the form of simple benzyl or substituted benzyl ethers, for example a simple 4-methoxybenzylthio ether complex benzolive or substituted benzolive esters, for example, complex 4-nitrobenzoate ether, or using trialkylsilyl groups (for example, trimethylsilyl ortert-butyldimethylsilyl).

Additional amino group can be protected by protective groups which can be removed selectively. For example, when the α-aminoamide group applies Boc-group, suitable protective groups for the following side chain are:p-toluensulfonyl (tselnye) fragments, which can be used for additional protection of amino groups; simple benzyl (Bn) ethers which can be used to protect the hydroxy groups; and complex benzyl esters that can be used to protect additional Carbo is a strong group. Or when the α-aminoamide group is selected Fmoc-group, usually are acceptable protective group on the basis oftert-butyl. For example, the Boc group can be used for additional amino groups; simpletert-butyl ester to hydroxyl groups; and complextert-butyl ester for additional carboxyl groups.

Any of the protective groups can be removed at any stage of the synthesis procedure, however, preferably a protective group, any of the functional groups not participating in the reaction, to remove after the completion of the construction of the macrocycle. Removing the protective groups can be done in one way or another, which are dictated by the choice of protective groups, and such methods are well known specialist in this field.

Intermediate products of the formula (1a), in which X represents N (referred to intermediates represented by formula (1a-1)), can be obtained from intermediates (5a), which are subject to interaction with alkeneamine (5b) in the presence of the agent, to introduce a carbonyl group, as outlined in the following reaction scheme.

Agents, to introduce a carbonyl group (CO), include phosgene or phosgene derivatives such as carbonyldiimidazole (CDI), etc. In one of the embodiments of the invention is connected to the e (5a) is subjected to interaction with the agent, introducing CO, in the presence of a suitable base and solvent, which can be a base and the solvent used in the reaction of formation of amides, as described above. In a specific embodiment of the invention the base is a carbonate, such as NaHCO3or tertiary amine, such as triethylamine and the like, and the solvent is a simple ether or halogenated hydrocarbon, for example THF, CH2Cl2, CHCl3etc. Then add the amine (5b), while receiving intermediate products (1a-1), as indicated in the diagram above. An alternative path synthesis using similar reaction conditions, provides first interaction agent, introducing CO, with the amine (5b) and then the interaction formed with the intermediate product with (5a).

Intermediate products (1a-1) alternative can be obtained as follows:

PG1is an O-protective group, which can be any of these groups, and, in particular, is benzoyloxy or substituted benzoyloxy group, such as 4-nitrobenzoyl. In the latter case, such a group can be removed by reaction with alkali metal hydroxide (LiOH, NaOH, KOH), in particular, when PG1is a 4-microbe the zoilus, using LiOH in aqueous medium containing water and a water-soluble organic solvent, such as alkanol (methanol, ethanol and THF.

Intermediate products (6a) is subjected to interaction with (5b) in the presence of the agent, to introduce a carbonyl group, similar to that described above, and as a result get such a reaction intermediate products (6c). With them off protection, in particular, by applying the above-mentioned reaction conditions. Thus obtained intermediate products (6d) can be converted directly to the target intermediate products (1a-1) using the reaction of Mitsunobu. Obtained in the reaction (6d) alcohol group can also be converted into a leaving group LG, obtained as intermediate products (6e), which is subjected to interaction with intermediates (4b), as described above for the reaction of (4a) with (4b), and this reaction leads to intermediate products (1a-1). Alcohol functional group can be converted into a leaving group using known in this field procedures, for example, by reacting the alcohol with a halogenation reagent such as SOCl2or POCl3or by the interaction of alcohol with sulphonylchloride, such as tosyl, mesyl,p,p-brompheniramine, triftormetilfullerenov etc.

Intermediate products of the formula (1a), in which X represents C (referred to the tick products represented by the formula (1a-2), can be obtained by using the reaction of formation of amides, based on intermediate products (7a), which is subjected to interaction with the amine (5b), as shown in the following reaction scheme, using the same reaction conditions for obtaining amides, as described above.

Intermediate products (1a-1) alternative can be obtained as follows:

PG1represents the above-described O-protective group. You can apply the same conditions of reaction as described above: amide formation as described above, deleting PG1as described in protective groups, the reaction of Mitsunobu with (4b) or the conversion of an alcohol functional group into a leaving group and the introduction of W, as in reactions (4a) with reagents (4b).

Intermediate products of the formula (2a) can be obtained first by cyclization of an amide open (9a) to complex macrocyclic ester (9b), which, in turn, is converted to (2a) as follows:

PG2is carboxyl-protective group, for example one of the above-mentioned carboxyl-protective group, in particular complex C1-4-alkilany or benzyl ether, such as complex methyl, ethyl ortert-butyl ether. Reaction (9a) with the formation of (9b) t is aetsa metathesis reaction and is carried out, as explained above. Group PG2remove it by following the above procedures. When PG1is a complex C1-4-alkilany ether, it is removed by alkaline hydrolysis, for example, preferably NaOH or LiOH in aqueous solvent, for example in a mixture of C1-4-alkanol/water. Benzyl group can be removed using catalytic hydrogenation.

An alternative synthesis of intermediate products (2a) can be obtained as follows:

Group PG1choose so that it was able to be removed selectively with respect to PG2. PG2can represent, for example, a complex of methyl or ethyl esters, which can be removed by treatment with alkali metal hydroxide in an aqueous medium, in cases where PG1for example, is atert-butyl or benzyl. PG2can be a difficulttert-butyl esters deleted in slightly acidic conditions, or PG1can be a difficult benzyl ethers removed using a strong acid or by catalytic hydrogenation, in the last two cases PG1for example, is an ester of benzoic acid, such as an ester of 4-nitrobenzoic acid.

First, intermediate products (10a) is subjected to cyclization to the false macrocyclic ethers (10b), then with the last shoot protection by removing group PG1obtaining compound (10c), which is subjected to interaction with intermediates (4b) to obtain intermediate products (10e), either directly by reaction of Mitsunobu, or by the introduction of the LG group and then replace it on W W H. Removal carboxyl-protective group PG2in (10e) leads to (2a). The cyclization, unprotect PG1and PG2the conversion to a leaving group LG, and the combination of (4b) is carried out just as described above.

Some of the groups R1you can enter at any stage of the synthesis, or in the last stage, as described above, either before formation of the macrocycle. The following diagram introduces the group R1represents-NH-SO2R12(above):

The diagram above PG2is a group that is defined above, and L1is a group P3

in which n and R3defined above, and when X represents N, L1may also represent a nitrogen protective group (PG, which is defined above), and when X represents C, L1can also represent a group-COOPG2ain which the group PG2ais carboxyl-protective group, the more similar the PG 2but in which PG2aremoved selectively with respect to PG2. In one of the embodiments of the invention PG2arepresents atert-butyl, and PG2represents methyl or ethyl.

Intermediate products (11c) and (11d), in which L1represents a group (b), the corresponding intermediate products (1a), can be processed additionally, as indicated above.

The combination of structural elements P1 and P2

Structural elements P1 and P2 are connected to each other by applying the reaction of formation of amide according to the above procedures. Structural element P1 may contain carboxyl-protective group PG2(as in (12b)) or may already be connected to the group P1'(as in (12c)). L2is an N-protective group (PG) or group (b)as described above. L3represents hydroxy, -OPG1or group W is listed above. When any of the following reaction schemes L3represents hydroxy, before each reaction stage can be protected in the form of group-OPG1and, if necessary, then remove the protection with the formation of the free hydroxy function. Just as described above, the hydroxy function can be converted into the group.

In the procedure described in the diagram above, cyclopropylamine (12b) or the (12c) is associated with the acid function of the structural element P2 (12a) with the formation of the amide bond, following the above procedures. Receive intermediate products (12d) and (12e). When was the last product L2represents a group (b), the resulting products represent a sequence P3-P2-P1, covering some of the intermediate products (11c) and (11d) in the previous reaction scheme. Remove from the compound (12d) kikoteseitol group suitable for the protective group of conditions with the subsequent combination with the amine H2N-SO2R12(2b) or with HOR11(2c), as described above, again gives intermediate products (12e), in which-COR1represent the amide or ester groups. When L2is an N-protective group, it can be removed, thus obtaining intermediates (5a) or (6a). In one of the embodiments of the invention PG in this reaction is a BOC group, and PG2represents methyl or ethyl. In addition, when L3represents hydroxy, the source material (12a) represents Boc-L-hydroxyproline. In a specific embodiment of the invention PG is a BOC, PG2represents methyl or ethyl and L3represents-W.

In one of the embodiments of the invention L2represents a group (b), and these reactions involve the combination of P1 with P2-P, which leads to intermediate products (1a-1) or (1a)above. In another embodiment, the invention L2is an N-protective group PG, which is described above, and the reaction mix leads to intermediate products (12d-1) or (12e-1), of which group PG can be removed by applying the above-mentioned reaction conditions, and thus the intermediate products (12-f) or respectively (12g), which cover intermediates (5a) and (6a)above:

In one of the embodiments of the invention, the group L3in the above diagrams represents a group-OPG1you can enter in the source material (12a), in which L3represents hydroxy. In this case, the group PG1is chosen so that it can be removed selectively with respect to the group of L2representing PG.

In this way the structural elements of P2, in which X represents C, which is a cyclopentane or cyclopentenone derivatives, can be connected with the structural elements P1, as summarized in the following diagram, in which R1, R2L3, PG2and PG2aare carboxyl-protective group. Group PG2ausually chosen so that it can be is about to be removed selectively with respect to the group PG 2. Delete group PG2afrom (13c) leads to intermediate products (7a) or (8a), which can be subjected to interaction with (5b), as described above.

