Macrocyclic inhibitors of hepatitis c virus

FIELD: pharmachology.

SUBSTANCE: invention describes new compounds with general formula (I-c) Where R1 is a radical (d-1) or (d-2) (radical values are given in the invention formula) and pharmaceutical composition containing them. The described compounds are the hepatitis C inhibitors and can be used in medicine.

EFFECT: enhanced hepatitis C inhibition.

5 cl, 1 tbl, 19 ex

 

The present invention relates to macrocyclic compounds having inhibitory activity against the replication of hepatitis C virus (HCV). In addition, the invention 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 containing 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 the whole the series co - and post-translational 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 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 e is the effects and is 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 WO 00/59929, and VX-950, as described in the application WO 03/87092. 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 drugs and, in particular, HIV protease inhibitors, on the barks emphasis 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 compliance with required the skills of reception.

In the application WO 05/010029 described azapeptide 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 of treating HCV infection in a subject by introducing pharmaceutical compositions containing the preferred compounds of the present invention.

The present invention relates to inhibitors of HCV replication, which are effective not only from the point of view of their activity as inhibitors of HCV, but also from the point of view of their good cell permeability and related bioavailability.

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

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

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

R1represents an aryl or a saturated, partially unsaturated or fully unsaturated 5 - or 6-membered monocyclic ring system or 9-12-membered bicyclic heterocyclic ring system where the above-mentioned ring system contains one of tomasita and optionally one to three additional heteroatoms, selected from the group consisting of oxygen atoms, sulfur and nitrogen, and where the remaining ring members are carbon atoms; where mentioned ring system optionally may be substituted on any ring carbon atom or nitrogen one, two, three or four substituents, each of which is independently selected from C3-7-cycloalkyl, aryl, Het, -C(=O)NR4AR4b-C(=O)R6-C(=O)or SIG5Aand C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl, Het, -C(=O)NR4AR4b, NR4AR4b-C(=O)R6, -NR4AC(=O)R6, -NR4ASOpR7, -SOpR7,

-SOpNR4AR4b-C(=O)or SIG5or-NR4AC(=O)or SIG5A; and where the substituents at any carbon atom of the heterocyclic ring can also be selected from-or SIG8, -SR8, halogen, polyhalogen-C1-6-alkyl, oxo, thio, cyano, nitro, azido, -NR4AR4b, -NR4AC(=O)R6, -NR4ASOpR7,

-SOpR7, -SOpNR4AR4b-C(=O)HE-NR4AC(=O)or SIG5A;

Lrepresents a direct bond, -O-, -O-C1-4-alcander, -O-C(=O)-, -O-C(=O)-NR4A- or-O-C(=O)-NR4AWith1-4-alcander-;

R2represents hydrogen, -or SIG5-C(=O)or SIG5-C(=O)R6,

-C(=O)NR4AR4b -C(=O)NR4S, -NR4AR4b, -NR4S, -NR4ASOpNR4AR4b,

-NR4ASOpR7or-IN(or SIG5)2;

R3represents hydrogen and when X is C or CH,R3can also be a C1-6-alkyl;

nis 3, 4, 5 or 6;

pis 1 or 2;

each ofR4aandR4bindependently represents hydrogen, C3-7-cycloalkyl, aryl, Het, C1-6-alkyl, optionally substituted with halogen, C1-4-alkoxy, cyano, polyhalogen-C1-4-alkoxy, C3-7-cycloalkyl, aryl or Het; orR4aandR4b,taken together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine, 4-C1-6-acylcarnitines and morpholinyl; where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals;

R4crepresents a C3-7-cycloalkyl, aryl, Het, -O-C3-7-cycloalkyl, -O-aryl, -O-Het, C1-6-alkyl or C1-6-alkoxy, where each of the mentioned C1-6-alkyl or C1-6-alkoxy optionally may be substituted by-C(O)OR5C3-7-cycloalkyl, aryl or Het;

R5represents hydrogen, C2-6alkenyl; Het; 3-7-cycloalkyl, optionally substituted C1-6-alkyl; or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het;

R5arepresents a C2-6alkenyl, C3-7-cycloalkyl, Het or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het;

R6represents hydrogen, C1-6-alkyl, C3-7-cycloalkyl or aryl;

R7represents hydrogen; polyhalogen-C1-6-alkyl; aryl; Het; C3-7-cycloalkyl, optionally substituted C1-6-alkyl; or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het;

arylas a group or part of a group represents a phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl, each of which optionally can be substituted one, two or three substituents selected from halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, hydroxy, C1-6-alkoxy, polyhalogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, carboxyl, C1-6-alkylsulphonyl, C1-6-alkoxycarbonyl, cyano, nitro, amino, mono - or di-C1-6-alkylamino, aminocarbonyl, mono - or di-C1-6-alkylaminocarbonyl, azido, mercapto, C3-7-cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinil is, 4-C1-6-alkylpiperazine, 4-C1-6-acylcarnitine and morpholinyl; where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals; and phenyl, peredelnye, thiazolidine, pyrazolidine group optionally can be substituted by 1, 2 or 3 substituents, each of which is independently selected from C1-6-alkyl, C1-6-alkoxy, halogen, amino, mono - or di-C1-6-alkylamino;

Hetas 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; the heterocyclic ring optionally may be condensed with a benzene ring, and in which the group Het as a whole may not necessarily be substituted by one, two or three substituents, each independently selected from the group consisting of halogen, C1-6-alkyl, polyhalogen-C1-6-alkyl, hydroxy, C1-6-alkoxy, polyhalogen-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, carboxyl, C1-6-alkylsulphonyl, C1-6-alkoxycarbonyl, cyano, nitro, amino, mono - or di-C1-6-alkylamino, aminocarbonyl, mono - or di-C1-6-alkilani is carbonyl, C3-7-cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine, 4-C1-6-acylcarnitine and morpholinyl; where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals; and phenyl, peredelnye, thiazolidine, pyrazolidine group optionally can be substituted by 1, 2 or 3 substituents, each of which is independently selected from C1-6-alkyl, C1-6-alkoxy, halogen, amino, mono - or di-C1-6-alkylamino.

Compounds of the present invention possess unexpected properties, because, despite their reduced structural flexibility, they are active drugs against HCV. This contradicts prevailing at the present time the opinion according to which it is believed that less-active drugs are expected to be less flexible macrocyclic ring.

Compounds of the present invention, having a relatively low molecular weight, easily synthesized, based on the starting materials, which are commercially available or easily accessible through the procedures of synthesis known in this field.

The invention additionally relates to methods of preparing compounds of formula (I),N-oxides, additive with the lei, Quaternary amines, metal complexes and their stereochemical isomeric forms, their intermediates, and the use of intermediate products for preparing 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 a carrier and an effective anti virus number specified here, the compounds of formula (I). 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 in the mentioned way, including the introduction effetive the amount of the compounds of formula (I) or N-oxide, additive salt, Quaternary amine, metal or stereochemical isomeric forms.

Unless otherwise specified, as used above and hereinafter, the following definitions.

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, voltage is emer, 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-pentyl, 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 C-6 -etkinlik groups of interest represents C2-4-quinil.

C3-7-cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. When C3-7-cycloalkyl is Deputy on the aryl group or Het, he, in particular, is cyclopropyl.

C1-6-alcander defines bivalent saturated 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.

Bivalent radical L can be represented as-O-C1-4-alcander-, -O-CO-, -O-C(=O)-NR5a- or-O-C(=O)-NR5a-C1-4and kandeel-; such bivalent radicals, in particular, join pyrolidine slice through its oxygen 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, piperazinil, pyrrolyl, pyrazolyl, 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, personaltrainer 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, honokalani, cinnoline, phthalazine, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl, benzisothiazole, benzothiazolyl, benzoxazolyl, benzothiazolyl, benzo-1,2,3-triazolyl, benzo-1,2,4-triazolyl, betterall, benzofuranyl, benzothiazol, benzimidazolyl etc. Among the radicals Het represent the interest of those radicals, which are unsaturated, in particular, radicals having aromatic character. Additional the considerable interest shown represent those radicals Het, which are monocyclic.

In the preceding and following paragraph assumes that each of the radicals Het, or R1optionally may be substituted by a certain number and kind of substituents mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I). In this and the following paragraph assumes that some of the radicals Het, or R1can be substituted by one, two or three hydroxy substituents. Such hydroxy-substituted rings may exist in their tautomeric forms, containing ketogroup. For example, 3-hydroxypyridinone fragment may exist in their tautomeric form 2H-pyridazin-3-one. Some examples of keto-substituted radicals Het, or R1represent 1,3-dehydrobenzperidol-2-he, 1,3-dihydroindol-2-it, 1H-indole-2,3-dione, 1H-benzo[d]isoxazol, 1H-benzo[d]isothiazol, 1H-quinoline-2-it, 1H-quinoline-4-one, 1H-hinzelin-4-one, 9H-carbazole and 1H-hinzelin-2-it. When Het represents piperazinil, it is preferably substituted in its 4-position Deputy related to 4-nitrogen via a carbon atom, for example, 4-C1-6-alkyl, 4-polyhalogen-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl, C1-6-alkylcarboxylic, C3-7-cycloalkyl.

As specified in this description and for the ule of the invention, R1can be a saturated, partially unsaturated or fully unsaturated 5 - or 6-membered monocyclic or 9-12-membered bicyclic heterocyclic ring system. Examples of the aforementioned monocyclic or bicyclic ring systems include, for example, any of the cycles mentioned in the previous paragraph as examples of the radical Het, and optionally any of monocyclic heterocycles mentioned in the previous paragraph, condensed with pyridium or pyrimidinium, such as pyrrolopyridine (in particular, 1H-pyrrolo[2,3-b]pyridine, 1Hpyrrolo[2,3-c]pyridine), naphthiridine (in particular, 1,8-naphthiridine), imidazopyridine (in particular, 1H-imidazo[4,5-c]pyridine, 1H-imidazo[4,5-b]pyridine), pyridopyrimidines, purine (in particular, 7H-purine), etc.

Interest radicals Het, or R1include, for example, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-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), indolin is l, 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.

When Het is pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-substituted piperazinil such radicals are preferably attached through its nitrogen atom (i.e. 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinil, 4-substituted piperazine-1-yl).

Each arrow" above and preferably represents phenyl, substituted by the above substituents. This definition is equally applicable to aryl-C1-6-alkyl, which, in particular, can be arylmethyl, for example benzyl.

It should be noted that the provisions of the radicals in any molecular fragment used 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 of Peremena any constituent element occurs more than once, 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), each and any of their sub-groups, 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 embodiment of the invention includes 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 is in the Deputy applies (R) or (S), the connection 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, that 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%, else b is more specifically containing excess stereoisomer from 94% to 100%, and most specifically 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. In such methods, mainly the substantial will be 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),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 obtained is the 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 they split up the original 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 carboxypropyl include complex C1-6-alkoxymethyl esters, for example, metaxen milovy, 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 carboxypropyl.

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 a 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 the 3 - or 4-position 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, e.g. hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, voltage is emer, acetic, propanoic, hydroxyestra (glycolic acid), lactic, pyruvic, oxalic (i.e. o), malonic, succinic (i.e. batandjieva), maleic, fumaric, malic (i.e. hydroxybutanone), 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 suitable salts of the bases include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, 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, the alcoholate is so

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, for example, methyliodide or benzylated. You can also use other reagents with suitable removable 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) are to be included in the amount of us who Otsego of the 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 R3represents a C1-6-alkyl, and the carbon atom 1'when X represents CH. Each of these centers of asymmetry may occur in its 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 matches the configuration of L-Proline. Carbonyl group, alsaudia in positions 1 '5'preferably reside in the structure of the following formula (I-a), as shown below:

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

where 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 particular subgroup of compounds of formula (I) represent the link is, 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-L-R1(in position 3'are inTRANS-configuration. Of particular interest are compounds of formula (I), which in position 1 have a configuration corresponding to L-Proline, and Deputy-L-R1isTRANS-configuration with respect to the position 1. Preferably the compounds of formula (I) have the stereochemistry as indicated below in structural formula (I-b):

One of the embodiments of the present invention 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) R3represents hydrogen;

(b) X represents nitrogen;

(C) L represents-O-;

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

One of the variations is tov implementation of the present invention 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) R3represents hydrogen;

(b) X represents CH;

(c) L represents-O-;

(d) 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) special 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 of formula (If), (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, L, 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 anyN-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), corresponds to the Penta is Dyilo. 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 special subgroup of compounds of formula (I).

Additional subgroup of compounds of formula (I) are those compounds of formula (I) or any of these subgroups of compounds of formula (I)in which R1represents phenyl, naphthyl, pyridyl, pyridazinyl, triazolyl, tetrazolyl, chinoline, ethenolysis, hintline, pyrimidinyl, [1,8]naphthyridines, indolinyl, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline; all of which optionally substituted with one, two or three substituents selected from the substituents mentioned above in relation to R1in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I).