In one of specific embodiments of the invention, where X represents C, R2represents H, and X and the carbon atom carrying the R2connected by a single bond (P2 represents a cyclopentane fragment), PG2aand L3taken together form a bond, and the structural element P2 is represented by the formula:

Bicyclic acid (14a) is subjected to interaction with (12b) or (12c) just as described above, obtaining (14b) and (14c), respectively, in which the lactone ring opens, giving intermediate products (14c) and (14e). The ring opening of lactones can be done by applying the procedure of hydrolysis of esters, for example, by applying basic conditions, such as alkali metal hydroxide, for example NaOH, KOH, and, in particular, LiOH.

Intermediate products (14c) and (14e) can be processed additionally, as described later.

The combination of structural elements P3 and P2

With regard to the structural elements of P2 that contain pyrolidine fragment, structural elements P3 and P2 or P3 and P2-P1 connect using reaction coord the carbamate and following the procedures described above for combination (5a) or (6a) with (5b). General procedure a combination of structural elements P2 containing pyrolidine fragment shown in the following reaction scheme, where L3represents the above group, and L4represents a group-O-PG2group

In one of the embodiments of the invention L4in (15a) is a group-OPG2; group PG2can be removed, and the resulting acid to bind with cyclopropylmagnesium (12a) or (12b), while receiving intermediate products (12d) and (12e), in which L2is a radical (d) or (e).

The General procedure of combining elements of P3 with elements of P2 or P2-P1, where P2 is a cyclopentane or cyclopentene shown in the following diagram.

Reactions to the two above schemes carried out using the same procedure described above for the reactions (5a), (7a) or (8a) with (5b) and, in particular, for the above-described reaction in which L4is a group (d) or (e)corresponding to the above-described reactions (5a), (7a) or (8a) with (5b).

Structural elements P1, P1'P2 and P3 are used to obtain compounds of formula (I), can be obtained on the basis of known in the Anna area of intermediate products. Some of these syntheses are described in more detail below.

The individual structural elements can first obtain and then link together or, alternatively, can be linked together predecessors structural elements and modify them at a later stage to the desired molecular structure.

Functional groups in each of the structural elements can be protected to prevent adverse reactions.

The synthesis of the structural elements P2

Structural elements P2 contain or pyrolidine, cyclopentane, or cyclopentenone fragment substituted by a group-W.

Structural elements of P2 containing pyrolidine fragment can be obtained from commercially available hydroxyproline.

Obtaining structural elements P2, which contain a cyclopentane ring, can be realized, as shown in the diagram below.

Bicyclic acid (17b) can be obtained, for example, 3,4-bis(methoxycarbonyl)Cyclopentanone (17a), as described in the publication Rosenquist and others,Acta Chem. Scand. 46 (1992) 1127-1129. The first stage of this procedure provides for the recovery of ketogroup using a reducing agent type sodium borohydride in a solvent such as methanol, followed by hydrolysis of esters and the final closure of the cycle before the bicyclic lactone (17b) using PR the procedures of formation of lactone, in particular, with acetic anhydride in the presence of a weak base such as pyridine. Then you can protect a functional group of carboxylic acid in (17b), by introducing a suitable carboxyl-protective group, such as group PG2, which is above the group, thereby obtaining a complex bicyclic ether (17c). Group PG2in particular, under the influence of acid is labile group, such astert-bucilina group, and is, for example, by treatment with Isobutanol in the presence of a Lewis acid or di-tert-BUTYLCARBAMATE in the presence of a base such as tertiary amine type dimethylaminopyridine or triethylamine in a solvent type dichloromethane. The ring opening of the lactone (17c) using the above reaction conditions, in particular using lithium hydroxide leads to acid (17d), which can be further used in the reactions combination with structural elements P1. Free acid (17d) can also be protected, preferably with kikoteseitol group PG2athat can be removed selectively with respect to the group PG2and hydroxy function can be converted to group-OPG1or to group W. the Intermediate products (17e) can be converted to intermediates (17i) through the introduction of group W, applies the I's reaction Mitsunobu. Alternatively, the alcohol functional group in (17e) can be converted to leaving groups, and the resulting intermediate products (17h) can be subjected to interaction with the reagent (4b), while receiving intermediate products (17i). The products obtained by removing group PG2represent intermediate products (17g), and (17j), which correspond to intermediate products (13a) or (16a)above.

Intermediate products with a defined stereochemistry can be obtained by separation of the intermediates in the above sequence of reactions. For example, (17b) can be divided, following well-known in this field procedures, for example, through the formation of an active form of salt with an optically active base or by using chiral chromatography, and the resulting stereoisomers can be further processed, as described above. The OH group and COOH in (17d) are inCIS-position.TRANSanalogs can be obtained by changing the stereochemistry at the carbon atom bearing the OH group (function), using specific reagents in reactions introduction OPG1or W, which alter the stereochemistry of, for example, in such reactions as the reaction Mitsunobu.

In one variant of the invention, the intermediate products (17d) associated with the elements of P1 (12b) or (12c) with p the shares of the combination, which correspond to the combination of (13a) or (16a) with the same elements P1, applying similar conditions. The subsequent introduction of a substituent-W, as described above, with the subsequent removal kikoteseitol group PG2leads to intermediate products (8a-1), which are a subclass of intermediates (7a) or part of the intermediate products (16a). The reaction products after removal PG2you can optionally associate with a structural element P3. In one of the embodiments of the invention PG2in (17d) is atert-butyl, which can be removed in acidic conditions, for example, using triperoxonane acid.

Unsaturated structural element P2, that is, cyclopentenone ring, can be obtained, as illustrated in the following scheme.

Using the reaction of synthesized-elimination of 3,4-bis(methoxycarbonyl)Cyclopentanone (17a), which is described in Dolby and others,J. Org. Chem.36 (1971) 1277-1285, with subsequent restoration of functional ketogroup using a reducing agent type sodium borohydride get Cyclopentanol (19a). Using selective hydrolysis of ester, for example, using lithium hydroxide in a solvent-type mixture of dioxane and water, get sophisticated monoether hydroxy-substituted cyclopent the Ola (19b).

Unsaturated structural element P2, in which R2may also be different from hydrogen, can be obtained, as shown in the following scheme.

Oxidation of commercially available 3-methyl-3-butene-1-ol (20a), in particular, with the help of oxidant type chlorochromate pyridinium leads to (20b), which convert to the corresponding complex methyl ester, for example, by treatment with acetylchloride in methanol, followed by reaction of the synthesized bromine, while receiving complex α-barometer (20c). The latter can then condensing with complex alkenilovyh ether (20e), obtained from (20d) with the formation of ester. Ester (20e) preferably represents a complextert-butyl ether, which can be obtained from the corresponding acid (20d), commercially available, for example, by treatment with di-tert-BUTYLCARBAMATE in the presence of a base type dimethylaminopyridine. The intermediate product (20e) is treated with base, such as sitedisability, solvent type, tetrahydrofuran, and subjected to interaction with (20c), while receiving complex alkenilovyh fluids (20f). The cyclization of (20f) using the metathesis reaction of olefins carried out as described above, receive a cyclopentenone derivative (20g). To obtain the epoxide (20h) can be done CTE is iosurface epoxidation (20g), applying the method of asymmetric epoxidation by Jacobsen. Finally, the reaction of the disclosure epoxide in basic conditions, for example, adding a base, in particular DBN (1,5-diazabicyclo[4.3.0]non-5-ene), leads to alcohol (20i). Optional double bond in the intermediate product (20i) can be restored, for example, catalytic hydrogenation using a catalyst of the type of palladium on carbon, and thus the corresponding cyclopentane connection. Complextert-butyl ether can be removed by obtaining the appropriate acid, which is then associated with a structural element P1.

The group W can be entered in pyrolidine, cyclopentane or cyclopentenone cycles at any convenient stage of the synthesis of compounds of the present invention. One approach is that the first mentioned loops lead the group-W and then add the other required structural elements, i.e. P1 (optional with terminal part P1'and P3, followed by the formation of the macrocycle. Another approach consists in linking structural elements P2 that does not contain the Deputy-W, with each of P1 and P3, and the addition of group-W, either before or after the formation of the macrocycle. The last procedure fragments P2 contain hydroxy group, which can be protected by using a hydroxy-protective group PG1.

5and L5aindependently from each other represent hydrogen or carboxyl-protective group PG2or PG2a. Group PG, PG2and PG2ahave the above values. When group L5and L5arepresent PG2or PG2athey are chosen so that each group can be removed selectively with respect to the other. For example, one of the groups L5and L5acan be a methyl or ethyl group and the other is benzyl ortert-boutelou group.

In one of the embodiments of the invention, the group PG is a BOC, L5represents hydrogen and the source material (21a) is a commercially available BOC-hydroxyproline or any of its stereoisomeric form, for example BOC-L-hydroxyproline, in particularTRANS-isomer of the latter. When L5in the connection (21c) is carboxyl-protective group can be removed by following the above procedures, obtaining (21d). In one of the embodiments of the invention PG connection (21c) is a Boc, and L5is a complex lower ALK is lovy ether, in particular complicated methyl or ethyl ester. Hydrolysis last of ester to acid can be performed using standard procedures, for example, using acid hydrolysis using hydrochloric acid in methanol or hydrolysis using an alkali metal hydroxide, such as NaOH, in particular, by using LiOH. In another embodiment of the invention hydroxy-substituted cyclopentane or cyclopentenone analogues (21e) transform to (21f), which, when L5and L5arepresent PG2or PG2acan be converted to the corresponding acids (21g) by removing group PG2. Remove PG2afrom (21f) leads to a similar intermediate products.

The synthesis of the structural elements P1

Cyclopropanecarboxylate used to obtain fragment P1, commercially available or can be obtained by applying known in the field of procedure.