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any of these subgroups of compounds of formula (I), in which

(a) R1represents phenyl, naphthyl (such as naphthas-1-yl or naphthas-2-yl), chinoline (in particular, quinoline-4-yl), ethenolysis (in particular, isoquinoline-1-yl), hintline (in particular, hinzelin-4-yl), pyridyl (in particular 3-pyridyl), pyrimidinyl (in particular, the pyrimidine-4-yl), pyridazinyl(in particular, pyridazin-3-yl and pyridazin-2-yl), [1,8]naphthyridine (in particular, [1,8]naphthiridine-4-yl);

(b) R1represents triazolyl (in particular, triazole-1-yl, triazole-2-yl), tetrazolyl (in particular, tetrazol-1-yl, tetrazol-2-yl), 6-oxopyridine-1-yl, pyrazolyl (in particular, the pyrazole-1-yl) or imidazolyl (in particular, imidazol-1-yl, imidazol-2-yl);

(c) R1represents a heterocycle selected from the

and in which each of the above-mentioned radicals R1optionally can be substituted one, two or three substituents selected from the substituents mentioned above in relation to R1in the definitions of the compounds of formula (I) or any 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 L represents a direct bond, -O-,

-OC(=O)- or-OC(=O)NR4a- or, in particular, in which L represents-OC(=O)NH - or-O-, or, more specifically, in which L represents-O-.

Preferably, L represents-O-, and R1has the meaning specified above in paragraph(a). Preferably L is a direct bond, and R1has the meaning specified above in paragraph(b). Preferably L is a divalent radical-OC(=O)-, and R1has the meaning of the criminal code is mentioned above in paragraph(c).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which L represents-O-, and R1is chinoline (in particular, quinoline-4-yl), ethenolysis (in particular, isoquinoline-1-yl), hintline (in particular, hinzelin-4-yl) or pyrimidinyl (in particular, the pyrimidine-4-yl), any of which optionally is independently mono-, di - or tizamidine C1-6-alkyl, C1-6-alkoxy, nitro, hydroxy, halogen, trifluoromethyl, -NR4aR4b, -C(=O)NR4aR4bC3-7-cycloalkyl, aryl, Het, -C(=O)OH or-C(=O)OR5a; in which each aryl or Het optionally independently substituted with halogen, C1-6-alkyl, C1-6-alkoxy, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (for example, 4-methylpiperazine), thiomorpholine or morpholinium; and in which morpholinyl, thiomorpholine and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which L represents-O-, and R1is chinoline (in particular, quinoline-4-yl), ethenolysis (in particular, isoh the nolin-1-yl), hintline (in particular, hinzelin-4-yl) or pyrimidinyl (in particular, the pyrimidine-4-yl), any of which optionally is independently mono-, di - or tizamidine the stands, ethyl, isopropyl,tert-bootrom, methoxy, trifluoromethyl, triptoreline, fluorine, chlorine, bromine, -NR4aR4b, -C(=O)NR4aR4b, phenyl, methoxyphenyl, cyanophenyl, halogenfree, pyridium, C1-4-alkylpyridinium, pyrimidinium, piperidinium, morpholinium, piperazinil, C1-4-alkylpiperazine, pyrrolidinium, pyrazolyl, C1-6-alkylpyridinium, thiazolium, C1-6-alkylation, cyclopropylmethyl or mono - or di-C1-6-alkylaminocarbonyl; and in which morpholinyl, thiomorpholine and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals (in particular, one or two methyl radicals).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1is chinoline, optionally substituted 1, 2, 3 or 4 (or 1, 2 or 3) substituents selected from the substituents mentioned as possible substituents on the monocyclic or bicyclic ring systems, R1as specified in the definitions of the compounds of formula (I) or Liu the Oh of the subgroups of compounds of formula (I).

Specific embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

the radical (d-1) formula

the radical (d-2) formula

the radical (d-3) formula

the radical (d-4) formula

the radical (d-4-a) of the formula

the radical (d-5) formula

or, in particular, the radical (d-5-a) of the formula

where the radicals (d-1) - (d-5), and in radicals (d-4-a) and (d-5-a) each R1a, R1b, R1b', R1d, R1d', R1e, R1findependently represents any of the substituents selected from the substituents mentioned as possible substituents on the monocyclic or bicyclic ring systems, R1specified in the definition of compounds of formula (I) or any subgroup of compounds of formula (I);

or, in particular, where in the radicals (d-1) - (d-5), and in radicals (d-4-a) and (d-5-a):

R1b, R1b'can independently represent hydrogen, C1-6-alkyl, C1-6-alkoxy, -NR4aR4b(in particular, amino or mono - or di-C1-6-alkylamino), -C(=O)NR4aR4b(in particular, aminocarbonyl and the and mono - or di-C 1-6-alkylaminocarbonyl), nitro, hydroxy, halogen, trifluoromethyl, -C(O)OH or-C(=O)OR5a(in particular, in which R5arepresents a C1-6-alkyl);

where the value of each of the above or further radicals R4a, R4b, R5aindependently specified in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I);

or, in particular, where in the radicals (d-1) - (d-5), and in radicals (d-4-a) and (d-5-a): R1arepresents hydrogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, mono-C1-6-alkylamino, amino, C3-7-cycloalkyl, aryl or Het;

more specifically, R1arepresents a C1-6-alkoxy, aryl or Het; interest embodiments of the invention, in which R1arepresents methoxy, ethoxy, propoxy, phenyl, pyridyl, thiazolyl, pyrazolyl, each of which is substituted as specified in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I); in specific embodiments of the invention each of the above-mentioned arrow or Het optionally may be independently substituted C1-6-alkyl, C1-6-alkoxy, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6-alkylpiperazine; and in which morpholinyl and piperidinyl groups are not battelino can be substituted by one or two C 1-6-alkyl radicals; and in particular, R1acan be a radical Het; where Het may include pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6-alkylpiperazine; and in which morpholinyl, thiomorpholine and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1Arepresents a radical

or, in particular, in which R1aselected from the group consisting of:

in which, whenever possible, the nitrogen atom may carry a substituent R1cor to be a connecting link with the remainder of the molecule; each R1crepresents any of the substituents R1and can be selected from the substituents mentioned as possible substituents on the monocyclic or bicyclic ring systems, R1specified in the definition of compounds of formula (I) or any subgroup of compounds of formula (I);

specifically, each R1ccan represent hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, polyhalogen-C1-6-alkyl (in particular trifluoromethyl), -NR4aR4b(in private is ti, amino or mono - or di-C1-6-alkylamino), -C(=O)NR4aR4b(in particular, aminocarbonyl or mono - or di-C1-6-alkylaminocarbonyl), nitro, hydroxy,

-C(=O)OH or-C(=O)OR5a(in particular, in which R5arepresents a C1-6-alkyl), phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine); and in which morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals;

more specifically, each R1ccan represent hydrogen, halogen, C1-6-alkyl, amino or mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6-alkylpiperazine; and in which morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals; and phenyl, peredelnye, thiazolidine, pyrazolidine group optionally can be substituted by 1, 2 or 3 (particularly 1 or 2) substituents, each of which is independently selected from C1-6-alkyl, C1-6-alkoxy, halogen, amino, mono - or di-C1-6-alkylamino;

more specifically, each R1ccan represent hydrogen, halogen, C1-6-alkyl, amino, or mono - or di-C1-6-alkylamino, PIR is original, piperidinyl, morpholinyl, piperazinil, 4-C1-6-alkylpiperazine; and in which morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals;

and when R1cis Deputy on the nitrogen atom, it preferably represents a carbon Deputy, which is connected to the nitrogen atom through a carbon atom or one of its carbon atoms;

specifically, each of R1dand R1d'independently can represent hydrogen, C1-6-alkyl, C1-6-alkoxy or halogen;

or, more specifically, each R1din (d-3) can represent hydrogen, C1-6-alkyl, C1-6-alkoxy or halogen;

specifically, R1ecan represent hydrogen, C1-6-alkyl, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine); where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals;

preferably each R1brepresents a C1-6-alkoxy, more preferably methoxy;

specifically, R1fcan represent hydrogen, C1-6-alkyl, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidino is, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine) or morpholinyl.

Specific embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1is a 7-methoxy-2-phenylindolin-4-yl, and L represents-O-.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

(e) ethenolysis (in particular, 1-ethenolysis), optionally substituted by 1, 2, 3 or 4 (or 1, 2 or 3) substituents selected from the substituents mentioned as possible substituents on the monocyclic or bicyclic ring systems, R1specified in the definition of compounds of formula (I) or any subgroup of compounds of formula (I).

Specifically, such embodiments of the invention include variants in which R1represents a radical (e-1) formula:

or, in particular, the radical (e-1-a) formula:

in which R9a, R9b, R9cindependently of one another represents any of the substituents selected from the substituents mentioned as possible substituents on the monocyclic or bicyclic ring systems, R specified in the definition of compounds of formula (I) or any subgroup of compounds of formula (I); in particular,

R9acan have the same meanings as R1aspecified above; in particular, it can represent an aryl or Het, each of which is optionally substituted by any of the radicals mentioned as substituents of aryl or Het, as specified in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I) (including the number of substituents); specifically, the above-mentioned aryl or Het may be substituted by 1, 2 or 3 (in particular one) radicals or radicals R10, where is referred to R10is any of the radicals mentioned as substituents of aryl or Het, specified in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I)defined above; or in particular, R10represents hydrogen, C1-6-alkyl, C3-7-cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, amino, optionally mono - or disubstituted by C1-6-alkyl, or aminocarbonyl or mono - or di-C1-6-alkylaminocarbonyl; where Het also includes pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (for example, 4-methylpiperazine) or morpholinyl; and where morpholinyl or piperidinyl group optionally can be substituted by one or two C1-6-skillname radicals; and phenyl, peredelnye, thiazolidine, pyrazolidine group optionally can be substituted by 1, 2 or 3 (particularly 1 or 2) substituents, each of which is independently selected from C1-6-alkyl, C1-6-alkoxy, halogen, amino, mono - or di-C1-6-alkylamino;

R9bcan have the same meanings as Rlbspecified above; in particular, it can represent hydrogen, C1-6-alkyl, C3-7-cycloalkyl, aryl, Het, halogen (e.g. bromine, chlorine or fluorine); R9ccan have the same meanings as Rlcspecified above; in particular, it can represent a hydrogen or C1-6-alkoxy.

In particular, R9ain izokhinolinom radical specified under the designation (e-1) or (1-e-a), includes phenyl, pyridyl, thiazolyl, oxazolyl or pyrazolyl, any of which is optionally substituted by R10as described above, in particular, optionally substituted R10that can be a hydrogen, C1-6-alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl), amino, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (for example, 4-methylpiperazine) or morpholinyl, C1-6-alkylamino, (C1-6-alkyl)2amino, aminocarbonyl or mono - or di-C1-6-alkylaminocarbonyl; and in which morpholinyl and piperidinyl group may not necessarily be the Deputy is shifted by one or two C 1-6-alkyl radicals.

Preferably R9ain izokhinolinom radical specified under the designation (e-1) or (e-1-a), includes any of the radicals (q), (q'), (q'-l), (q-1) (q-2), (q-3), (q-4), above, and

in which each R10is any of the radicals mentioned as substituents of Het specified in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I); or, in particular, R10the same as defined above; specifically, R10represents hydrogen, C1-6-alkyl (e.g. methyl, ethyl, isopropyl,tert-butyl), amino, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (for example, 4-methylpiperazine), morpholinyl, C1-6-alkylamino, (C1-6-alkyl)2amino, aminocarbonyl or mono - or di-C1-6-alkylaminocarbonyl; and in which the morpholine and piperidine optionally can be substituted by one or two C1-6-alkyl radicals.

Also preferably, R9ain izokhinolinom radical specified under the designation (e-1) or (e-1-a), includes

in which each R10defined above, and specifically represents hydrogen, halogen, C1-6-alkyl (e.g. methyl, ethyl, isopropyl,tert-butyl), amino, pyrrolidinyl, PIP is reinel, piperazinil, 4-C1-6-alkylpiperazine (for example, 4-methylpiperazine), morpholinyl, C1-6-alkylamino, (C1-6-alkyl)2amino, aminocarbonyl or mono - or di-C1-6-alkylaminocarbonyl; and in which morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals.

R9bin izokhinolinom radical specified under the designation (e-2)may represent hydrogen, C1-6-alkyl, halogen (e.g. bromine, chlorine or fluorine), specifically a hydrogen or bromine.

R9bin izokhinolinom radical specified under the designation (e-2)may represent hydrogen or C1-6-alkoxy (e.g. methoxy).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

in which R9brepresents a hydrogen or halogen (e.g. bromine) and R9crepresents hydrogen or C1-6-alkoxy (e.g. methoxy).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

in which R9ashall have the meaning given for any of the groups or subgroups connection the settings of the formula (I); and

R9brepresents hydrogen, halogen or trifluoromethyl.