In particular, complex aminobenzylpenicillin ester (12b) can be obtained according to the procedure described in the application WO 00/09543, or procedure, is illustrated in the following diagram, where PG2represents the above carboxyl-protective group:

Treatment of commercially available or easily obtained imine (22A) 1,4-dehalogenation in the presence of bases is of receive connection (22b), which after hydrolysis leads to cyclopropylamine (12b)containing the allyl substituent in theShin-position relative to the carboxyl group. Separation of a mixture of enantiomers (12b) leads to (12b-1). The separation is carried out using known in this field procedures, such as enzymatic separation; crystallization with a chiral acid; or receipt of chemical derivatives; or by using a chiral column chromatography. Intermediate products (12b) or (12b-l) can be associated with suitable derivatives of Proline, as described above.

Structural elements P1 to obtain the compounds of General formula (I)in which R1represents-OR11or-NH-SO2R12you can get by interacting amino acids (23a) with a suitable alcohol or amine, respectively, under standard conditions, intended for the formation of ester or amide. Cyclopropylamine (23a) is obtained by introducing an N-protective group PG, delete PG2and conversion of amino acids (23a) to amides (12c-1) or esters (12c-2), which are subgroups of intermediate products (12c), as outlined in the following reaction scheme, in which PG represents the above group.

The reaction of (23a) with the amine (2b) is the procedure of formation of the amide. On the one reaction (2c) is a reaction formation of ester. Both the reaction can be performed by following the above procedures. This reaction leads to intermediate products (23b) and (23c), of which aminosidine group is removed by standard methods, such as described above. Such removal, in turn, leads to the desired intermediate product (12c-1). Source material (23a) can be obtained from the above-mentioned intermediate products (12b) with the initial introduction of the N-protective group PG and the subsequent removal of the group PG2.

In one of the embodiments of the invention the reaction of (23a) with (2b) is carried out by treatment of the amino acid condensing agent, such as N,N'-carbonyl diimidazol (CDI) or the like, in a solvent type THF followed by reaction with (2b) in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively, the amino acid can be treated with the help of (2b) in the presence of a base type diisopropylethylamine with the subsequent processing of the condensing agent such as hexaphosphate benzotriazol-1 iloxi-Tris-pyrrolidinone (commercially available under the trademark PyBOP®), for the introduction of sulfonamidnuyu group.

Intermediate products (12c-1) or (12c-2), in turn, can be associated with appropriate prolinamide, cyclopentane or cyclopentenone derivative as described above.

SinTe the structural elements P3

Structural elements of P3 are commercially available or can be obtained according to methods known to the person skilled in the art. One of these methods, shown in the following scheme and applies monosilane amines, such as triptorelin or Boc - protected amine.

In the above scheme, R together with a group of CO forms a N-protective group, in particular R is atert-butoxy, trifluoromethyl; R3and n are defined above and LG represents a leaving group, in particular halogen, for example chlorine or bromine.

Monosilane amines (24a) is treated with a strong base such as sodium hydride, and then subjected to interaction with LG-C5-8-alkenyl reagent (24b), in particular halogen-C5-8-alkenyl, to form the corresponding protected amines (24c). Unprotect (24c) ensure receipt (5b), which is a structural element P3. Removing the protection will depend on the functional group R such that if R is atert-butoxy, removing protection from the corresponding Boc-protected amines can be accomplished by treatment with acid, for example triperoxonane acid. Alternatively, when R represents, for example, trifluoromethyl, delete group R is carried out using bases, such as hydrocyanate.

The following diagram illustrates another method of obtaining structural element P3, namely the synthesis of primary C5-8-alkenylamine by Gabriel, which can be performed using processing phthalimide (25a) base, such as NaOH or KOH, and with the help of (24b), which is specified above, followed by hydrolysis of the intermediate product N-alkenylamine to primary education C5-8-alkenylamine (5b-1).

The diagram above n has the value specified above.

The compounds of formula (I) can be converted into each other following well-known in this field transformation reactions of functional groups. For example, the amino group can be N-alkilirovanii, nitro revert to the amino group, halogen atom can be replaced with another atom of halogen.

The compounds of formula (I) can be converted to the correspondingN-oxide forms, the following well-known in this field procedures conversion of trivalent nitrogen into itsNoxide form. Mentioned reactionN-oxidation can usually be accomplished by interaction of the starting material of the formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, for example peroxide is the atrium, peroxide potassium; appropriate organic peroxides may include peroxyacids (nagkalat), such as, for example, benzonorbornadiene or halogen-substituted benzonorbornadiene, for example 3-chlorobenzalmalononitrile, paracalanidae acid, for example purakayastha (peracetic acid, alkylhydroperoxide, such astert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Stereochemical pure isomeric forms of the compounds of formula (I) can be obtained by applying known in this field procedures. The diastereomers can be divided by physical methods such as selective crystallization and chromatographic methods, such as counter current distribution, liquid chromatography and the like

The compounds of formula (I) can be obtained as racemic mixtures of enantiomers which can be separated from each other, following well-known in this field the separation procedures. Racemic compounds of the formula (I), which are sufficiently basic or acidic, can be converted into the corresponding diastereomeric form salts by reacting podhodyashey chiral chiral acid or base, respectively. Mentioned diastereomeric forms salts are then separated, for example, using selective or fractional crystallization and release of these enantiomers using an alkali or acid. An alternative method of separating the enantiomeric forms of the compounds of formula (I) provides for liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Mentioned pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that is stereospecific reaction. If you want a specific stereoisomer, preferably, the above compound can be synthesized by using stereospecific methods of obtaining. In such methods can preferably be used enantiomerically pure starting materials.

In an additional aspect, the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula (I), which is indicated here, or compounds of any of the subgroups of compounds of formula (I)described herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context means a quantity sufficient to preventive environmenta what I viral infection, to stabilize or reduce viral infection, in particular HCV viral infection in infected subjects or subjects at risk to be infected. In yet another additional aspect of the invention relates to a method for producing a pharmaceutical composition, which is defined here, which includes direct mixing pharmaceutically acceptable carrier with a therapeutically effective amount of the compounds of formula (I), which is defined here, or compounds of any of the subgroups of compounds of formula (I)listed here.

Therefore, with the aim of introducing the compounds of the present invention or any subgroup can be obtained in various pharmaceutical forms. As appropriate compositions here, you can reference all compositions usually employed for the systematic administration of drugs. To obtain pharmaceutical compositions according to this invention an effective amount of a particular compound, optionally in the form of additive salt or complex with the metal, as the active ingredient combine to receive a direct mixture with a pharmaceutically acceptable carrier, where the carrier may take a wide variety of forms depending on the form of preparation desired for administration. Such pharmaceutics is their composition are required in a standard dosage forms, suitable, in particular, for administration orally, rectally, subcutaneously, or by parenteral injection. For example, upon receipt of the compositions in a dosage form for oral administration, you can use any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja agents, etc. in the case of powders, pills, capsules and tablets. Due to ease of administration, tablets and capsules represent the most preferred standard dosage form for oral administration, in which case of course are solid pharmaceutical carriers. In compositions for parenteral administration, the carrier will usually contain sterile water, at least to a large extent, although there may be other ingredients, for example, to facilitate solubility. For example, you can get solutions for injection, in which the medium contains saline solution, glucose solution or a mixture of saline and glucose solution. You can also get a suspension for injection, in which case you can use p Rhodesia liquid media suspendresume agents, etc. are Also included preparations in solid form, which are intended to result in medication in the form of liquid shortly before use. In the compositions suitable for subcutaneous administration, the carrier optionally contains a substance that promotes infiltration, and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which does not have a significant negative impact on the skin.

Compounds of the present invention can also be entered via oral inhalation or insufflation using the methods and drugs used in this area for the introduction of this way. Thus, in General, compounds of the present invention can enter into the lungs in the form of a solution, suspension or dry powder, a solution is preferred. For the introduction of these compounds can be any system designed for the delivery of solutions, suspensions or dry powders with oral inhalation or insufflation.

Thus, the present invention also relates to pharmaceutical compositions adapted for administration by inhalation or insufflation through the mouth and containing a compound of the formula (I) and a pharmaceutically acceptable carrier. Join us oedema invention preferably are administered through inhalation solution in the form of a sputtered or harrisbank doses.

Especially, it is preferable to obtain the above-mentioned pharmaceutical composition in a standard dosage form for ease of administration and uniformity of dosage. Used here, the term "standard dosage form" refers to physically discrete elements, suitable as a single dose; each element contains a given quantity of active ingredient calculated to obtain the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or coated tablets), capsules, pills, suppositories, sachets of powder, pills, solutions or suspensions for injection, etc. and their segregated set.

The compounds of formula (I) possess antiviral properties. Viral infections and associated diseases treatable using compounds and methods of the present invention include infections caused HCV and other pathogenic flaviviruses, such as yellow fever virus, Dengue virus (types 1-4), the virus encephalitis St. Louis, Japanese encephalitis virus, the virus encephalitis Murray valley, West Nile virus and virus Kunjin. Diseases associated with HCV include progressing fibrospect, inflammation and necrosis leading to liver cirrhosis, liver disease in end-stage HCC; and diseases associated with other pathogenic flaviviruses include yellow fever, Dengue, hemorrhagic fever and encephalitis. In addition, a number of compounds according to the present invention show activity against mutated strains of HCV. In addition, many of the compounds of the present invention have favorable pharmacokinetic profile and properties that are attractive from the point of view of bioavailability, including an acceptable half-life, AUC (area under the curve), peak value and the absence of adverse effects, such as slow response and retention in the tissues.

Antiviral activity of the compounds of formula (I) in relation to HCVin vitrotested on the cell HCV replication system based on publishing Lohmann and others, (1999)Science, 285:110-113, with the additional modifications described in Krieger and others, (2001)Journal of Virology,75: 4614-4624 that is additionally provided in the "examples"section. This model, though not a complete model of HCV infection, widespread as the most reliable and effective model of Autonomous replication of HCV RNA among existing ones. The compounds exhibiting antiviral activity against HCV in this cellular model is, considered as candidate compounds in the further development of tools for the treatment of HCV infections in mammals. You should take into account that it is important to distinguish between compounds that specifically inhibit the expression of the functions of HCV, and compounds that cause cytotoxic or cytostatic effects in the model suppressing the replication of RNA replicon HCV and, consequently, cause a decrease in the concentration of HCV RNA or concentration of the linked reporter enzyme. Well-known research in the field of cell cytotoxicity, for example, based on the activity of mitochondrial enzymes using fluorogenic redox dyes such as resazurin. In addition, there are protective cellular screens to assess selective inhibition activity linked reporter gene such as luciferase Firefly. Suitable types of cells can be endowed with a stable transfection using the luciferase reporter gene, expression of which depends on the constitutive active gene promoter, and such cells can be used as protective shields for the elimination of non-selective inhibitors.