Additional preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

in which R9arepresents methoxy, ethoxy or propoxy; and

R9brepresents hydrogen, fluorine, bromine, chlorine, iodine, methyl, ethyl, propyl or trifluoromethyl.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents:

in which R9brepresents hydrogen, halogen or trifluoromethyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

(f) hintline (in particular, hinzelin-4-yl), optionally substituted by 1, 2, 3 or 4 (or 1, 2 or 3) substituents selected from the substituents mentioned as possible substituents on the monocyclic or bicyclic ring systems, R1as specified in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I). Hintline embodiments of R1VK is ucaut in itself

radical (f-1):

or, in particular, the radical (f-1-a):

in which R9a, R9band R9chave the meanings specified above in relation to R1representing ethenolysis (such as radicals (e-1), (e-1-a), and so on);

where exactly R9arepresents a C3-7-cycloalkyl, aryl or Het, each of which is optionally substituted one, two or three (in particular one) R10; where;

R10represents hydrogen, C1-6-alkyl, C3-7-cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinil, 4-methylpiperazine, thiomorpholine or morpholinyl, aminocarbonyl, mono - or di-C1-6-alkylaminocarbonyl; in which piperidinyl and morpholinyl optionally can be substituted by one or two C1-6-alkyl radicals; and phenyl, peredelnye, thiazolidine, pyrazolidine group optionally can be substituted by 1, 2 or 3 (or 1 or 2) substituents, each of which is independently selected from C1-6-alkyl, C1-6-alkoxy, halogen, amino, mono - or di-C1-6-alkylamino (in particular selected from C1-6-alkyl);

R9brepresents hydrogen, halogen, C1-6-alkyl (preferably methyl), C3-7-cycloalkyl, aryl, Het, halogen (in particular bromine, chlorine Il is fluorine);

R9crepresents hydrogen or C1-6-alkoxy.

The most preferred embodiments of R9afor hintline include aryl or Het, specifically those in which R9arepresents phenyl, pyridyl, thiazolyl, oxazolyl or pyrazolyl, any of which is optionally substituted one, two or three (in particular one) R10as defined.

Embodiments of R10for hintline include hydrogen, methyl, ethyl, isopropyl,tert-butyl, methoxy, halogen (including dihalogen, such as debtor), pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (for example, 4-methylpiperazine) or morpholinyl, C1-6-alkylamino, (C1-6-alkyl)2amino, aminocarbonyl, mono - or di-C1-6-alkylaminocarbonyl or C3-7-cycloalkyl (in particular, cyclopropyl).

R9ain chinatelecom radical specified under the designation (f-1) or (f-1-a), preferably includes any one of the radicals (q), (q'), (q'-1), (q-1) (q-2), (q-3), (q-4), (q-5), (q-6), (q-7), (q-8), above,

in which the value of R10in these radicals defined above or, in particular, represents hydrogen, C1-6-alkyl, such as methyl, ethyl, isopropyl,tert-butyl), pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine, N-methylpiperazine or morpholine is l, C1-6-alkylamino, (C1-6-alkyl)2amino or aminocarbonyl, mono - or di-C1-6-alkylaminocarbonyl.

R9afor hintline may include

where R10represents hydrogen, halogen, C1-6-alkyl (such as methyl, ethyl, isopropyl,tert-butyl, C1-6-alkylamino, (C1-6-alkyl)2amino, C1-6-alkylamino, morpholinyl or piperidine-1-yl; morpholinyl and piperidinyl, optionally substituted by one or two C1-6-alkyl groups.

Additional embodiments of R9afor hintline include phenyl, substituted with one or two groups R10such as hydrogen, methyl, ethyl, isopropyl,tert-butyl, methoxy, saturated monocyclic amino, C1-6-alkylamino, (C1-6-alkyl)2amino or aminocarbonyl, mono - and di-C1-6-alkylaminocarbonyl or halogen (particularly fluorine).

Embodiments of R9bfor hintline include hydrogen, C1-6-alkyl (in particular methyl), halogen (e.g. bromine, chlorine or fluorine), specifically those in which R9brepresents a hydrogen or bromine.

Embodiments of R9cfor hintline include hydrogen or C1-6-alkoxy (in particular methoxy).

Specific embodiments of the compounds of formula (I)or any subgroup of compounds of formula (I) are those options, in which R1represents a

in which R10and R9chave the above values and, in particular, and R9crepresents hydrogen or C1-6-alkoxy (e.g. methoxy).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

in which R9ahas the values defined for any of the groups or subgroups of compounds of formula I, preferably R9arepresents ap-methoxyphenyl orp-vermeil; and R9brepresents hydrogen, methyl, halogen or trifluoromethyl.

Additional preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

in which R9arepresents methoxy, ethoxy or propoxy; and

R9brepresents hydrogen, fluorine, bromine, chlorine, iodine, methyl, ethyl, propyl or trifluoromethyl.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R1represents a

in which R9b/sup> represents hydrogen, halogen or trifluoromethyl.

Preferred among the embodiments of the subgroups of compounds in which R1represents the above radical (d-1)-(d-5), (e-1)to(e-3), (f-1)to(f-3), (g-1)to(g-2)are those compounds within these subgroups, in which L represents-O-.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which L represents a direct bond and R1selected from the group consisting of 1H-pyrrole, 1H-imidazole, 1H-pyrazole, furan, thiophene, oxazole, thiazole, isoxazol, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, phthalazine, cinoxacin, heatline, quinoline, cinnoline, 1H-pyrrolo[2,3]-b]pyridine, 1H-indole, 1H-benzoimidazole, 1H-indazole, 7H-Purina, benzothiazole, benzoxazole, 1H-imidazo[4,5-c]pyridine, 1H-imidazo[4,5-b]pyridine, 1,3-dehydrobenzperidol-2-it, 1,3-dehydrobenzperidol-2-thione, 2,3-dihydro-1H-indole, 1,3-dihydroindol-2-it, 1H-indole-2,3-dione, 1H-pyrrolo[2,3-c]pyridine, benzofuran, benzo[b]thiophene, benzo[d]isoxazol, benzo[d]isothiazole, 1N-quinoline-2-it, 1H-quinoline-4-it, 1H-hinzelin-4-it, 9H-carbazole and 1H-hinzelin-2-it, each of which is not necessarily Sames the n substituents R 1specified in the definition of compounds of formula (I) or any subgroup of compounds of formula (I).

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which L represents a direct bond, and R1selected from the group consisting of pyrrolidine, 4,5-dihydro-1H-pyrazole, pyrazolidine, imidazolidine-2-it, pyrrolidin-2-it, pyrrolidin-2,5-dione, piperidine-2,6-dione, piperidine-2-it, piperazine-2,6-dione, piperazine-2-it, piperazine, research, pyrazolidine-3-one, imidazolidin-2,4-dione, piperidine, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2,3,6-tetrahydropyridine, each of which is optionally substituted by substituents R1specified in the definition of compounds of formula (I) or any 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 L represents a direct bond, and R1represents an optionally substituted tetrazolyl, which is shown below:

in which Rlgrepresents hydrogen, C1-6-alkoxy, hydroxy, -NR4aR4b, -C(=O)R6, -SOPR7C3-7-cycloalkyl, aryl, Het, or C1-6-alkyl, long is correctly substituted C 3-7-cycloalkyl, aryl or Het;

Rlhrepresents hydrogen, -NR4aR4bC3-7-cycloalkyl, aryl, Het, or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het; and

R4a, R4b, R6and R7have the above values.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which L represents a direct bond, and R1represents an optionally substituted triazolyl, which is shown below:

in which each of R1iand Rljindependently selected from the group consisting of hydrogen, halogen, -C(=O)NR4aR4b, -C(=O)R6C3-7-cycloalkyl, aryl, Het and C1-6-alkyl, optionally substituted by-NR4aR4bor aryl; or alternatively, R1iand Rljtaken together with the carbon atoms to which they are attached, may form a cyclic fragment selected from the group consisting of aryl and Het.

More preferred substituents for R1when L is a direct bond, include pyridazine and its derivatives, which are shown below:

where R1k, R1land Rlmindependently selected from the group SOS is oasa from hydrogen, azido, halogen, C1-6-alkyl, -NR4aR4bC3-7-cycloalkyl, aryl and Het; or alternatively R1kand R1lor R1land Rlmtaken together with the carbon atoms to which they are attached, form a phenyl fragment, which, in turn, optionally may be substituted for azido, halogen, C1-6-alkyl, -NR4aR4bC3-7-cycloalkyl, aryl or Het.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which L represents-O-(C=O)-NR5a- or, in particular, in which L represents-O-(C=O)-NH-, and R1represents aryl, which is defined above; or R1represents phenyl, optionally substituted by 1, 2 or three substituents selected from the substituents mentioned as possible substituents of aryl radical, as in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I); specifically, R1represents a radical of the formula:

in which

R9erepresents hydrogen, C1-6-alkyl, polyhalogen-C1-6-alkyl or halogen;

R9frepresents-COOH, -C(=O)OR6a, halogen, Het or aryl; in which Het and aryl are defined here, the value, and

R6arepresents Neely C 1-6-alkyl, preferably R6arepresents methyl or ethyl;

In particular, R9ecan be a hydrogen, fluorine or trifluoromethyl.

In particular, R9fcan be a-COOC1-6-alkyl (for example, -C(O)OEt), phenyl, thiazolyl, 1-piperidinyl or 1-pyrazolyl, phenyl, piperidinyl and pyrazolidine group, optionally substituted C1-6-alkyl, in particular, stands.

Other embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which L represents-O-(C=O)-NR5a- or, in particular, in which L represents-O-(C=O)-NH-, and R1represents a radical of the formula:

in which R10and R11independently of one another represent hydrogen, halogen, hydroxy, nitro, cyano, carboxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkylsulphonyl, C1-6-alkoxycarbonyl, amino, azido, mercapto, C1-6-alkylthio, polyhalogen-C1-6is alkyl, aryl or Het; specifically, R10and R11independently of one another represent hydrogen, halogen, nitro, carboxyl, methyl, ethyl, isopropyl,tert-butyl, methoxy, ethoxy, isopropoxy,tert-butoxy, methylcarbamyl, ethylcarboxyl, isopropylcarbonate,tertthe bout is carbonyl, methoxycarbonyl, etoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, methylthio, ethylthio, isopropylthio,tert-butylthio, trifluoromethyl or cyano;

W represents aryl or Het, or W represents-COOH or-COOR6ain which R6arepresents a C1-6-alkyl, preferably methyl or ethyl.

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 phenyl, naphthyl (in particular, naphthas-1-yl or naphthas-2-yl), pyrrolyl (in particular, pyrrol-1-yl), pyridyl (in particular 3-pyridyl), pyrimidinyl (in particular, the pyrimidine-4-yl), pyridazinyl (in particular, pyridazin-3-yl and pyridazin-2-Il), 6-oxopyridine-1-yl, triazolyl (in particular, 1,2,3-triazolyl, 1,2,4-triazolyl, more specifically, 1,2,3-triazole-2-yl, 1,2,4-triazole-3-yl), tetrazolyl (in particular, tetrazol-1-yl, tetrazol-2-yl), pyrazolyl (in particular, the pyrazole-1-yl, pyrazole-3-yl), imidazolyl (in particular, imidazol-1-yl, imidazol-2-yl), thiazolyl (in particular, thiazol-2-yl), pyrrolidinyl (in particular, pyrrolidin-1-yl), piperidinyl (in particular, piperidine-1-yl), piperazinil (in particular, 1-piperazinil), 4-C1-6-alkylpiperazine (in particular, 4-C1-6-alkylpiperazine-1-yl, more specifically, 4-methylpiperazin-1-yl), furanyl (in particular furan-2-yl), thienyl (in particular,Tien-3-yl), morpholinyl (in particular, morpholine-4-yl); all of which optionally substituted by one or two substituents selected from C1-6-alkyl, polyhalogen-C1-6-alkyl or C1-6-alkoxycarbonyl.

In particular, W can represent phenyl, naphthas-1-yl, naphthas-2-yl, pyrrol-1-yl, 3-pyridyl, pyrimidine-4-yl, pyridazin-3-yl, pyridazin-2-yl, 6-oxopyridine-1-yl, 1,2,3-triazole-2-yl, 1,2,4-triazole-3-yl, tetrazol-1-yl, tetrazol-2-yl, pyrazole-1-yl, pyrazole-3-yl, imidazol-1-yl, imidazol-2-yl, thiazol-2-yl, pyrrolidin-1-yl, piperidine-1-yl, furan-2-yl, Tien-3-yl, morpholine-4-yl; all of which optionally substituted by one or two substituents selected from C1-6-alkyl, polyhalogen-C1-6-alkyl (such as trifluoromethyl) and (C1-6-alkoxycarbonyl.

Additional subgroup of compounds of formula (I) include those compounds of formula (I) or any specified here subgroup of compounds of formula (I)in which W represents thiazol-2-yl, substituted by one or two C1-6-alkilani, such as methyl, ethyl, isopropyl ortert-butyl. Preferred subgroups of compounds of formula (I) include those compounds of formula (I) or any specified here subgroup of compounds of formula (I)in which W is selected from the following structures:

Embodiments of the invention relate to joint the m formula (I) or any subgroup of compounds of formula (I), in which R10and R11independently of one another represent hydrogen, halogen, nitro, carboxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylsulphonyl, C1-6-alkoxycarbonyl, C1-6-alkylthio, polyhalogen-C1-6-alkyl, cyano, aryl or Het.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R10and R11independently of one another represent hydrogen, halogen, nitro, carboxyl, methyl, ethyl, isopropyl,tert-butyl, methoxy, ethoxy, isopropoxy,tert-butoxy, methylcarbamyl, ethylcarboxyl, isopropylcarbonate,tert-butylcarbamoyl, methoxycarbonyl, etoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, methylthio, ethylthio, isopropylthio,tert-butylthio, trifluoromethyl or cyano.

Preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which one of R10and R11represents hydrogen.

Preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which one of R10and R11represents halogen (in particular fluorine, trifluoromethyl, or C1-6-alkyl (particularly methyl). The other site is citicoline embodiments of the invention relate to compounds of formula (I), in which one of R10and R11represents halogen (in particular fluorine, trifluoromethyl or methyl and the other of R10and R11represents hydrogen.

Preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which one of R10and R11ispair-position relative to group W. the Additional preferred embodiments of relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which one of R10and R11represents halogen (in particular fluorine, trifluoromethyl or methyl and is inpair-position relative to group W; the other of R10and R11can have the meaning given above, or may be a hydrogen.

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

(a) R2is an-other4cin particular, in which R4crepresents a C1-6is alkyl, aryl, Het, C1-6-alkoxy, -O-aryl, or-O-Het;

(b) R2represents-OR5in particular, in which R5represents a C1-6-alkyl, such as methyl, ethyl ortert-butyl, and preferably in which R5is dored;

(c) R2represents-NHS(O)2R7in particular, in which R7represents a C1-6-alkyl, C3-7-cycloalkyl, optionally substituted C1-6the alkyl or aryl, for example, in which R7represents methyl, cyclopropyl, methylcyclopropyl or phenyl;

(d) R2represents-C(=O)OR5, -C(=O)R6, -C(=O)NR4aR4bor-C(=O)other4cin which R4a, R4b, R4c, R5or R6have the above specified values, and R2preferably represents-C(=O)other4cin which R4cis cyclopropyl;

(e) R2represents-NHS(=O)2NR4aR4bin particular, in which each R4aand R4bindependently represents hydrogen, C3-7-cycloalkyl or C1-6-alkyl, for example, NHS(=O)2N(C1-3-alkyl)2.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R2is an-other4cand R4cis a group Het selected from the

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R2is an-other4cThat is R 4crepresents a C1-6-alkyl, substituted-C(O)OR5.

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

(a) R3represents hydrogen;

(b) R3represents 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 attached by a single bond), and R3represents hydrogen;

(b) X represents C (X attached via a double bond) and R3represents a C1-6-alkyl, preferably methyl.

The compounds of formula (I) consist of three structural elements P1, P2, P3, each of which is limited to a wavy line. Structural element P1 further comprises an end portion P1'. The connection of the structural elements of P1 with P2 and optional P1 with P1'implies the formation of amide linkages. The connection of the structural elements of P3 with P2 involves acylation, when P2 is a pyrolidine ring. The connection of the structural elements P1 and P3 involves the formation of double bond. The connection of the structural elements P1, P1' P2 and P3 to obtain the compounds of formula (I) can be performed in any particular sequence. One of the stages involves cyclization, which is formed macrocycle. The compounds of formula (I-j) can be obtained from the compounds of formula (I-i) by restoring the double bond, for example, using hydrogen in the presence of a catalyst based on noble metals such as Rh, Pd or Pt.

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-b).

In one of the embodiments of the invention the compound (I-i) receive, forming a first amide bond between P2 and P1, linking the fragment P3 with P2, and then forming a double bond between P3 and P1 with concomitant cyclization to the macrocycle.

In a preferred embodiment of the invention the compound (I), in which the relationship between the carbon atoms C7and C8is a double bond, and which depict ablaut a 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 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(oisopropoxide metilen)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, hydrocarbons such as toluene. In a preferred embodiment of the invention, the metathesis reaction is carried out in toluene. 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-j), can be obtained from compounds of formula (I-i) by restoring the double bond C7-C8 in the compounds of formula (I-i). This recovery can be accomplished 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 mixtures thereof. Such solvents or mixtures of solvents can also be added water.

The group R2can prisoedinyat to the structural element P1 at any stage of the synthesis, that is, before or after the cyclization, or before or after the cyclization and recovery, as described above. The compounds of formula (I)in which R2represents-NR4AR4b-The other4c, -NHSOpNR4aR4b, -NR5aSOpR7, [such groups are collectively represented as-NR2-aR2-band the above mentioned compounds represented by formula (I-d-1)]can be obtained by joining the group R2to P1 through education between the two fragments of the amide bond. Similarly the compounds of formula (I)in which R2represents-OR5, that is, the compound (I-d-2), can be obtained by joining the group R2to P1 through education ester bonds. In one variant of the invention, the group-NR2-aR2-bor5introduced 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 as,N,N'-carbonyl diimidazol (CDI), EEDQ, IIDQ, EDCI or hexaphosphate benzotriazol-1 and the hydroxy- Tris-pyrrolidinone (commercially available under the trademark PyBOP®) in a solvent such as simple ether, for example THF, or a halogenated hydrocarbon, for example dichloromethane, chloroform, dichloroethane, followed by reaction with the desired amine (2b), preferably after the interaction (2a) with a condensing agent. Reaction (2a) with (2b) is preferably carried out in the presence of a base, such as trialkylamine, such as triethylamine or diisopropylethylamine, or in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Intermediate (2a) can also be translated into an activated form, for example in the activated form of the General formula G-CO-Z, in which Z represents halogen or the residue of an active complex ester, for example, Z represents alloctype, such as phenoxy,p-nitrophenoxy, Pantothenate, trichlorophenoxy, pentachlorophenoxy and the like; or Z may represent a remnant of the mixed anhydride. In one of the embodiments of the invention G-CO-Z is an acid chloride (G-CO-Cl) or a mixed anhydride (G-CO-O-CO-R or G-CO-O-CO-OR, in the latter case, R represents, for example, C1-4-alkyl, such as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, isobutyl or benzyl). The activated form of G-CO-Z is subjected to interaction with the desired (2b).

The activated carbon is acid (2a), as described for the above-mentioned reactions can lead to a response of the internal cyclization of the intermediate azlactone formula

in which the values of L, R1, R3n such as described above, and in which the stereogenic centers may have the above stereochemical configuration, for example, as in the compounds (I-a) or (I-b). Intermediate products (2a-1) can be isolated from the reaction mixture using conventional methodology, and selected intermediate product (2a-1) is then subjected to interaction with (2b), or the reaction mixture containing (2a-1), can optionally be subjected to interaction with (2b) without selection (2a-1). In one of the embodiments of the invention, when the reaction with a condensing agent is carried out in a water-immiscible solvent, the reaction mixture containing (2a-1), can be cleaned with water or slightly alkaline water in order to remove all water-soluble by-products. Thus obtained washed solution is then can be subjected to interaction with (2b) without additional purification stages. On the other hand, the allocation of intermediate products (2a-1) can provide some advantages in the sense that the isolated product after an optional additional purification can be subjected to interaction with (2b), while receiving fewer obecnych products and the pursuit of a more simple implementation of the response.

Intermediate (2a) can be associated with alcohol (2c) via the formation of ester. For example, (2a) and (2c) are subjected to interaction together with the removal of water or physically, for example by azeotropic removal of water, or chemically, using a dehydrating agent. Intermediate (2a) also can be converted to the activated form of G-CO-Z, such as the above-mentioned activated form, 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 or bicarbonate of an alkali metal such as sodium bicarbonate or potassium, or a tertiary amine, such as amines, mentioned here in connection with the reaction of formation of amides, in particular, in the presence of trialkylamine, such as triethylamine. Solvents that can be used in the reaction of formation of esters include ethers such as THF; halogenated hydrocarbons such as dichloromethane, CHCl3; hydrocarbons such as toluene; polar aprotic solvents such as DMF, DMSO, DMA; and the like solvents.

The compounds of formula (I)in which R2represents hydrogen, i.e. compounds I-d-3, can also be obtained as follows. First esters (I-d-2-a), which represent p megatokyo products of formula (I-d-2), where R6represents a C1-4-alkyl, reduced to the corresponding alcohols (3), for example, using complex metal hydrides, such as LiAlH4or NaBH4with subsequent oxidation reaction mild oxidizing agent, for example MnO2thus the intermediate products (I-d-3).

The compounds of formula (I) can also be obtained by reacting intermediate (4a) with intermediates (4b)-(4f), as briefly shown in the following reaction scheme, in which the various radicals have the above values and C1-4-Alk represents a C1-4-alcander:

Y in (4b) represents hydroxy or a group to delete, such as a halide, e.g. 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-arilirovaniya, and Y represents a group to delete. This reaction can be performed following the procedures described in the publication E.M. Smith and others (J.Med.Chem.(1988), 31, 875-885). 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 for established what I amide bond.

In a specific embodiment 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, in the presence of alkali of the alkali metal hydride such as LiH or sodium hydride 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 Y represents a suitable removable group which is mentioned above. Conversion (4a) to (I) with the use of this type of reaction O-arilirovaniya does not change the stereochemical configuration at the carbon atom bearing the hydroxy - or-L-R1group.

Alternative reaction (4a) with (4b) can also be carried out using the reaction of Mitsunobu (Mitsunobu, 1981,Sinthesis, January, 1-28; Rano and others,Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak and others,Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter and others,Tetrahedron Lett., 1994, 35, 27, 4705-4706). This reaction involves the manipulation of the intermediate product (4a) of the compound (4b), in which Y represents hydroxyl, in the presence of triphenylphosphine and an activating agent, such as dialkyldithiocarbamate, such as diet azodicarboxylate (DEAD), diisopropylsalicylic (DIAD) or the like by the reaction of Mitsunobu change the stereochemical configuration at the carbon atom bearing the hydroxy - or-L-R1group.

The compounds of formula (I)in which L represents a urethane group, L represents-O-C(=O)-NR5a-), can be obtained by reacting (4a) to (4c) or (4d) in the presence of the agent, to introduce a carbonyl group. The latter includes reagents such as phosgene or fossanova derivatives, such as carbonyldiimidazole (CDI). In one of the embodiments of the invention (4a) is subjected to interaction with phosgene, thereby providing the appropriate chloroformate, which when reacted with the amine R1-NH2or H-NR1R5Aensures carbamates, that is, L represents-OC(=O)NH -, or-OC(=O)NR5a-. Reaction chloroformiate with the amine is preferably carried out using the same solvents and bases, which are mentioned in connection with the formation of amide linkages, referred to hereinafter, in particular, solvents and bases mentioned in connection with the reaction of the compound (2a) from compound (2b). Concrete bases are carbonates or bicarbonates of alkali metals such as sodium bicarbonate or potassium, or tertiary amines, such as trialkylamine, such as triethylamine.

The reaction IPN is that (4a) with acid (4e) leads to ester derivative of the formula (4a), that is, L is a

-O-C(=O)-. For the formation of ester it is possible to apply standard procedures, in particular, the procedures described above in connection with the reaction of the compound (2a) from compound (2C). Such procedures, for example, may include converting the acid (4e) in the active form such as an acid anhydride or gelegenheid acid, for example the acid chloride (R1-C(=O)Cl), and the interaction of the active forms with alcohol (4a).

The compounds of formula (I)in which L represents a

-O-C1-4-alcander - can be obtained via the reaction of formation of simple ether (4f). Education simple ester can be accomplished by azeotropic removal of water or chemically, for example by reaction of Williamson.

Alternatively, to obtain the compounds of formula (I) first, to form amide bond between the structural elements P2 and P1 with the following combination of structural element P3 fragment P1 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 following combination of 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 associated with the R the tion cycle.

Structural elements P1 and P3 can be connected, and the so formed element P1-P3 can be associated with a structural element P2, and thus formed a sequence P1-P2-P3 then collisional by formation of a urethane or ester amide bond.

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, for example, 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 a combination of structural elements P2 and P1; before or after a combination of 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 viola is native, you can link together predecessors structural elements and modify 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 combinations of 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 a condensing agent, 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 SPO is about (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-DMAP. 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-dihydro shall inulin (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, 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 between 0°C and 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 that can be applied, arecoline, for example, in the publications 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 groups 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 or 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-methoxybenzyl the CSOs 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 carboxyl groups. 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 the build is completed microsillon 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 by using the reaction of formation of carbamate, on the basis of intermediates (5a), which is subjected to interaction with the reagent, forming a carbamate, a derivative of alkanol (5b), as outlined in the following reaction scheme.