Due to its antiviral properties, in particular antiviral properties against HCV compounds of formula (I) or any subgroup, their proletar the VA, Noxides, additive salts, Quaternary amines, complexes with metals and stereochemical isomeric form applicable to the treatment of individuals exposed to viral infections, in particular HCV infection and for prevention of such infections. In General, compounds of the present invention can be used for the treatment of warm-blooded animals infected with viruses, in particular flaviviruses, such as HCV.

Therefore, the compounds of the present invention or any subgroup can be used as medicines. Mentioned use as a medicine or method of treatment comprises the systemic administration to subjects infected with a virus, or subjects who are susceptible to viral infections, amount, effective to combat the conditions associated with viral infection, in particular HCV infection.

The present invention also relates to the use of these compounds or any of the subgroups for the manufacture of a medicinal product for the treatment or prophylaxis of viral infections, particularly HCV infection.

In addition, the present invention relates to a method of treating a warm-blooded animal infected with a virus or at risk of HIV infection, in particular HCV virus, the said method includes wvedenia.infection the number of scan the compounds of formula (I), which is specified here, or compounds of any of the subgroups of compounds of formula (I)listed here.

In combination therapy as a drug it is also possible to use a combination of previously known anti-virus against HCV compounds, such as, for example, interferon-α (IFN-α), pegylated interferon-α and/or ribavirin, and the compounds of formula (I). The term "combination therapy" refers to a product containing mandatory (a) the compound of formula (I) and (b) optionally another anti-virus against HCV compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections, in particular in the treatment of infections caused by HCV.

Antivirus against HCV compounds comprise means selected from an inhibitor of HCV polymerase, HCV protease inhibitor, an inhibitor of another object in the HCV life cycle, and immunomodulatory agent, an antiviral agent, and combinations thereof.

Inhibitors of HCV polymerase include, but are not limited to, NM283 (valopicitabine), R803, JTK-109, JTK-003, HCV-371, HCV-086, HCV-796 and R-1479.

Inhibitors of HCV protease (NS2-NS3 inhibitors and NS3-NS4A inhibitors) include, but are not limited to, compounds according to the application WO02/18369 (see, for example, lines 9-22 on page 273, and from line 4 on page 274 page to the key on page 11 276,); BILN-2061, VX-950, GS-9132 (ACH-806), SCH-503034 and SCH-6. Additional tools that can be used are the tools described in the application WO98/17679, WO00/056331 (Vertex); WO 98/22496 (Roche); WO 99/07734 (Boehringer Ingelheim), WO 2005/073216, WO 2005073195 (Medivir) and structurally similar tool.

Inhibitors of other objects in the HCV life cycle include NS3-helicase; inhibitors metalloprotease; inhibitors, antisense oligonucleotides, such as ISIS-14803, AVI-4065, etc.; small interfering RNA (siRNA), such as SIRPLEX-140-N and the like; encoded by vector short hairpin RNA (RNA hairpin); DNA-enzymes; HCV-specific ribozymes, such as heptazyme, RPI.13919 and the like; entry inhibitors such as HepeX-C, HuMax-HepC and the like; inhibitors of α-glucosidase, such as celgosivir, UT-231B, etc.; KPE-02003002; and BIVN 401.

Immunomodulating items include, but are not limited to, compounds of natural and recombinant interferon isoforms, including α-interferon, β-interferon, γ-interferon, ω-Advaferon®, Infergen®, Humoferon®, Sumiferon MP®, Alfaferone®, IFN-beta®, Feron®and the like; compounds of interferon, derivateservlet polyethylene glycol (pegylated interferon), such as PEG-interferon-α-2a (Pegasys®), PEG-interferon-α-2b (PEG-Intron®), pegylated IFN-α-con1, etc.; sustained-release preparations and derivatives of the compounds of interferon, such as the α-Albuferon - interferon fused to albumin, and the like; compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of response helper T-cell 1-type, such as SCV-07 and the like; TOLL-like receptor agonists such as CpG-10101 (actilon), isatoribine etc.; thymosin α-1; ANA-245; ANA-246; histaminergic; tetrachlorodecaoxide papermania; ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and the like; prophylactic and therapeutic vaccines such as InnoVac C, HCV E1E2/MF59 and the like

Other antiviral agents include, but are not limited to, ribavirin, amantadine, viramidine, nitazoxanide; telbivudine; NOV-205; taribavirin; inhibitors of entry into the interior region of the ribosome; viral broad-spectrum inhibitors, such as IMPDH inhibitors (e.g., compounds described in U.S. patents№№ 5807876, 6498178, 6344465, 6054472, in applications WO97/40028, WO98/40381, WO00/56331, mycofenolate acid and its derivatives, including, but not limited to, VX-950, the drug Merimepodib (VX-497), VX-148, and/or VX-944); or a combination of any of the funds of the above.

Thus, to combat HCV-infection or for treatment of compounds of formula (I) can together be entered in combination with, for example, interferon-α (IFN-α), pegylated interferon-α and/or ribavirin, and therapeutics is their means based on the antibodies, targeted against HCV-epitopes, small interfering RNA (siRNA), ribozymes, DNA enzymes, antisense RNA, small molecules antagonists, such as NS3 protease, NS3-helicase and NS5B polymerase.

Accordingly, the present invention relates to the use of compounds of formula (I) or any of its subgroups listed above, for the manufacture of a medicinal product, applicable for inhibiting HCV activity in a mammal infected with HCV viruses, mentioned when the drug is used for combination therapy mentioned combination therapy preferably includes a compound of formula (I) and another connection-inhibitor of HCV, for example (pegylated) IFN-α and/or ribavirin.

In yet another aspect, get the combination of the compounds of formula (I), which is indicated here, and compounds directed against HIV. The latter preferably represent those of the inhibitors HIV, which have a positive effect on the metabolism of drugs and/or pharmacokinetics, which improves bioavailability. An example of such an inhibitor of HIV is ritonavir.

In this regard, in the present invention is additionally achieved by a combination containing (a) an inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt; and (b) ritonavir or his farm is citiesi acceptable salt.

Connection ritonavir and its pharmaceutically acceptable salts and methods for their preparation are described in the application WO94/14436. On the preferred dosage forms of ritonavir, see U.S. patent No. 6037157 and quoted it documents: U.S. patent No. 5484801, 08/402690 and application WO95/07696 and WO95/09614. Ritonavir has the following formula:

In an additional embodiment of the invention combination containing (a) an inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt; and (b) ritonavir or its pharmaceutically acceptable salt; optionally contains an additional connection against HCV selected from the compounds described here.

In one of the embodiments of the present invention proposes a method of obtaining described here, the combination comprising a stage aggregation inhibitor of the NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt and ritonavir or its pharmaceutically acceptable salt. In an alternative embodiment, the present invention proposes a method in which the combination contains one or several additional tools that are described here.

The combination of the present invention can be used as medicines. Mentioned use as a medicine or method of treatment including the AET in itself a systematic introduction to the subjects, infected with HCV, amount, effective to combat the conditions associated with HCV and other pathogens, flavi and pestiviruses. Therefore, the combination of the present invention can be applied to manufacture of a medicinal product that is applicable for the treatment, prevention or combating infection or disease associated with HCV infection in a mammal, in particular for treating conditions associated with HCV and other pathogens, flavi and pestiviruses.

In one of the embodiments of the present invention features a pharmaceutical composition containing a combination of any of these embodiments and a pharmaceutically acceptable excipient. In particular, the present invention features a pharmaceutical composition comprising (a) a therapeutically effective amount of an inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt, (b) a therapeutically effective amount of ritonavir or its pharmaceutically acceptable salt and (c) pharmaceutically acceptable filler. The pharmaceutical composition also optionally contains an additional agent selected from an inhibitor of HCV polymerase, HCV protease inhibitor, an inhibitor of another object in the HCV life cycle, and immunomodulatory tools antivirus is the means and their combinations.

The composition can be obtained in suitable pharmaceutical dosage forms such as described above dosage forms. Each of the active ingredients can be obtained separately, and medications you can enter together or as a single preparation containing both ingredient and, if necessary, you can apply additional active ingredients.

It is implied that used here, the term "composition" includes a product containing specific ingredients, as well as any product which results, directly or indirectly, from combination of the specific ingredients.

In one of the embodiments of the invention described here, the combination can also be obtained in the form of a combined preparation for simultaneous, separate or sequential use in HIV therapy. In this case, the compound of General formula (I) or any of its subgroups is included in the pharmaceutical compositions that contain other pharmaceutically acceptable excipients, and ritonavir included in a separate pharmaceutical compositions containing other pharmaceutically acceptable excipients. Conveniently, when two separate pharmaceutical compositions can be a part of a set for simultaneous, separate or sequential use.

Thus, the e components of the combination according to the present invention during the course of therapy can be entered separately, at different times or concurrently in divided or single combination forms. Therefore, it should be understood that the present invention includes all such schemes simultaneous or alternative treatment, and the term "introducing" shall be construed accordingly. In the preferred embodiment of the invention the separate dosage forms are introduced approximately at the same time.

In one of the embodiments of the invention the combination of the present invention contains the number of ritonavir or its pharmaceutically acceptable salt which is sufficient to clinically improve the bioavailability of the inhibitor of NS3/4a protease of HCV of formula (I) in comparison with bioavailability in the case where the above-mentioned inhibitor of NS3/4a protease of HCV of formula (I) is entered alone.