Intermediates (5A) is subjected to interaction with the said reagent, to form a carbamate, using the same solvents and bases, which are used for the formation of amide linkages, as described above.

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.

Intermediate products (6a) is subjected to interaction with the reagent, forming a carbamate derived from alkenyl (5b), and this reaction leads to intermediate products (6c). With them off protection, in particular, by applying the above in the conditions of the reaction. For example, when PG1represents a benzoyl or substituted benzoyl, such a group is removed by reaction with alkali metal hydroxide (LiOH, NaOH, KOH), in particular, when PG1is a 4-nitrobenzoyl, using LiOH in aqueous medium containing water and a water-soluble organic solvent, such as alkanol (methanol, ethanol and THF. The resulting alcohol (6d) is subjected to interaction with intermediates (4b)-(4f), as described above for the reaction of (4a) with (4b)-(4f), and this reaction leads to intermediate products (1a).

The reaction of formation of carbamates can be done using different methods, in particular by reacting amines with alkylchlorosilanes; by reacting alcohols with carbamylcholine or isocyanates; using reactions involving metal complexes or agents for transferring acyl groups. See, for example, the publication T.W. Greene and P.G.M. Wuts "Protective Groups in Organic Synthesis"; 1999; Wiley and Sons, pp. 309-348. For the synthesis of carbamates from some of the parent compounds, including amines, it is possible to apply monoxide and certain catalysts based on metals. As catalysts it is possible to use metals, such as palladium, iridium, uranium, and platinum. You can also apply the methods in which for the synthesis of carbamates used carbon dioxide, and which is also described (see, n is the sample, publications Y. Yoshida and others,Bull.Chem.Soc.Japan1989, 62, 1534; and M. Aresta and others,Tetrahedron, 1991, 47, 9489).

One approach to obtain carbamates associated with the use of reagent

where W represents a removable group, such as halogen, in particular chlorine and bromine, or a group used in the method of activated esters for the formation of amide linkages, such as the above-mentioned groups, for example, phenoxy or substituted fenoxaprop, such asp-chlorine - andp-nitrophenoxy, trichlorophenoxy, pentachlorophenoxy, N-hydroxysuccinimidyl, etc. Reagent (7) can be formed from alkenol (5b) and phosgene, forming alkenylboronic, or by transfer of chlorine in the second case, the reagents (7), in which W is a W1where the latter represents any of the activated ester fragments, such as the above-mentioned fragments, hereinafter referred to as the reagents (7a). Reagents (7) is subjected to interaction with (5a) or (6a), while receiving (1a-1) or (6c).

Reagents (7a) can also be obtained by reacting alkenols (5b) with carbonates W1-CO-W1such as, for example, bisphenol-a, bis(substituted phenol)orbis-N-hydroxysuccinimidyl:

Reagents (7a) can also be obtained from chloroformiate Cl-CO-W1follow the way:

The above reaction receipt reagents (7a) can be performed in the presence of a suitable base and in a reaction inert solvent, such as bases and solvents mentioned above for the synthesis of amide bonds, in particular triethylamine and dichloromethane.

Intermediate products of the formula (1a), in which X represents C [mentioned intermediates represented by formula (1a-2)]can be obtained by using the reaction of formation of ester, based on intermediate products (8a), which is subjected to interaction with alkanols (5b), as shown in the following reaction scheme, and applying the conditions for the reaction of obtaining esters, such as reaction conditions described above for the reaction of (4a) to (4e).

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: the formation of ester, as in the reaction of (4a) to (4e), remove group PG1as described in protective groups, and the introduction of R1as in the reaction of (4a) with reagents (4b)-(4f).

Intermediate products of the formula (2a) can be obtained by using the initial cyclization of OTKRYTOGO the complex ester (9a) to macrocyclic complex ester (9b), which, in turn, converted (2a) as follows:

L-R1has the above meaning, and 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) is a metathesis reaction and is carried out as described above. Group PG2remove the following procedures, as described above. When PG1is a complex C1-4-alkilany ether, it is removed using alkaline hydrolysis, for example, preferably NaOH or LiOH in aqueous solvent, for example, mixtures

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 is selectively removed with respect to PG2. PG2can represent, for example, a complex of methyl or ethyl ester, which can be removed when processing piroxicam alkali metal in the aquatic environment, in which case PG1tert-butyl or benzyl. PG2can be a difficulttert-butyl ether removed in slightly acidic conditions, or PG1can be a difficult benzyl ethers removed using a strong acid or catalytic hydrogenation, in the last two cases PG1represents, for example, compound benzoin ether, such as a complex 4-nitrobenzoyl ether.

First, intermediate products (10a) is subjected to cyclization to complex macrocyclic ethers (10b), with the latter disable the protection by removing group PG1with the formation of (10c), which is subjected to interaction with intermediates (4b)-(4f) with the formation of intermediate products (9b) and the subsequent destruction of carboxyl-protective group PG2which leads to intermediate products (2a). The cyclization, unprotect PG1and PG2and the reaction mix with (4b)-(4f) is carried out, as described above.

Group R2you 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 R2represents-NR2-aR2-b(specified above), or R2representing-OR6:

The diagram above L and PG2have Azania above values, and L1is a group P3

in whichnhas the above meaning, and when X represents N, L1may also represent a nitrogen protective group (PG, as described above), and when X represents C, L1can also represent a group-COOPG2ain which the group PG2ais carboxyl-protective group, such as PG2but 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)correspond to intermediate products (1a) and can be processed additionally, as indicated above.

The combination of structural elements P1 and P2

Structural elements P1 and P2 are combined with the use of the reaction of formation of amide, following 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

-L-R1that is listed above. When I the th of the following reaction schemes L 3represents 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 to a group-L-R1.

In the procedure described above in the diagram, cyclopropylamine (12b) or (12c) is associated with acid-function (group) structural element P2 (12a) with the formation of amide linkages, 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

HN-R2R2-b(2b) or with HOR6(2c), as described above, again gives intermediate products (12e), in which-COR2represent 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 on the TES 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-L-R1.

In one of the embodiments of the invention L2represents a group (b), and these reactions involve the combination of P1 with P2-P3, 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 2representing PG.

In this way the structural elements of P2, in which X represents C, which are a cyclopentane or cyclopentenone derivatives, can be connected with the structural elements P1, as summarized in the following diagram, in which R2, R3L3, PG2and PG2aare carboxyl-protective group. Group PG2ausually chosen so that it can be removed selectively with respect to the group PG2. 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, when X represents C, R3represents H, and if X and the carbon atom carrying the R3connected by a single bond (P2 represents a cyclopentane fragment), taken together PG2aand L3form a bond, and the structural element P2 is represented by the formula:

Bicyclic acid (14a) is subjected to interaction with (12b) or (12c)in the same way as described above, obtaining (14b) and (14c), respectively, in which the lactone ring opens, giving intermediate products (14c) and (14e). The disclosure of the lactone can be done using proceduredata esters, for example, 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 the reaction of formation of carbamate and following the above procedures for a combination of (5a) with (5b). General procedure for combining the structural elements of 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 the connection (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).

General procedure a combination of structural elements P3 with elements of P2 or P2-P1, where P2 is a cyclopent is or cyclopenten, shown in the following diagram.

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

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 field of intermediate products. Some of these syntheses are described in more detail below.

The synthesis of the structural elements P2

Structural elements P2 contain or pyrolidine, cyclopentane, or cyclopentenone fragment substituted by a group-L-R1.

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 reductant type blogId the IDA sodium in a solvent, such as methanol, followed by hydrolysis of esters and the final closure of the cycle before the bicyclic lactone (17b) using 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 monopersulfate to group-OPG 1or to the group-L-R1. The products obtained by removing group PG2represent intermediate products (17g), and (17i), 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-L-R1that change stereochemistry, 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) using reaction combinations that correspond to the reactions of a combination of (13a) or (16a) with the same elements P1, applying similar conditions. The subsequent introduction of the substituent-L-R1as described above, will follow them removing kikoteseitol group PG 2leads to intermediate products (8a-1), which are a subclass of intermediate products (8a) 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 the publication 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 of Cyclopentanol (19b).

Unsaturated structural element P2, in which R3may also be different from hydrogen, can be obtained, as shown in the following scheme.

Oxidation them is the existing sales 3-methyl-3-butene-1-ol (20a), in particular, using an oxidant type Harrogate 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 stereospeakers epoxidation (20g), using 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..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-L-R1you can enter 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 introduce the group R1and 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 is to combine the structural elements of P2 that does not contain the Deputy

-L-R1each P1 and P3, and add a group-L-R1either before or after the formation of the macrocycle. The last procedure fragments P2 contain the hydroxy-group, which can be protected by using a hydroxy-protective group PG1.

Group-L-R1you can enter in the structural elements of P2 by reacting hydroxy-substituted intermediates (21a) or (21b) with intermediates (4b)-(4f) is a s to as described above for the synthesis of (I)coming from (4a). Such reactions are presented below in schemes where the value of L2above and L5and L5aindependently from each other represent hydroxy, carboxyl-protective group-PG2or PG2aor L5may also represent a group of P1, such as the above group (d) or (e), or L5amay also represent a group R3, such as the above group (b). Group-PG2or

-PG2aabove. 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 compound (21a) L2is a PG, and L5represents-OPG2or in connection (21d) L5arepresents-OPG2and L5represents-OPG2and group PG2delete, as described above.

In another embodiment of the invention, the group L2represents BOC, L5represents hydroxy and the source material (21a is a commercially available BOC-hydroxyproline or any of its stereoisomeric form, for example BOC-L-hydroxyproline, in particular,TRANS-isomer of the latter. When L5in the compound (21b) is carboxyl-protective group can be removed by following the above procedures, obtaining (s). In yet another embodiment of the invention PG connection (21b-1) represents Boc, and PG2represents the lower complex alkilany ether, in particular, difficult methyl or ethyl ester. Hydrolysis last of ester to acid can be performed using standard procedures, for example, by acid hydrolysis using hydrochloric acid in methanol or carrying out the 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 (21d) transform to (e), which, when L5and L5arepresent-PG2or PG2acan be converted to the corresponding acids (21f) by removing group PG2. Remove PG2afrom (a-1) leads to a similar intermediate products.

Intermediates (4b), (4C), (4d) and (4f), which are known in the connections pane, you can obtain the following well-known in this area methods using known starting materials.

Intermediate the products (4b), which are derivatives of quinoline, can be obtained, as shown in the following scheme. Such intermediates (4b), for example, are products in which R1is a radical (d-1), (d-2), (d-3), (d-4), (d-4-a), (d-5) or (d-5-a), above.

The acylation according to the Friedel-Crafts 3-methoxyaniline (22a), a commercially available or produced using known in this field procedures, using Alliluyeva agent, such as acetylchloride or the like, in the presence of one or more Lewis acids, such as trichloride boron or trichloride aluminum, solvent type dichloromethane provides the product (22b). The combination of (22b) with 4-isopropylthiazole-2-carboxylic acid (22c), preferably in basic conditions, such as pyridine, in the presence of an activating agent for the carboxylate groups, such as POCl3with the subsequent closure ring and dehydration in the basic conditions of typetert-butyl potassiumtert-butanol leads to a quinoline derivative (4b-1). The latter can be converted to (4b-2), in which LG represents a removable group, for example, through reaction (4b-1) with a halogenation agent, such as phosphorylchloride or the like, or through reaction (4b-1) arylsulfonamides, for example mozillateam.

Substituted anilines (22a) are in p is adage, or you can get them from appropriately substituted benzoic acid (23a), which is subjected to interaction with diphenylphosphorylacetate at elevated temperature and then treated with C1-4-alkanols, in particular,tert-butanol, while receiving C1-4-alkoxycarbonyl, such as compound (23b). Removing protection from a compound (23b) leads to substituted anilines (22a).

Alternatively, the substituted anilines (22a) can be obtained from the corresponding substituted nitrobenzenes when restoring the last elemental zinc, tin or iron in the presence of acid.

In the above synthesis can be applied to various carboxylic acids with the General structure (22c). Such acids are commercially available or can be obtained by using known in this field procedures. An example of obtaining derivatives of 2-(substituted)aminocarboxylate (22c-1), according to the procedure described in the publication Berdikhina and others,Chem.Heterocycl.Compd.(Engl. Transl.) (1991), 427-433, shown in the following reaction scheme, which illustrates receiving 2-carboxy-4-isopropylthiazole (22c-1):

Atitikimas (24a) is subjected to interaction with β-bromoethanol (24b) with the formation of ester thiazolecarboxamide acid (24c), which is hydrolyzed to the corresponding acid (22c-1). SL is iny ethyl ester in intermediate products, you can substitute other carboxyl-protective groups PG 2that stated above. In the above scheme, Rlfhas the above meaning and, in particular, represents a C1-4-alkyl, more specifically, isopropyl.

Bratton (24b) can be obtained from 3-methylbutane-2-it (MIK) with similitude agent (such as TMSCl) in the presence of a suitable base (in particular, LiHMDS) and bromine.