In another embodiment of the invention the combination of the present invention contains the number of ritonavir or its pharmaceutically acceptable salt which is sufficient to increase at least one of the pharmacokinetic variables of the inhibitor of NS3/4a protease of HCV of formula (I)selected from t1/2CminCmaxCssAUC at 12 hours, or AUC at 24 hours, compared with these values, at least one pharmacokinetic variable in the case, to the hdacs inhibitor of NS3/4a protease of HCV of formula (I) is entered alone.

An additional variant embodiment of the invention relates to a method for improving the bioavailability of the inhibitor of NS3/4a protease of HCV, comprising introducing to a subject in need of such improvement, the above combination containing a therapeutically effective amount of each of the components mentioned combination.

In an additional embodiment, the invention relates to the use of ritonavir or its pharmaceutically acceptable salt as improving additive, at least one of the pharmacokinetic variables of the inhibitor of NS3/4a protease of HCV of formula (I)selected from t1/2CminCmaxCssAUC at 12 hours, or AUC at 24 hours; provided that the said use is not carried out in practice in relation to the human or animal.

Used herein, the term "individual" refers to an animal, preferably to a mammal, most preferably to the person who is the object of treatment, observation or experiment.

Bioavailability is defined as the percentage of injected dose that reaches the systemic circulation; t1/2represents the elimination half-life or the time required for the concentration in plasma decreased to half of its original value. Cssrepresents the concentration in the number of main telephone is Narkom condition, that is, the concentration at which the rate of input of the medicinal product is equal to the rate of its removal. Cminis defined as the lowest (minimum) concentration measured during the interval between doses of the drug. Cmaxrepresents the highest (maximum) concentration measured during the interval between doses of the drug. AUC is defined as the area under the curve "concentration-time" for a certain period of time.

The combination of the present invention can be supplied by the person according to the consumption patterns defined for each component contained in the above-mentioned combinations. Components contained in the above-mentioned combinations, you can enter together or separately. Inhibitors of NS3/4a protease formula (I) or any subgroup and ritonavir, its pharmaceutically acceptable salt or ester can have the dosage levels in the range from 0.02 to 5.0 grams per day.

When the inhibitor of the NS3/4a protease of HCV of formula (I) with ritonavir are introduced in combination, a suitable mass ratio of inhibitor of NS3/4a protease of HCV of formula (I) R is in the range from about 40:1 to about 1:15, or from about 30:1 to about 1:15, or from about 15:1 to about 1:15, usually from about 10:1 to the roughly 1:10, and more specifically, from about 8:1 to about 1:8. Also applicable mass relationships of inhibitors of NS3/4a protease of HCV of formula (I) to ritonavir in the range from about 6:1 to about 1:6, or from about 4:1 to about 1:4, or from about 3:1 to about 1:3, or from about 2:1 to about 1:2, or about 1.5:1 to about 1:1,5. In one aspect, the amount by weight of inhibitors of NS3/4a protease of HCV of formula (I) is equal to or greater than the amount by weight of ritonavir, in which a suitable mass ratio of inhibitor of NS3/4a protease of HCV of formula (I) R is in the range from about 1:1 to about 15:1, typically from about 1:1 to about 10:1, and more specifically, from about 1:1 to about 8:1. Also applicable mass relations inhibitor of NS3/4a protease of HCV of formula (I) to ritonavir in the range from about 1:1 to about 6:1, or from about 1:1 to about 5:1, or from about 1:1 to about 4:1, or from about 3:2 to about 3:1, or from about 1:1 to about 2:1 or from about 1:1 to about 1.5:1.

Used here, the term "therapeutically effective amount" refers to an amount of active compound or to mponent or pharmaceutical means, which causes the biological or medicinal response in a tissue, system, animal or human, which in the light of the present invention is desirable for the researcher, veterinarian, physician, or other practitioner, and which includes a partial withdrawal symptoms of the disease being treated. Since the present invention relates to combinations containing two or more funds, "therapeutically effective amount" represents a number of combined funds, in which the total effect causes the desired biological or medicinal response. For example, a therapeutically effective amount of a composition containing (a) compound of formula (I) and (b) ritonavir, can be a number of together the compounds of formula (I) and ritonavir, with a total effect that is therapeutically effective.

In the General case it is assumed that the effective daily amount of the anti-virus tools can be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg of body weight. Perhaps that would be appropriate introduction of the desired dose in the form of one, two, three, four or more (sub-)doses with appropriate intervals throughout the day. These (sub-)doses can be obtained in a standard dosage forms, in the example, containing from 1 to 1000 mg, in particular from 5 to 200 mg of the active ingredient at a standard dosage form.

The exact dosage and frequency of injection depends on specifically used the compounds of formula (I), the specific condition being treated, the severity of the condition being treated, age, weight, sex, extent of disturbance, and General physical condition of the particular patient, as well as other drug treatments, taken individually, as is well known to the person skilled in the art. In addition, it is obvious that the said effective daily amount you can decrease or increase depending on the reaction being treated subject and/or depending on the evaluation of the physician prescribing the compounds of the present invention. Therefore, the above-mentioned ranges effective daily amounts are only of an Advisory character.

According to one embodiments of the invention the inhibitor of the NS3/4a protease of HCV of formula (I) and ritonavir can be entered together once or twice a day, preferably orally, the number of compounds of the formula (I) in a dose of from about 1 to about 2500 mg, and the amount of ritonavir at a dose of from about 1 to about 2500 mg In another embodiment of the invention, the quantity is as prescribed in the joint introduction of one or two times daily amount from about 50 to about 1500 mg of the compounds of formula (I) and from about 50 to about 1500 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately 100 to approximately 1000 mg of the compounds of formula (I) and from about 100 to about 800 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately from 150 to about 800 mg of the compounds of formula (I) and from about 100 to about 600 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately 200 to approximately 600 mg of the compounds of formula (I) and from about 100 to about 400 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately 200 to approximately 600 mg of the compounds of formula (I) and from about 20 to about 300 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately 100 to approximately 400 mg of the compounds of formula (I) and from about 40 to about 100 mg of ritonavir.

Typical combinations of connection fo the formula (I) (mg)/ritonavir (mg) at the dosage of one or two times per day include 50/100, 100/100, 150/100, 200/100, 250/100, 300/100, 350/100, 400/100, 450/100, 50/133, 100/133, 150/133, 200/133, 250/133, 300/133, 50/150, 100/150, 150/150, 200/150, 250/150, 50/200, 100/200, 150/200, 200/200, 250/200, 300/200, 50/300, 80/300, 150/300, 200/300, 250/300, 300/300, 200/600, 400/600, 600/600, 800/600, 1000/600, 200/666, 400/666, 600/666, 800/666, 1000/666, 1200/666, 200/800, 400/800, 600/800, 800/800, 1000/800, 1200/800, 200/1200, 400/1200, 600/1200, 800/1200, 1000/1200 and 1200/1200. Other typical combinations of the compound of formula (I) (mg)/ritonavir (mg) at the dosage of one or two times per day include 1200/400, 800/400, 600/400, 400/200, 600/200, 600/100, 500/100, 400/50, 300/50, and 200/50.

In one of the embodiments of the present invention is proposed product industrial production containing composition effective for treatment of HCV infection or to inhibit the NS3 protease of HCV; and packaging material comprising a label which indicates that the composition can be used to treat infections caused by hepatitis C virus; in which the composition contains a compound of the formula (I) or any subgroup or described herein in combination.

Another variant of implementation of the present invention relates to a collection or container containing the compound of formula (I) or any subgroup or combination according to the invention combines the inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt and ritonavir or its pharmaceutically acceptable salt in an amount effective for use as a standard or is eagent in the test or the test for determining the ability of a potential pharmaceutical to inhibit the NS3/4a-protease of HCV, the growth of HCV, or both. This aspect of the invention may find application in pharmaceutical research programs.

The compounds and combinations according to the present invention can be used in high throughput analysis of target samples, such as tests to measure the efficacy of said combination for the treatment of HCV.

Examples

The following examples are intended to illustrate the present invention and not limit it.

Example 1: Getting 17-(5-phenyltetrazol-2-yl)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (9).

Stage A

Boc-protected hydroxyproline1(4.0 g, 17.3 mmol), HATU (6,9 g, 18.2 mmol) and compound ethyl ester 1-(amino)-2-(vinyl)cyclopropanecarboxylic acid (3.5 g, and 18.3 mmol) was dissolved in DMF (60 ml) and cooled to 0°C in a bath with ice. Then was added DIPEA (6.0 ml). Bath ice was removed and the mixture was left at ambient temperature for 12 hours. Then added dichloromethane and the organic phase was washed with an aqueous solution of sodium bicarbonate, citric acid, water, saturated salt solution and dried (Na2SO4). When cleaning using flash chromatography (gradient from simple ether to a mixture of simple ether/methanol 93:7) received 6,13 g (96%) of the desired PR the product 2in the form of oil.

Stage

Connection2(6,13 g of 16.6 mmol), 4-nitrobenzoic acid (4,17 g, 25 mmol) and PPh3(6,55 g, 25 mmol) was dissolved in THF (130 ml). The solution was cooled to 0°C and slowly added DIAD (of 5.1 g, 25 mmol). Then deleted the cooling and the mixture was left at ambient conditions for 12 hours. Was added an aqueous solution of sodium bicarbonate (60 ml) and the mixture was extracted with dichloromethane, dried (Na2SO4) and was evaporated. When cleaning using flash chromatography (gradient from a mixture of pentane/simple ether, 2:1 to a mixture of pentane/simple ether/methanol, 30:68:2) was obtained 6.2 g (72%) of the desired product3:m/z= 518 (M+H)+.

Stage

Connection3(6.2 g, 12 mmol) was dissolved in ice-cold mixture triperoxonane acid (33%) in dichloromethane. Then bath with ice was removed and leave the mixture at room temperature for 1.5 hour. The solvent is evaporated and then the residue was distributed between 0.25 M sodium carbonate solution and dichloromethane, was dried (Na2SO4) and evaporated, thus obtaining 4.8 g (95%) of the desired product4in the form of yellowish powder:m/z= 418 (M+H)+.

Stage D

To a solution of compound4(4.5 g, a 10.8 mmol) in THF (160 ml) was added a tablespoon of bicarbonate into three is. Then was added phosgene (11.3 ml, 20% in toluene). The mixture was vigorously stirred for 1 hour, then filtered and re-dissolved in dichloromethane (160 ml). Was added sodium bicarbonate (tablespoon), followed hydrochlorideN-methyl-N-HEXEN-5-yl (2.9 g, 21.6 mmol). The resulting reaction mixture was stirred at room temperature overnight. When processing and purification using flash chromatography (gradient from simple ether to a mixture of simple ether/methanol, 97:3) was received of 5.48 g (91%) of the desired product6:m/z= 557 (M+H)+.

Stage E

Connection6(850 mg, 1.53 mmol) was dissolved in 1.5 liters of degassed and anhydrous 1,2-dichloroethane was heated under reflux in an argon atmosphere for 12 hours. Added acceptor (scavenger) (MP-TMT, P/N 800470 from Argonaut technologies, 1/2 teaspoon) and stirred the mixture for 2 hours, filtered and concentrated under reduced pressure. The crude product is recrystallized from a mixture of dichloromethane/n-hexane, while receiving 600 mg (74%) of the desired product7:m/z= 529 (M+H)+.

Stage F

Connection7(200 mg, 0.38 mmol) was dissolved in methanol/THF/water, 1:2:1, (20 ml) and cooled in a bath with ice. Then slowly added lithium hydroxide is (1.9 ml, 1 M in water). The mixture was stirred for 4 hours at 0°C, then neutralized with an aqueous solution of acetic acid (20 ml) and was extracted with dichloromethane. The organic phase is washed with sodium bicarbonate, water, saturated salt solution and dried (MgSO4). When cleaning using column chromatography (methanol/dichloromethane, 96:4) received 120 mg of the desired compound8in the form of grayish powder: m/z = 380 (M+H)+.

Stage G

DIAD (218 μl, 1.11 mmol) was added at 0°C under nitrogen atmosphere to a solution of compound8(280 mg, 0,738 mmol), 5-phenyl-1H-tetrazole (150 mg, of 1.03 mmol) and triphenylphosphine (271 mg, of 1.03 mmol) in dry THF (15 ml). Then the reaction mixture was heated to room temperature. After 1.5 hours the solvent is evaporated and the crude product was purified using flash chromatography on a column (AcOEt/heptane, 3:7). The resulting product was re-dissolved in THF (15 ml) and MeOH (10 ml). Then was added a solution of LiOH (200 mg) in water (3 ml). After 48 hours, the solvent evaporated and the residue was distributed between water and simple ether. The aqueous layer was acidified (pH = 3) and was extracted with AcOEt, dried (MgSO4) and was evaporated. The residue was recrystallized from a simple ether, thus obtaining the desired compound9.

Example 2: ReceiveN-[17-(5-phenyltetrazol-2-yl)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.0 4,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (10).

A mixture of compound9(50 mg, 0.104 g mmol) and CDI (68 mg, 0,418 mmol) in dry THF (5 ml) was heated at the boil under reflux for 2 hours in nitrogen atmosphere. The reaction mixture was cooled to room temperature and added cyclopropylalanine (101 mg, 0,836 mmol). Then added DBU (73 mg, 0,481 mmol) and the reaction mixture was stirred at room temperature for 1 hour and then heated at 55°C for 24 hours. The solvent is evaporated and the residue was distributed between AcOEt and acidified water (pH = 3). The crude material was purified by column chromatography (AcOEt/CH2Cl2/petroleum ether, 1:1:1). The residue was recrystallized from Et2O and filtered, thus obtaining the desired compound contaminated with cyclopropylalanine. The material obtained was washed with 1.5 ml of water, filtered, washed with water and dried overnight using a high vacuum pump, while receiving the requested connection.

Example 3: Getting 17-(5-phenyltetrazol-2-yl)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (9).

Stage A

To HATU (1,34 g to 3.52 mmol) andN-metrex-5-enylamine (435 mg, of 3.84 mmol) in DMF (3 ml) at 0°C was added rest the p 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid ( 1, 500 mg, 3.2 mmol) in 4 ml of DMF, followed by addition of DIEA. After stirring for 40 min at 0°C the mixture was stirred at room temperature for 5 hours. Then the solvent evaporated, the residue was dissolved in EtOAc (70 ml) and washed with saturated solution of NaHCO3(10 ml). The aqueous phase was extracted with EtOAc (2 × 25 ml). The organic phases were combined, washed with saturated solution of NaCl (20 ml), dried (Na2SO4) and was evaporated. When cleaning using flash chromatography (EtOAc/petroleum ether, 2:1) received 550 mg (68%) of the desired product as a colorless oil:m/z= 252 (M+H)+.

Stage

To lactamide3at 0°C was added a solution of LiOH (105 mg in 4 ml of water). The conversion was complete (HPLC) after 1 hour. The mixture was acidified to pH 2-3 1N HCl solution, extracted with AcOEt, dried (MgSO4), was evaporated, was evaporated several times with toluene and dried under high vacuum over night, while receiving 520 mg (88%) of the desired product:m/z= 270 (M+H)+.

Stage C

Hydrochloride complex ethyl ester 1-(amino)-2-(vinyl)cyclopropanecarboxylic acid (4,92 g, and 31.7 mmol) and HATU (12,6 g, a 33.2 mmol) was added to the compound4(8,14 g, 30.2 mmol). The mixture was cooled in a bath of ice in the atmosphere of argon and then was added DMF (100 ml) and DIPEA (12,5 ml, 11.5 mmol). After 30 min at 0°C the solution was stirred at room temperature for additional 3 hours. Then the reaction mixture was distributed between EtOAc and water, then washed with 0.5 N HCl solution (20 ml) and saturated NaCl solution (2 × 20 ml) and dried (Na2SO4). When cleaning using flash chromatography (AcOEt/CH2Cl2/petroleum ether, 1:1:1) received 7,41 g (60%) of the desired product6in the form of a colorless oil:m/z= 407 (M+H)+.

Stage D

To a solution of compound6(300 mg, 0,738 mmol), 5-phenyl-1H-tetrazole (150 mg, of 1.03 mmol) and triphenylphosphine (271 mg, of 1.03 mmol) in dry THF (15 ml) at 0°C under nitrogen atmosphere was added DIAD (218 μl, 1.11 mmol). Then the reaction mixture was heated to room temperature. After 1.5 hours the solvent is evaporated and the crude product was purified using flash chromatography on a column (AcOEt/heptane, 3:7), while receiving 142 mg (43%) of the desired product7:m/z= 535 (M+N)+.

Stage E

A solution of compound7(175 mg, 0.33 mmol) and catalyst Hoveyda-verification of the 1st generation (39 mg, of 0.066 mmol) in anhydrous and degassed 1,2-dichloroethane (200 ml) was heated at 70°C in nitrogen atmosphere for 12 hours. The solvent is then evaporated and the residue was purified by chromatography on silica gel (petroleum ether/CH2 Cl2/Et2O; 3:1:1)to give 83 mg (50%) of the desired product: m/z = 507 (M+H)+.

Stage F

To a solution of compound8in THF (15 ml) and MeOH (10 ml) with stirring was added a solution of LiOH (200 mg) in water (3 ml). After 48 hours, the solvent evaporated and distributed the balance between water and simple ether. The aqueous layer was acidified (pH = 3) and was extracted with AcOEt, dried (MgSO4) and was evaporated. The residue was recrystallized from a simple ether, thus obtaining 68 mg (87%) of the desired compound9: m/z = 479 (M+H)+.

Example 4: ReceiveN-[17-(5-phenyltetrazol-2-yl)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (10).

A mixture of compound9(50 mg, 0.104 g mmol) and CDI (68 mg, 0,418 mmol) in dry THF (5 ml) was heated at the boil under reflux for 2 hours in nitrogen atmosphere. The reaction mixture was cooled to room temperature and added cyclopropylalanine (101 mg, 0,836 mmol). Then added DBU (73 mg, 0,481 mmol), the reaction mixture was stirred at room temperature for 1 hour and then heated at 55°C for 24 hours. The solvent is evaporated and the residue was distributed between AcOEt and acidified water (pH = 3). The crude material was purified by column chromatography (AcOEt/CH 2Cl2/petroleum ether, 1:1:1). The residue was recrystallized from Et2O and filtered, thus obtaining the desired compound contaminated with cyclopropylalanine. The material obtained was washed with 1.5 ml of water, filtered, washed with water and dried overnight using a high vacuum pump, while receiving 28 mg (46%) of the desired compound as a white powder:m/z= 582 (M+H)+.

Example 5The synthesis of complextert-butyl ester 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid (12)

To a solution of compound11(180 mg, 1.15 mmol) in 2 ml of CH2Cl2in an inert atmosphere of argon at 0°C and stirring was added DMAP (14 mg, 0,115 mmol) and Vos2O (252 mg, 1.44 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated and the crude product was purified using flash chromatography on a column (gradient: toluene/ethyl acetate, 15:1, 9:1, 6:1, 4:1, 2:1), while receiving specified in the title compound (124 mg, 51%) as white crystals.

1H-NMR (300 MHz, CD3OD) δ 1,45 (s, N), 1,90 (d, J=11.0 cm Hz, 1H), 2,10-2,19 (m, 3H), was 2.76-and 2.83 (m, 1H), 3,10 (s, 1H), 4,99 (s, 1H);

13C-NMR (75.5 MHz, CD3OD) δ 27,1, 33,0, 37,7, 40,8, 46,1, 81,1, 81,6, 172,0, 177,7.