Intermediate products (22b)containing methoxy-Deputy [mentioned intermediates represented by formula (22b-1)]can be obtained as described in the publication by Brown and others,J.Med.Chem.1989, 32, 807-826, or as shown in the following diagram.

Source materials, ethylacetoacetate and ethoxymethylenemalononitrile, which are commercially available, are subjected to interaction in the presence of a suitable base, such as sodium ethylate, and solvent, such as ethanol, etc. This reaction leads to the intermediate product (25a). The latter is hydrolyzed, for example, using a base such as an alkali metal hydroxide, for example NaOH or LiOH, in a suitable solvent, such as ethanol/water to obtain (25b). Decarboxylation of the intermediate product (25b) to intermediate (25c) is carried out at elevated temperature, preferably in the presence of a basic solvent, such as quinoline. Methylation of the intermediate product (25c), and the hour of the activity, using meteorologi agent, such as MeI, in the presence of a suitable base (e.g., K2CO3) in a suitable solvent (such as DMF and the like) leads to (25d). The latter is subjected to interaction with a Grignard reagent such as MeMgBr in the presence of a suitable solvent (such as THF), followed by hydrolysis, for example using aqueous HCl solution, thus obtaining the intermediate product (22b-1).

Synthesis of additional carboxylic acid (22c), in particular, substituted aminothiazoline acid (22c-2)illustrated below:

The thiourea (-26 C) with different substituents R4athat, in particular, represents a C1-6-alkyl, can be created with the cooperation of the appropriate amine (26a) withtert-butylstyrene in the presence of a base type diisopropylethylamine in solvent type dichloromethane followed by removal oftert-butilkoi group in acidic conditions. Subsequent condensation of a derivative of thiourea (-26 C) with 3-bronirovochnoy acid provides diazocarbonyl acid (22c-2).

Compounds of the present invention or structural elements P2, in which heterocyclic group, R1attached via a ring nitrogen atom directly to pyrolidine, cyclopentane is or cyclopentenone ring, that is, L is a direct relationship in the General formula (I)can be obtained, for example, through a substitution reaction in which a suitable removable group on pyrolidine ring substituted nitrogen-containing cyclic group. This procedure can be done at the stage of creation of the structural elements or after the merger and/or cyclization of the structural elements. When one of the procedures derived pyrrolidine (4a), (XI), (XVI), (XXV) or any intermediate product containing the group L3that represents hydroxy, subjected to interaction with a reagent that introduces the group that you want, such as halogenation agent, such as phosphorylchloride or the like, or with arylsulfonamides, for example mozillateam. Educated at this intermediate product is then subjected to the interaction with the heterocycle containing a ring nitrogen atom substituted with hydrogen (N-H).

The compounds of formula (I)in which L represents a direct bond and R1represents a ring system bonded to pyrrolidinium fragment via a carbon atom, can be obtained by creating a ring, based on the hydroxy-compounds. This can be done either at the stage of creation of the structural elements, or after merging and/or cyclization of the structural elements. For example, hydrox the function can be converted into a group to delete, which, in turn, substituted with cyano. This cyano, in turn, can be further converted to the desired heterocycles. For example, compounds in which the derived tetrazole attached through a carbon atom tetrazole ring, easy to get by creating tetrazole fragment directly on the predecessor of the pyrolidine ring. This can be achieved, for example, by condensation entered thus ceanography with subsequent interaction with azide reagent of the type of sodium azide. Derivatives of triazole can also be created directly on the predecessor of the nitrogen-containing ring, for example, by converting the hydroxy-group of the precursor nitrogen-containing ring of the azide group with subsequent cycloaddition reaction of 3+2 obtained with a suitable azide alkhanovym derived.

Structurally different tetrazole for use in the above reactions for the introduction of the group R1can be obtained by reacting commercially available nitrile compounds with sodium azide. Derivatives of triazole can be obtained by reacting compounds of alkyne and trimethylsilane. Applicable connection alkynes either available commercially, or they can be obtained, for example, according to the reaction Sonogashira, i.e. the reaction of the primary alkyne, aring is LoginID and triethylamine in the presence of PdCl 2(PPh)3and CuI, as described, for example, in the publication A. Elangovan, Y.-H. Wang, T.-I. Ho,Org. Lett, 2003, 5, 1841-1844. Heterocyclic Deputy, when he joins a structural element P2, also can be modified either before or after combination of the structural element P2 with other structural elements.

An additional alternative to obtain compounds in which L is a bond, and R1represents an optionally substituted heterocycle, can be found, for example, in the application WO 2004/072243.

Structural elements of P2, in which L represents a urethane group, L represents-O-C(=O)-NR4a-)can be obtained by using the reaction of (4a), (6a) or cyclopentane analogues, for example, (5a), with phosgene, while receiving appropriate chloroformic that when interacting with the amine R1-NH2or H-NR1R4Aprovides carbamates, that is, L represents-OC(O)NH -, or-OC(=O)NR4a-whereas the reaction of alcohols (4a), (6a) or (5a) with allermuir agent type anhydride or gelegenheid acid, for example, the acid chloride (R1-C(=O)C1), provides esters, that is, L represents-O-C(=O)-. Preferably the reaction of chloroformate with the amine and acid chloride with the alcohol (4a), (6a) or (5a) is carried out in the presence of a base such as a carbonate or bicarbonate of alkali metal is, for example sodium bicarbonate, or in the presence of trialkylamine, such as triethylamine.

Intermediates (4b), which are derivatives of isoquinoline, can be obtained by applying known in this field procedures. For example, in U.S. patent 2005/0143316 described various methods of synthesis of isoquinolines in the form of intermediate products R1HE or R1-LG. The technique of synthesis of isoquinolines such is described in the publication N. Briet and others,Tetrahedron, 2002, 5761 and below, where R1a, R1band R1b'are substituents on the isoquinoline fragment having the values listed here for substituents on the group R1.

Derivatives of cinnamic acid (27b) converts to 1-chloroisoquinoline according to the three-stage method. The resulting chloroisoquinoline can then be associated with derivatives described here hydroxypyrrolidine, hydroxycyclopent or hydroxycyclopent. In the first stage, the carboxyl group of cinnamic acid (27b) activate, for example, the processing of C1-6-alkylphosphonates (in particular methyl - or etelcharge.com) in the presence of a base. Received mixed anhydrides is then treated with sodium azide, while receiving allside (27c). For the formation of arylazides of carboxylic acids suitable some other way is, for example, the carboxylic acid can be treated with diphenylphosphorylacetate (DPPA) in an aprotic solvent such as methylene chloride, in the presence of a base. At the next stage acylated (27c) is converted into the corresponding isohedron (27d) by heating utilised in a solvent with a high boiling point, such as a simple diphenyl ether. Source derivatives of cinnamic acid are commercially available, or can be obtained from the relevant benzaldehyde (27a) by direct condensation with malonic acid or their derivatives, or by using the Wittig reaction. Intermediate ishinomori (27d) can be converted into the corresponding 1-chloroisoquinoline processing halogenation agent such as phosphorus oxychloride.

Group R1that represent isoquinolines, can also be obtained by following the procedures described in the publication K. Hirao, R. Tsuchiya, Y. Yano, H. Tsue,Heterocycles42(1) 1996, 415-422.

An alternative method of synthesis of the isoquinoline ring system is the procedure of Orange-Fritsch. This method begins with the conversion of benzaldehyde derivative (28a) in the functionalized Imin (28b), which is then converted into an isoquinoline ring system during treatment with acid at elevated temperature. This method, in particular, is applicable to obtain sochinyennykh intermediate products, which are substituted at the C8 position, indicated by an asterisk. Intermediate isoquinolines (28c) can be converted to the corresponding 1-chlorinolysis (28e) using the two-stage method. The first stage involves the formation ofN-oxide, isoquinoline (28d) by processing isoquinoline (28c) peroxide, such asmeta-chlormadinone acid, in a suitable solvent such as dichloromethane. The intermediate compound (28d) transform to the corresponding 1-chloroisoquinoline when processing a halogenation agent such as phosphorus oxychloride.

Another method of synthesis of the isoquinoline ring system shown in the diagram below.

In this way anionic form derivedortho-alkylbenzene (29a) are treated as a strong base, such astert-utility, in a solvent such as THF, and then condense with the derived nitrile, while receiving isoquinoline (29b). The latter can be converted into the corresponding 1-chloroisoquinoline using the methods described above. R'and R" in the compound (29a) are alkyl groups, in particular, C1-4is an alkyl group such as methyl or ethyl.

The following diagram illustrates an additional method for the synthesis of isoquinolines.

The intermediate compound (29a) diprotodon the Ute, using a strong base as described above. R'and R" have the above values. The obtained intermediate anion condense complex ether (30a), while receiving the intermediate ketone (30b). In the following reaction last intermediate product (30b) is subjected to interaction with ammonia or ammonium salt, such as ammonium acetate at elevated temperatures, which leads to the formation isohedron (29b).

One additional way of getting isoquinolines illustrated in the following reaction scheme.

In the first stage of this method is derivedortho-alkilammonia (31a) is subjected to processing in conditions of deprotonation (for example,Deut-utility, THF)and the resulting anion is condensed with a derivative of an activated carboxylic acid such as amide Weinrebe (31b). The resulting ketamin (31c) is converted into isoquinoline (31d) by condensation with ammonium acetate at elevated temperatures. The isoquinolines can be converted to the corresponding 1-chloroisoquinoline using the methods described here.

Described here isoquinolines, either as such or included in hydroxypyrrolidine, hydroxycyclopent or hydroxycyclopent fragments of compounds of formula (I) or any of these intermediate products is mswb, can be further functionalized. An example of such functionalization is illustrated below.

The diagram above illustrates the conversion of 1-chloro-6-vtoritchnaia in the corresponding 1-chloro-6-C1-6-alkoxyethanol fragment (32b) when processing compounds (32a) a sodium alcoholate or potassium hydroxide in an alcohol solvent, from which the alcoholate. L6the diagram above represents a halogen or a group

R the diagram above represents a C1-6-alkyl, and LG represents a group to delete. In one of the embodiments LG represents fluorine. L7and L8represent various substituents that can be attached to specified provisions of the fragment P2, in particular, groups such as OL5or L8may represent a group P1, and L7can be a group P3, or L7and L8taken together, may form the remainder of the macrocyclic ring system of the compounds of formula (I).

The following diagram shows an example of modification of isoquinolines using Suzuki reactions. Such combinations can be used for functionalization of isoquinoline in each position of the ring system, provided that the said ring fitting the m way activated or functionalized, for example, using chlorine.

The sequence starts with 1-chloroisoquinoline (33a), which when processed by a peroxide, such asmeta-chlormadinone acid, convert to the appropriateN-oxide (33b). Recent convert the intermediate product to the corresponding 1,3-dichlorethylene (33c) when processing a halogenation agent such as phosphorus oxychloride. The intermediate product (33c) can be associated with the intermediate product (33d), where L6is a group PG, when X represents N, or L6represents a group-COOPG2when X represents C, applying the described methods for the introduction of a-L-R1groups and thus the intermediate product (33e). The intermediate product (33e) derivateservlet, using the reaction mix by Suzuki with arylboronic acid in the presence of palladium catalyst and a base in a solvent such as THF, toluene, or a dipolar aprotic solvent such as DMF, while receiving the intermediate C3-allisonian (15f). In such ways of combination can also be used heteroarylboronic acid to obtain C3-heteroarylboronic.

The reaction of a combination of Suzuki systems isoquinolines with aryl or heteroaryl groups can also be used on posledney synthesis step in obtaining compounds of formula (I). Isoquinoline ring system can also be functionalitywith using other catalyzed by palladium reactions such as reaction of a combination of Hake, Sonogashira or Steele, as illustrated, for example in U.S. patent 2005/1043316.

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.

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 (34a) 1,4-dehalogenation in the presence of a base to receive a connection (34b), 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. Temporarily the diversified products (12b) or (12b-l) can be associated with suitable derivatives of Proline, as explained above.

The introduction of the N-protective group PG and deleting PG2leads to cyclopropylmagnesium (35a), which convert to amides (12c-1) or esters (12c-2), which are subgroups of intermediate products (12c), as outlined in the following reaction scheme, in which R2-a, R2-band PG stated above.

The reaction of (35a) with the amine (2b) is the procedure of formation of the amide. A similar reaction with (2C) is a reaction formation of ester. Both the reaction can be performed by following the above procedures. This reaction leads to intermediate products (35b) and (35C), 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). Raw materials (35a) 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 (35a) 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 and subsequent interaction with (2b) in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DB). Alternative 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 suitable derivatives of Proline, as described above.

Structural elements P1 to obtain the compounds of General formula (I)in which R2represents-OR5or-NR4aR4byou can get by interacting amino acids (35a) with a suitable alcohol or amine, respectively, under standard conditions, intended for the formation of ester or amide.

The synthesis of the structural elements P3

Structural elements of P3 are commercially available, or they can be created according to the methods known to the expert in this field.