An alternative method of obtaining compounds of12

Connection11(13,9 g, 89 mmol) was dissolved in dichloromethane (200 ml) and then cooled to approximately -10°C in nitrogen atmosphere. Then the solution was barbotirovany isobutylene up until the total amount has not increased to approximately 250 ml, while receiving an opaque solution. Added BF3× Et2O (5.6 ml, of 44.5 mmol, 0.5 EQ.) and the reaction mixture was stirred at about -10°C in nitrogen atmosphere. After 10 min was obtained a clear solution. Monitored the reaction mixture by TLC (EtOAc-toluene, 3:2, acidified with a few drops of acetic acid and hexane-EtOAc 4:1, painted basic permanganate solution). After 70 minutes, when only traces of the connection11,to the reaction mixture was added aqueous saturated solution of NaHCO3(200 ml) and then vigorously stirred for 10 minutes the Organic layer was washed with saturated solution of NaHCO3(3 × 200 ml) and saturated salt solution (1 × 150 ml), then dried over sodium sulfite, filtered and concentrated in the form of small droplets containing the oil. Adding to the residue of the hexane, the product was destroyed. Adding an additional amount of hexane and heated under reflux was obtained a clear solution, from which the crystallized product. The crystals were collected during the filtration and washed with hexane (br t is MT.), then was dried in air for 72 hours, thus obtaining a colorless needle crystals (12,45 g of 58.7 mmol, 66% of initial output).

Example 6: The activity of the compounds of formula (I)

Analysis of replicons

Investigated the activity of compounds of the formula (I) in respect of inhibition of HCV RNA replication in cell analysis. The analysis showed that the compounds of formula (I) have activity against HCV replicons, functional in cell culture. Cell analysis is based on bicistronic expressing constructs, which are described in the publication Lohmann and others,Sciencet, pp. 110-113 (1999), with modifications described in Krieger and others,Journal of Virology75: 4614-4624 (2001), strategy for multi-screening. Essentially, the method consists in the following.

The analysis used the line stably transfected cells Huh-7 luc/neo (hereinafter referred to as the Huh-Luc). This cell line contains RNA encoding bicistronic expressing a construct that contains the field NS3-NS5B wild-type HCV type 1b, broadcast from the site of internal planting ribosomes (IRES) of the virus encephalomyocarditis (EMCV), with the previous reporter group (FfL-luciferase) and the group selective marker (neoR, neomycinphosphotransferase). The design is bordered 5'and 3'-NTR (untranslated regions) of the virus HCV type 1b. Continuous coltivirus is replacecodebase cells in the presence of G418 (neo Rdepends on the replication of HCV RNA. Stable transfetsirovannyh cells containing the replicon expressing HCV RNA that replicates autonomously and at high levels, coding, among other things, the luciferase is used for screening of antiviral compounds.

The replicon-containing cells were sown in 384-well plates in the presence of different concentrations of the tested and control connections. After incubation for three days was determined by the replication of HCV by analyzing the luciferase activity (using standard substrates and reagents for luciferase analysis and device for imaging microplate Perkin Elmer ViewLuxTmultraHTS). Replicartertje cells in the control cultures in the absence of any inhibitors was characterized by high expression of luciferase. Monitored inhibitory activity of compounds against luciferase activity in cells Huh-Luc, receiving a curve according to the dose-effect for each of the test compounds. Then calculated EC50which corresponds to the number of connections required to reduce the level of detected luciferase activity by 50%, or, more specifically, we determined the ability of RNA genetically linked HCV replicon replication.

Analysis of inhibition

The objective of this analysisin vitrowas ODA is the division of the degree of inhibition protease complexes NS3/4A HCV virus compounds according to the invention. This analysis shows how effective are the compounds according to the invention in the inhibition of the proteolytic activity of NS3/4A HCV virus.

The full inhibition of proteolytic enzyme NS3 of hepatitis C was determined, mainly, as described in the publication Poliakov, Prot Expression & Purification 25 363 371 (2002). Briefly, the degree of hydrolysis of depsipeptide substrate, Ac-DED(Edans)EEAbuψ[COO]ASK(Dabcyl)-NH2(AnaSpec, San Jose, USA), was determined spectrofluorometrically in the presence of cofactor peptide KKGSVVIVGRIVLSGK (Åke Engström, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nm) were incubated in 50 mm HEPES, pH 7.5, 10 mm DTT, 40% glycerol, 0.1%ofn-octyl-D-glucoside, with 25 μm of the NS4A cofactor and inhibitor at 30ºC for 10 min, after which initiated the reaction by adding 0.5 µm substrate. Inhibitors were dissolved in DMSO, were subjected to the action of ultrasound for 30 seconds and stirred. Between measurements the solutions were stored at-20ºC.

The final concentration of DMSO in the analyzed sample was brought up to 3.3%. Carried out the correction of the degree of gerosa with consideration of the effects inside the filter according to published literature procedures [Liu, 1999 Analytical Biochemistry 267 331-335]. The Ki values were estimated using nonlinear regression analysis (GraFit, Erithacus Software, Staines, MX, UK), using the model of competitive inhibition and a fixed value l is I Km (0,15 µm). All taken measurements were carried out at least in two parallel samples.

In the following table 1 lists the compounds that are obtained according to one of the above examples. Table 1 also presents the activity of the investigated compounds.

Table 1
Connection # Example No.EU50(µm)
Analysis of replicons
Ki (nm)
Enzymatic analysis
9Example 3>10>1000
10Example 43,42730

1. The compound of the formula

its pharmaceutically acceptable salt or a stereoisomer,
where R1represents-OR11, -NH-SO2R12;
R2represents hydrogen, and
R3represents a C1-6-alkyl;
n is 3, 4, 5, or 6; W is a

R5represents phenyl, optionally substituted C1-6-alkyl or C1-6-alkoxy; azolyl, optionally substituted C1-6-alkyl; or pyridyl;
R11represents hydrogen;
R12represents a C3-7-cycloalkyl.

2. The compound according to claim 1, in which R1represents-NH-SO2R12in which R12is cyclopropyl.

3. Pharmaceutical composition having inhibitory activity against HCV replication, containing a carrier and, as active ingredient, an effective anti virus number of compounds according to any one of claims 1 to 2.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components - substituted indoles of general formula 1 and pharmaceutically acceptable salts thereof, which can be used to treat and/or prevent viral diseases caused by hepatitis C virus (HCV). In general formula , R1 denotes a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, ethoxycarbonyl, nitro group; R2 denotes a hydrogen atom; R3 denotes N-mono- or N,N-disubstituted 1-methylene-piperidine-3-carboxamide of general formula 1a or N-mono- or N,N-disubstituted 1-methylene-piperdine-4-carboxamide of general formula 1b; R4 denotes a hydrogen atom, optionally substituted C2-C3alkyl, a -CH2-R12 group, where R12 denotes a hydrogen atom or phenyl which is optionally substituted with halogen or C1-C4alkyl; or R2, R3, and R4 together with atoms with which they are bonded form a substituted azaheterocycle of general formula 1.2; or R2 and R3 together with carbon atoms with which they are bonded form a substituted 2,3,4,9-tetrahydro-1H-carbazole of general formula 1.1, in which R1 denotes methyl, ethoxycarbonyl, nitro group; R4 denotes a hydrogen atom, methyl, C2-C3alkyl substituted with N-benzylamine; R7 and R8 denote hydrogen atoms or R7 and R8 together with a carbon atom with which they are bonded form a C=O group; R5 and R6, which are optionally identical, denote a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl; or R5 and R6 together with a nitrogen atom with which they are bonded form an optionally substituted 5- or 6-member azaheterocyclyl containing one or two nitrogen atoms, etc.

EFFECT: improved properties of compounds.

11 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of general formula (I) or pharmaceutically acceptable salts thereof, having JANUS: JAK2, JAK3 protein kinase, protein kinase A (PKA), serine/threonine protein kinase ROCK inhibiting properties. The compounds can be used to treat such diseases as allergy, asthma, atopic dermatitis and others. In structural formula (I): R1 denotes H; R2 denotes H; Z1 denotes C1-6aliphatic group or C5-7cycloaliphatic group, optionally substituted with 0-1 groups Jz; if the bond between Z1 and C is a double bond, then Z1 can also denote =O or =C(R)2; Z2 denotes H; or C1-10halogenalkyl, -(Vn)-CN, (Vn)-(heterocyclyl), where the heterocyclyl is a 6-member ring containing a nitrogen atom or two oxygen atoms as heteroatoms, -(Vn)-(phenyl) or -(Vn)-(C3-10cycloaliphatic group), optionally substituted with 0-1 groups Jz; or Z1 and Z2 together with the carbon atom with which they are bonded form a ring Q; Z3 denotes H or C1-6alkyl, optionally substituted with 0-1 groups Jz; or Z1, Z2 and Z3 together with the carbon atom with which they are bonded form a 6-8-member saturated bicyclic ring Q; where if the bond between Z1 and C is a triple bond, then Z2 and Z3 are absent; if the bond between Z1 and C is a double or triple bond, then Z3 is absent or Z2 and Z3 are absent; Q denotes a 3-8-member saturated or partially saturated monocyclic ring containing 0-2 heteroatoms selected from nitrogen, oxygen or sulphur, where said Q is optionally and independently condensed with Q1; where said Q is optionally substituted with 0-4 groups JQ, where said Q is optionally substituted with 0-4 groups JQ. Values of other radicals are given in the claim.

EFFECT: high efficiency of using the compositions.