The combination of the respective structural element P3 with fragments P2-P or P2 described above. A combination of structural element P3 with fragments of P1 or P1-P2 can be achieved through the formation of a double bond in such reactions as synthesis of Wittig or, preferably, the metathesis reaction of olefins described above.

The compounds of formula (I) can be converted to other the other, following well-known in this field transformation reactions of functional groups. For example, the amino group can be N-alkilirovanii, nitro - restore 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, e.g. sodium peroxide, potassium peroxide; 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 coal is hydrogens, for example 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 with a suitable 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 respective stereochemical the pure isomeric forms of the appropriate starting materials, provided that the reaction is stereospecific. 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 effect on viral infection, in order to stabilize or reduce viral infection and, 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 is ormula (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 pharmaceutical compositions 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, SMA is key, binders, dezintegriruetsja agents, etc. in the case of powders, pills, capsules and tablets. Thanks to the convenience of their administration tablets and capsules are the most preferred standard dosage forms for oral administration, in which case, of course, are for 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 the appropriate liquid carriers, 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 Autry is telego effects 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. Compounds of the present 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 number of active ingred the enta, designed 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 and the like, and 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 progressive liver fibrosis, 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 exhibits activity against mutated strains of HCV. In addition, many of the compounds of the present invention have favorable pharmacokinetic profile and the properties 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 the publication 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, are 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 scaling the 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, the compounds of formula (I) or any subgroup, their prodrugs,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 podgroup which 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, in particular 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 method includes introducing an effective amount of the antiviral compounds of formula (I), which is indicated 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 (a) and (b) optionally another anti-virus against HCV compound, in the form of 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 WO 02/18369 (see, for example, lines 9-22 on page 273, and from line 4 on page 274 to line 11 on page 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 applications WO 98/17679, WO 00/056331 (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); Dicference; 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-interferon and the like, such as Intron-A®, Roferon-A®, Canferon-A300®, Advaferon®, Infergen®, Humoferon®, Sumiferon MP®, Alfaferone®, IFN-beta®, Feron® and the like; compounds of interferon, derivateservlet (peg) polyethylene glycol, 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 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 antivirus the e means include, but 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. patent No. 5807876, 6498178, 6344465, 6054472, in applications WO 97/40028, WO 98/40381, WO 00/56331, mycofenolate acid and its derivatives, including, but not limited to, VX-950, the drug erimepodib (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, as well as therapies based on antibodies directed against HCV-epitopes, small interfering RNA (siRNA), ribozymes, DNA enzymes, antisense RNA, small molecules antagonists, for example, the 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, when referred to the drug used for combination therapy day is; the 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 HIV inhibitors 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 its pharmaceutically acceptable salt.

Connection ritonavir and its pharmaceutically acceptable salts and methods for their preparation are described in the application WO 94/14436. 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 applications WO 95/07696 and WO 95/09614. 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 farmacevtichesky acceptable salt; further comprises 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 involves the systematic introduction of 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 variant new implementation 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 tools 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, of the comb is nation 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 individual 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 infusion is to him the invention contains an amount 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 when the inhibitor of the 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 additives, for at least one headlight is cokinetics variables 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 stationary state, i.e. 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 enter the human the ku according to the schemes of reception, 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 may be 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 weight 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 about 1:10, and more specifically, from about 8:1 to about 1:8. Also applicable weight ratio 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 weight ratio in which hibitor NS3/4a protease of HCV of formula (I) R is in the range from about 1:1 to about 15:1, usually from about 1:1 to about 10:1, and more specifically, from about 1:1 to about 8:1. Also applicable weight ratio of 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 component or pharmaceutical agent that causes a 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, therapeutically effective the e amount of the 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 at appropriate intervals throughout the day. The said sub-doses can be obtained in a standard dosage forms, for 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 as the subject of the a and/or depending on the doctor's evaluation, 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 amount per dose in a joint introduction once or twice per day approximately from 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 up to approximately 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 the compound of 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-is noteasy HCV; and the packaging material contains a label indicating 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 reagent in a test or tests for 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

Synthesis of 1,3-dichloro-6-methox is of isoquinoline ( 6)

Stage A

To a suspension of 3-methoxycatechol acid1(49,90 g, 280 mmol) in acetone (225 ml) at 0°C under nitrogen atmosphere was added triethylamine (80,5 ml, 578 mmol). After 10 min at 0°C was added dropwise ethylchloride (46,50 g, 429 mmol), at the same time maintaining the temperature at 0°C. After 1 hour at 0°C was slowly added a solution of sodium azide (27,56 g, 424 mmol) in water (200 ml), then the reaction mixture was allowed to warm to room temperature. After 16 hours the reaction mixture was poured into water (500 ml) and evaporated acetone. The residue was extracted with toluene, thus obtaining a solution of the product2, which was used as such in the next stage.

Stage

A solution of the product2in toluene with the previous stage was added dropwise to the heated at 190°C the solution difenilmetana (340 ml) and tributylamine (150 ml). Toluene immediately drove by the apparatus of the Dean-stark. After complete addition, the temperature of the reaction mixture was raised to 210°C within 2 hours. After cooling, the precipitated precipitated product was collected with filtration and washed with heptane, while receiving 49,1 g (29%) of the desired product3in the form of a white powder: m/z = 176 (M+H)+;

1H-NMR (CDCl3): 8,33 (l,J=the 8.9 Hz, 1H), 7,13 (d, J=7,15 Hz, 1H), 7,07 (DD,J=8,9 Hz, 2.5 Hz, 1H), 6.90 to (q,J=2,5 Hz, 1H),6.48 in (q, J=7,15 Hz, 1H), 3,98 (s, 3H).

Stage

The product3(10,00 g, 57 mmol) was slowly added phosphorus oxychloride (25 ml) and the resulting mixture was heated with gentle boiling under reflux for 3 hours. After completion of the reaction of phosphorus oxychloride is evaporated. The residue was poured into cold water with ice (40 ml) and brought to pH 10 with NaOH solution in water (50 wt.%). The mixture was extracted with CHCl3, washed with saturated salt solution, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (CH2Cl2), while receiving 8,42 g (76%) of the desired product4in the form of a yellow solid: m/z = 194 (M+H)+;

1H-NMR (CDCl3): 8,21 (l,J=9,3 Hz, 1H); 8,18 (l,J=5.7 Hz, 1H); 7,47 (l,J=5.6 Hz, 1H); 7,28 (DD,J=9,3 Hz, 2.5 Hz, 1H); 7,06 (l,J=the 2.5 Hz, 1H), 3,98 (s, 3H).

Stage D

Metaglidasen acid (6,41 g, 28.6 mmol) was added in small portions at 0°C to a solution of the product4(2.70 g, a 13.9 mmol) in CH2Cl2(10 ml). After 30 min at 0°C the reaction mixture was heated to room temperature within 12 hours. Then the reaction mixture was distributed between 1N NaOH solution and CH2Cl2and sequentially washed with 1N NaOH solution and saturated salt solution. The organic layer was dried (Na2 SO4), filtered and evaporated, thus obtaining 1,89 g (64%) of the desired product5as an orange solid: m/z = 209,9 (M+H)+

Stage E

A solution of the product5(1.86 g, 8,86 mmol) in phosphorus oxychloride (18 ml) was heated at the boil under reflux for 3 hours. Then phosphorus oxychloride is evaporated in vacuum. The residue was poured into cold water with ice (50 ml) and the pH was brought to 10 with a solution of 50 wt.% NaOH in water. The mixture was extracted with CHCl3, the organic layer was washed with saturated salt solution, dried (Na2SO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2), while receiving 350 mg (17%) of the desired product6in the form of a yellow solid: m/z = 227,9 (M+H)+;

1H-NMR (CDCl3): 8,16 (l,J=9,3 Hz, 1H), 7,50 (s, 1H), 7,25 (DD,J=9,3 Hz, 2.5 Hz, 1H), 6,98 (l,J=2,5 Hz, 1H), 3,98 (s, 3H).

Synthesis of 4-bromo-1-hydroxy-6-methoxyethylamine (7)

To a solution of the product3(of 2.06 g of 11.8 mmol) in DMF (40 ml) was addedN-bromosuccinimide (2,33 g of 14.3 mmol). The resulting mixture was stirred at room temperature overnight. Then the DMF is evaporated and to the residue was added CH2Cl2. The resulting suspension was heated at 45°C for 15 minutes. White solid vases which was filtered and washed simple isopropyl ether, while receiving 2,07 g (69%) of the desired product7: m/z=over 253.7 (M+H)+;

1H NMR (DMSO d6):to 8.14 (d,J=8,8 Hz, 1H); 7,52 (s, 1H), 7,17 (DD,J=8,8 Hz, 2.5 Hz, 1H), 7,11 (l,J=2.4 Hz, 1H), 3,83 (s, 3H).

SynthesisO-(Gex-5-enyl)-O-(Succinimidyl)carbonate (8)

A mixture of Gex-5-enol (5,00 g to 49.9 mmol), disuccinimidyl (13,08 g of 51.1 mmol) and triethylamine (6.50 g, 64,2 mmol) in CH2Cl2(50 ml) was stirred at room temperature overnight. After completion, the reaction mixture was poured on ice, the organic layer was washed with water, dried (Na2SO4), filtered and evaporated, thus obtaining of 10.25 g (85%) of product8in the form of a colorless oil. m/z = 242 (M+H)+;

1H NMR (CDCl3): of 5.82-5,73 (m, 1H), 5,07-4,96 (m, 2H), 4,33 (t,J=6.3 Hz, 6.6 Hz, 2H), 2,85 (s, 4H), 2,15-to 2.06 (m, 2H), 1,82-1,72 (m, 2H), 1.56 to about 1.47 (m, 2H).

SynthesisO-(Gex-5-enyl)-O-(4-nitrophenyl)carbonate (9)

With stirring to a solution of Gex-5-enol (0.50 g, 5.0 mmol) in pyridine (1.2 ml, 15 mmol) and dichloromethane (20 ml) at 0°C was added 4-nitrophenolate (1.1 g, 5.5 mmol) in one portion. After stirring for 1.5 hours at room temperature the reaction mixture was diluted with dichloromethane (10 ml) and successively washed with aqueous 10% citric acid solution (3×15 ml) and aqueous saturated RA is tworoom of sodium bicarbonate (3×15 ml), then was dried (Na2SO4), filtered and concentrated. When cleaning flash chromatography (gradient mixture of AcOEt/hexane 10:90 to 15:85) received 0.97 g (73%) of the desired product9in the form of a slightly yellow oil:

1H NMR (CDCl3at 298K) 8,28 (m, 2H), 7,38 (m, 2H), of 5.81 (m, 1H), 5,02 (m, 2H), 4,30 (t, 2H), 2.13 in (m, 2H), 1,78 (m, 2H), and 1.54 (m, 2H).

Example 2: Synthesis of 17-(3-chloro-6-methoxyethanol-1 yloxy)-2,14-dioxo-3,15-diaza-13-ocatillo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (16)

Stage A

To a solution of Boc-hydroxyproline (760 mg, 3,29 mmol) in DMSO (50 ml) was addedtert-butyl potassium (1,11 g, 9,87 mmol). The solution was stirred at ambient temperature under nitrogen atmosphere for 1 hour. Then was added 1,3-dichloro-6-methoxyethanol6(750 mg, 3,29 mmol). After 12 hours at room temperature, the reaction mixture was extinguished cold water with ice, acidified to pH 4 with diluted HCl, and was extracted with EtOAc, dried (Na2SO4), filtered and evaporated, thus obtaining 1.39 g (90%) of the desired product10in a solid: m/z = 242 (M+H)+;

1H NMR (CDCl3): 8,10 (l,J=9,3 Hz, 1H), 7,15 (l,J=the 2.4 Hz, 1H), 7,10 (DD,J=9,3 Hz, 2.5 Hz, 1H), 6.90 to (s, 1H), 5,80-5,67 (user. s, 1H), 4,45 (t,J=7.9 Hz, 1H), 3,95 (s, 3H); 3,80-3,90 (user. s, 1H), 3,70-of 3.80 (m, 1H), 2,75-2,60 (m, 1H), 2,35 at 2.45 (m, 1H), and 1.5 (s, 9H).

Stage

A mixture of the product10(1.25 g, 2,96 mmol), hydrochloride complex ethyl ester of 1-amino-2-vinylcyclopropanes acid11(526 mg, 2,96 mmol), HATU (1.12 g, 2,96 mmol) and DIPEA (955 mg, 7,39 mmol) in DMF (50 ml) was stirred at room temperature under nitrogen atmosphere for 12 hours. Then the reaction mixture was diluted with dichloromethane and then washed in an aqueous solution of NaHCO3and water. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 95:5), thus obtaining 1.5 g (90%) of the desired product12in the form of a yellow foam: m/z = 561 (M+H)+;

1H NMR (CDCl3): 8,10 (l,J=9,3 Hz, 1H), 7,50 (s, 1H), 7,25 (DD,J=9,3 Hz, 2.5 Hz, 1H), 6,98 (l,J=the 2.4 Hz, 1H), 5,80-5,67 (m, 1H), from 5.29 (d,J=of 17.1 Hz, 1H), 5,12 (l,J=10,3 Hz, 1H), 4,45-4,50 (user. s, 1H), 4,1-4,18 (m, 2H), 3,95 (s, 3H), 3,8-3,9 (user. s, 1H), of 3.7-3.8 (m, 1H), of 3.25 to 3.35 (m, 2H), 2,35 at 2.45 (m, 1H), 1,50-2,20 (m, 7H), of 1.50 (s, 9H).