35 cl, 5 dwg, 5 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel conformationally stable compounds of general formula (I), which imitate the secondary structure of reverse-configuration regions of biologically active peptides and proteins which are reverse-configuration mimetics. The compounds can be used to inhibit or treat disorders modulated by Wnt-signalling pathway, such as cancer, especially colorectal cancer. The invention also relates to a library containing the disclosed compound. In general formula (I), A denotes -(C=O)-, B denotes -(CHR4)-, D denotes -(C=O)-, E denotes -(ZR6)-, G denotes -(XR7)-, Z denotes CH, X denotes a nitrogen atom, W denotes -(C=O)NH-, R1 denotes benzyl; R2 denotes a heterocyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms; a substituted hetercyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, an the ring has 1-3 substitutes independently selected from a group comprising halogen, piperidinyl, morpholinyl, C2-6alkenyl, phenyl, hydroxyphenyl, C1-6alkoxycarbonyl, dialkylamino, hydroxypiperidinyl, C1-6alkyl, hydroxyC1-6alkylpiperazinyl, amino, piperidinyl carbonyl; heterocyclyl-C1-6alkyl group having a 9-member condensed bicyclic ring which has one or two nitrogen atoms; and other values given in the claim. R4 denotes a substituted benzyl, having a substitute selected from disodium phosphate, monosodium phosphate, phosphate; R6 denotes hydrogen; R7 denotes: C1-6alkyl; C1-6alkynyl; C2-6alkenyl; substituted benzyl, having one or more substitutes independently selected from halogen and C1-6alkyl.

EFFECT: high efficiency of the compounds.

8 cl, 34 dwg, 19 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing novel compounds of general formula , where NR1R2=NH2; NHAlk, where Alk=C1-C6, or cycloalkyl-C3-C6; NAlk2, where Alk=C1-C6, or cycloalkyl-C3-C6; N(CH2)n, where n=2, 3, 4, 5, 6; N(CH2CH2)2O; NHAr, where Ar=C6H5, C6H4R3, where R3=Alk(C1-C6), NO2, halide, which can be used as biologically active substances and intermediate products in synthesis of biologically active substances (anomalous nucleosides, nucleotides etc). Sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones are obtained via successive substitution of chlorine atoms in 2-NR1R2-4,6-dichloro-1,3,5-triazines with a hydroxy and azido group. The corresponding 2-NR1R2-4,6-dichloro-1,3,5-triazine reacts with aqueous sodium hydroxide solution followed by acidation and the obtained 4-NR1R2-6-chloro-(3H)-1,3,5-triazin-2-one is treated with sodium azide in an organic solvent such as acetone, acetonitrile, dimethylformamide or mixtures thereof.

EFFECT: obtaining sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones directly from 2-amino-4,6-dichloro-1,3,5-triazines without obtaining and use of bis- and mono-trinitromethyl-1,3,5-triazines.

1 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel derivatives of condensed pyrazole-, imidazole-, oxazole- and triazole pyrimidines, structural formulae of which are disclosed in the claims, as well as pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with cannabinoid receptor 1 (CB1) activity.

EFFECT: improved properties of compounds.

33 cl, 448 ex, 1 tbl

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 5,6-dihydro-4H-benzo[f]pyrrolo[ 1,2-α][1,4]diazepin-6-one 1, involving moulding a pyrrolodiazepine frame as a result of reduction of nitro-groups of N-(2,5-dioxoalkyl)-2-nitrobenzamides 4, in acetic acid in the presence of iron while carrying out the reaction until boiling and holding for 60 minutes at room temperature.

EFFECT: simultaneous formation of a pyrrole and a diazepine ring, and high output of end products owing to change in the sequence and conditions of the reaction.

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formulae Ia, Ic, Ig, Ik and pharmaceutically acceptable salts thereof, having activity towards cannabinoid 1 receptor. In formulae

, ,

, ,

R2 is selected from halogen, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, pyridinyl-N-oxide and phenyl; where the said pyrimidinyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl and phenyl are optionally substituted with an amino group; R3 is selected from hydrogen, methylsulphonyl, methlsulphoxide and dimethylaminocarbonyl; R4 is selected from hydrogen, cyano, nitro, carbamimidoyl, tetrazolyl, aminosulphonyl, aminocarbonyl, methylsulphonylamino and methylsulphonyl; R6 is selected from hydrogen, hydroxyethylaminomethyl and methylsulphonylaminomethyl. The invention also relates to a pharmaceutical composition, methods of treating and preventing diseases mediated by the cannabinoid 1 receptor, and use of said compounds in preparing a medicinal agent used to treat such diseases.

EFFECT: improved properties of the derivatives.

12 cl, 1 tbl, 62 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): or to their pharmaceutically acceptable derivatives selected from a group consisting of pharmaceutically acceptable salts and esters; in which: R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R8c and R8d are such as presented in the patent claim 1. The invention also refers to compounds of formula (I), to a compounds selected from a group, to a pharmaceutical composition, to methods of treating, to a method of decreasing the plasma cholesterol level in a patient, to a method of modulating cholesterol metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal, to a method of modulating farnesoid X receptor activity, to a compound representing 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b]indole-5-isopropylcarboxamide, to a composition, to a method of reducing the risk of an onset or a recurrence, to a method of modulating triglyceride metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal, and also to a method of modulating bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal.

EFFECT: preparation of the new biologically active compounds showing possessing nuclear receptor activity.

73 cl, 76 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 1H-quinazoline-2,4-diones of formula and to their pharmaceutically acceptable salts where R1 and R2 have the values specified in cl. 1 of the patent claim. The specified compounds exhibit antagonistic activity with respect to the AMPA receptor.

EFFECT: reception of a pharmaceutical composition for preparing a preparation used for treating a condition mediated by the AMPA receptor and first of all for treating epilepsy or schizophrenia.

8 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole derivatives of formula any isomers thereof or any mixture of isomers thereof or a pharmaceutically acceptable salt, where R is -(CR'R")n-Rc, where Rc is C1-6-alkyl, R' is hydrogen or C1-6-alkyl, and R" is hydroxy; n equals 1; X is N; and Y, Z and W is CRd, where each Rd is hydrogen; Ro is halogen. The invention also relates to a pharmaceutical composition containing a compound of formula I, use of the compound of formula I and a GABAA-receptor complex modulating method.

EFFECT: obtaining novel benzimidazole derivatives which are sensitive to GABAA-receptor complex modulation.

8 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2,6-substituted-4-monosubstituted aminopyrimidines of formula (I) or pharmaceutically acceptable salts thereof, which have prostaglandin D2 receptor antagonist properties. In formula R1 is 2,4-dichlorophenyl or 4-trifluoromethoxyphenyl, and when R1 is 2,4-dichlorophenyl, R2 is 3-carboxypyrrolidinyl, 3,5-di-(1-hydroxy-1-methylethyl)phenyl, 3-aminopiperdin-1-yl, 4-aminopiperidin-1-yl, 4-acetamidepiperidin-1-yl, 1-methyl-2-carboxy-2,3-dihydro-1H-indol-5-yl, 3-(1-tert-butylsulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminosulphonylaminocarbonyl-1-methylethyl)phenyl, 3-(1-thiomorpholin-4-ylcarbonyl-1-methylethyl)phenyl, 3-(1-aminocarbonyl-1-methylethyl)phenyl, 3-(1-dimethylaminocarbonyl-1-methylethyl)phenyl, 3-carboxymethylpiperidin-1-yl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 3-ethylsulphonylaminocarbonylpiperidin-1-yl, 3-tert-butylsulphonylaminocarbonylpiperidin-1-yl, 3-trifluoromethylsulphonylaminocarbonylpiperidin-1-yl, 3-[(1H-tetrazol-5-yl)aminocarbonyl]piperidin-1-yl, 3-aminocarbonylpiperidin-1-yl, 3-dimethylaminocarbonylpiperidin-1-yl, 3-dimethylaminosulphonylaminocarbonylpiperidin-1-yl or 2-carboxy-2,3-dihydrobenzofuran-5-yl, and when R1 is 4-trifluoromethoxyphenyl, R2 is 3-(1-methyl-1-carboxyethyl)piperidinyl, 3-carboxypiperidinyl, 3-methylsulphonylaminocarbonylpiperidin-1-yl, 5-carboxythiophen-2-yl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: high efficiency of using said compounds.

3 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: method is realised by reacting 2-n-propyl-4-methyl-6-(1'-methylbenzimidazol-2'-yl)benzimidazole with a compound of formula

, in which Z denotes a leaving group. The compound obtained this way undergoes suitable treatment if necessary. The cyano group of the obtained 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(1'"-methylbenzimidazol-2'"-yl)benzimidazol-1"-ylmethyl]biphenyl of formula

is then converted to an acid functional group through hydrolysis at temperature ranging from 140°C to 200°C in the presence of a base in a system of high-boiling solvents, and the obtained telmisartan is converted to a hydrochloride during processing if necessary.

EFFECT: easy processing, treatment and extraction of telmisartan.

12 cl, 7 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dihydroquinazolines of formula (I), which are used to prepare medicinal agents. In formula

Ar denotes phenyl, possibly substituted with a C1-C4alkoxy group, R1 and R2 are selected from hydrogen, C1-C4alkoxy group and trifluoromethyl, R3 is selected from C1-C4 alkoxy group and trifluoromethyl, R4 denotes hydrogen or C1-C4alkyl, R5 denotes hydrogen or C1-C4alkyl, each of R6 R7 and R8 denotes hydrogen or halogen. The method involves hydrolysis of an ester of a compound of formula (II) in which Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, with a base or acid, where the compound of formula (II) obtained from reaction of a compound

of formula (III), is used, in which R1, R2, R3, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, in the presence of a base, with a compound of formula (IV) in which Ar, R4 and R5 are as described above. The method simplifies extraction of products.

EFFECT: invention also relates to novel intermediate compounds and a method of obtaining said compounds.

11 cl, 5 dwg, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition, which has anti-viral activity against hepatitis C, includes solid suspension, obtained by extrusion of melt of hydrochloride (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutiryoxytetrahydrofuran-2-ylmethyl ether of isobutyric acid (I) and block-copolymer polyethyleneglycol (PEG)/polypropylenglycol (PPG). Preferably block-copolymer PEG/PPG represents poloxamer 188.

EFFECT: pharmaceutical composition has improved speed of dissolution and bio-availability.

14 cl, 2 ex

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