Stage

A solution of the product12(3.0 g, are 5.36 mmol) in TFA-DCM 1:2 (30 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was evaporated to dryness in conjunction with toluene (3.0 ml), thus obtaining the desired product13(>95% purity after HPLC): m/z = 460 (M+H)+.

Stage D

To a solution of the product13(1.5 g, 3,26 mmol) in CH2Cl2(50 ml) was added to hydrocarbonate sodium (2.7 g, 32 mmol). Then was added triethylamine (681 μl, 4,89 mmol) and compound8(1.08 g, 4,24 mmol). The reaction mixture was stirred for 12 hours at room temperature, then filtered. The reaction mixture was distributed between water and CH2Cl2, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica (CH2Cl2/EtOAc, 95:5), while receiving 1.73 g (90%) of the desired product14: m/z = 587 (M+H)+;

1H NMR (CDCl3): 8,10 (l,J=9,3 Hz, 1H), 7,50 (s, 1H), 7,39 (s, 1H), 7,25 (DD,J=9,3 Hz, 2.5 Hz, 1H), 6,98 (l,J=the 2.4 Hz,lH), 5,81-5,62 (m, 2H), 5.56mm (t,J=3.8 Hz, 1H), from 5.29 (DD,J=of 1.3 Hz and 17.2 Hz, 1H), 5,12 (DD,J=1.5 Hz, 10.4 Hz, 1H), 5,00-a 4.86 (m, 3H), 4,35 (t,J=7.5 Hz, 2H), 4,20-4,06 (m, 2H), 3,98 (s, 3H), 3,48-3,37 (m, 1H), 3,10-3,00 (m, 1H), 2.77-to to 2.67 (m, 1H), 2,41 of-2.32 (m, 1H), 2,10 (DD,J=8.6 Hz, to 17.4 Hz, 1H), 1,98 (DD,J=7,1 Hz, 14.4 Hz, 2H), of 1.88 (DD,J=5,6 Hz and 8.1 Hz, 1H); 1,57 of 1.46 (m, 3H); 1,35-of 1.18 (m, 5H).

Stage E

Connection14(1.73 g, 2,95 mmol) was dissolved in degassed dry dichloroethane (1 l), barbotirovany nitrogen. Then add the catalyst Hoveyda-verification (1st generation) (355 mg, 20 mol.%) and the reaction mixture was heated to 70°C for 20 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated using rotary evaporation. The oil obtained was purified using column is cromatografia on the silicon dioxide (CH 2Cl2/EtOAc, 90:10), while receiving 530 mg (32%) of the desired compound15in a solid beige color: m/z = 559 (M+H)+;

1H NMR (CDCl3): 8,10 (l,J=9,3 Hz, 1H), 7,50 (s, 1H), 7,39 (s, 1H), 7,25 (DD,J=9,3 Hz, 2.5 Hz, 1H), 7,2 (s, 1H), 7,1 (user. s, 1H), 5,76-5,67 (m, 1H), 5,6-5,57 (user. s, 1H), the 5.45 (dt, 7=1.0 Hz, 10.0 Hz, 1H), 4,4 (t,J=7,8 Hz, 2H), 4.2V (sq,J=the 7.1 Hz, 2H); from 3.9 (s, 3H), 4,00-3,88 (m, 1H), 3,8-3,9 (DD,J=of 12.5, 4.0 Hz, 1H), 2.5 and 2.7 (m, 3H), 2,15-2,3 (m, 2H), 1,8-2,0 (m, 3H), a 1.5-1.6 (m, 1H), 1,4-of 1.45 (m, 1H), 1,22 (t,J=the 7.1 Hz, 3H).

Stage F

To a solution of compound15(200 mg, 0,358 mmol) in THF (10 ml) and methanol (2 ml) was added lithium hydroxide (307 mg, 7,17 mmol) in water (3 ml). After 48 hours at room temperature the reaction mixture was diluted with water and acidified to pH 3 1N HCl solution, extracted with AcOEt, dried (Na2SO4) and was evaporated. The obtained solid is triturated with simple ether, while receiving 160 mg (84%) of the desired product16in the form of a white solid m/z = 530 (M+H)+;

1H NMR (CDCl3): 8,10 (l,J=9,3 Hz, 1H), 7,50 (s, 1H), 7,39 (s, 1H), 7,25 (DD,J=9,3 Hz, 2.5 Hz, 1H), 7,39-7,30 (user. s, 1H), 5,90-of 5.83 (user. s, 1H), 5,71 (DD,J=8,0 Hz, and 17.9 Hz, 1H), 5,18 (t,J=10.1 Hz, 1H), 4,79 (DD,J=7,3 Hz, 9.0 Hz, 1H), 4,1 (s, 3H), 4.09 to of 3.97 (m, 1H), 3,81-3,66 (m, 2H), 3,62 (l,J=to 11.6 Hz, 1H), 3,19 was 3.05 (m, 1H), 2,59-2,22 (m, 4H), 2,01-1,90 (m, 1H), 1,89 (DD,J=5.8 Hz,J=8.6 Hz, 1H), 1,70 (DD,J=6,1 Hz, 9.8 Hz, 1H), 1,67 is 1.58 (m, 2H), 1,43 of 1.28 (m, 2H).

SynthesisN-[17-(3-chloro-6-methoxyethanol-1 yloxy)-2,14-dioxo-3,15-diaza-13-ocatillo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamida (17)

A solution of the product16(120 mg, 0.23 mmol) and carbonyldiimidazole (44 mg, 0.27 mmol) in dry THF (25 ml) was boiled under reflux for 3 hours in nitrogen atmosphere. If you want, if desired, derived azlactone can be distinguished. Then the reaction mixture was cooled to room temperature and added cyclopropylalanine (33 mg, 0.27 mmol) and DBU (52 mg, 0.34 mmol). The reaction mixture was heated at 50°C for 24 hours, then cooled to room temperature and distributed between water and CH2Cl2. The organic layers were dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography on silica gel (CH2Cl2/EtOAc, 95:05), while receiving a solid substance, which sequentially triturated in water, filtered, dried, triturated with simple ether and again dried in a high vacuum, thus obtaining 23 mg (16%) specified in the header of the product17in the form of a white powder: m/z = 530 (M+H)+;

1H NMR (CDCl3): 8,10 (l,J=9,3 Hz, 1H), 7,50 (s, 1H); 7,39 (s, 1H); to 7.25 (DD,J=9,3 Hz, 2.5 Hz, 1H); 7,39-7,30 (user. s, 1H); 5,90-of 5.83 (user. s, 1H); 5,71 (DD,J=8,0 Hz, and 17.9 Hz, 1H); 5,18 (t,J=the 10.1 Hz, 1H), 4,79 DD, J=7,3 Hz, 9.0 Hz, 1H), 4,1 (s, 3H), 4.09 to of 3.97 (m, 1H), 3,81-3,66 (m, 2H), 3,62 (l,J=the 11.6 Hz, 1H), 3,19 was 3.05 (m, 1H); 2,59-2,22 (m, 4H); 2,01-1,90 (m, 1H), 1,89 (DD,J=5.8 Hz, 8.6 Hz, 1H), 1,70 (DD,J=6,1 Hz, 9.8 Hz, 1H), 1,67 is 1.58 (m, 2H), 1,75-0,76 (m, 7H).

Example 4: Synthesis of 17-(7-methoxy-2-phenylindolin-4-yloxy)-2,14-dioxo-3,15-diaza-13-ocatillo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (22)

Stage A

With stirring to a solution ofN-Boc-hydroxyproline (3,9 g of 16.9 mmol) in DMSO (90 ml) was addedtert-butyl potassium (4.5 g, 40.1 per mmol). After 1 hour was added 4-chloro-2-phenyl-7-methoxyquinoline (4.5 g, and 16.7 mmol) and the resulting solution was stirred at room temperature for 12 hours. Then the mixture was diluted with water (180 ml), washed with ethyl acetate (30 ml) and neutralized 1N HCl solution. The solid was filtered, washed with water and dried, thus obtaining the 4.65 g of the desired product18; m/z = 464,2 (M+H)+.

Stage

To a solution of complex ethyl ester of 1-amino-2-vinylcyclopropanes acid (11, 41 mg, 0.26 mmol)in18(11 mg, 0.22 mmol), HATU (204 mg, 0.54 mmol) in DMF (4 ml) was added DIPEA (187 μl, of 1.08 mmol). After stirring at room temperature for 1 hour was added dichloromethane (4 ml). The solution is then washed in an aqueous solution of NaHCO3(saturated) and two portions of water. Organizes the second layer was dried (Na 2SO4) and concentrated, thus obtaining specified in the header of the product19: m/z = 602,2 (M+H)+.

Stage

To a solution of the product19(0.36 g, of 0.60 mmol) in dichloromethane (5 ml) at 0°C was added triperoxonane acid in one portion. The reaction mixture was stirred at 0°C for 30 min and optional for 40 min at room temperature, then concentrated and concentrated from toluene (3×15 ml), while receiving the substance in the form of not-quite-white foam. To the obtained residue was added a solution of the product9(0,175 g, 0.66 mmol) in dichloromethane (10 ml) followed by the addition of diisopropylethylamine (of 0.32 ml, 1.8 mmol) and then boiled under reflux for 48 hours. Then the reaction mixture was concentrated and re-dissolved in dichloromethane (15 ml) and diisopropylethylamine (of 0.32 ml, 1.8 mmol), and then boiled under reflux for an additional 48 hours. Then, the resulting light brown solution was diluted with dichloromethane (15 ml), washed with saturated aqueous sodium bicarbonate (3×20 ml), dried (Na2SO4), filtered and evaporated. When cleaning using flash chromatography (gradient mixture of AcOEt/hexane 40:60 to 50:50) received 240 mg (63%) of the desired product20in the form of a colorless oil: m/z = 628 (M+H)+.

Stage D

The solution dialkene20(0.24 g, 0.38 mmol) in dichloroethane (240 ml) was consistently degirolami three times with nitrogen, followed by a single degassing with argon, then was added the catalyst Hoveyda-verification of the 1st generation (0,016 g, 0.07 EQ.) and the reaction mixture two more times was degirolami with argon, then boiled under reflux in an argon atmosphere for 16 hours. Then the reaction mixture was allowed to cool to room temperature, was added acceptor catalyst (0,13 g) and the resulting mixture was stirred for 1 hour. Then the mixture was filtered and evaporated. The residue was purified using flash chromatography (gradient mixture of AcOEt/hexane 40:60 to 50:50), while receiving 150 mg (67%) of the desired product21in the form of a colorless solid.

Stage E

To a solution of complex ethyl ester21(0.15 g, 0.25 mmol) in a mixture of 1:1 dioxane-methanol (6 ml) at room temperature was added a 1M solution of lithium hydroxide (3 ml). After 2 hours was added methanol (1 ml) to obtain a gel-like suspension and the resulting solution was stirred for additional 24 hours. Then the reaction mixture was acidified with acetic acid (0.5 ml) and concentrated under reduced pressure. The residue was purified using flash chromatography (AcOEt/MeOH, 92:8 To + 0.5% AcOH), the floor is th at the 110 mg (76%) of the desired compound 22in the form of a colorless solid: m/z = 572 (M+H)+.

Example 5: Synthesis ofN-[17-(7-methoxy-2-phenylindolin-4-yloxy)-2,14-dioxo-3,15-diaza-13-ocatillo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (23)

Under stirring to a suspension of acid22level (0.041 g, 0,072 mmol) in a mixture of 3:1 dichloromethane-dimethylformamide (1.2 ml) was addedN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide × HCl (0,027 g, 0,143 mmol), thus obtaining the solution. The reaction mixture was stirred for 10 min, and then were added 4-(dimethylamino)pyridine (0,009 g, 0,072 mmol) and stirred the reaction mixture for another 40 min at room temperature. Then solution was added cyclopropanesulfonyl (0.035 g, 0,287 mmol)obtained by the method described in the application WO 03/053349, and 1,8-diazabicyclo[5.4.0]-undec-7-ene (0,043 ml, 0,287 mmol)was sealed tube and then was irradiated in microwave oven at 100°C for 40 minutes. Then the reaction mixture was distributed between ethyl acetate (20 ml), 1M aqueous solution of hydrochloric acid and a saturated solution of salt. The organic layer was combined with the organic layer from other portions received on the basis of acid (0,062 g to 0.108 mmol), treated similarly as described above. The resulting solution was dried (Na2SO4), filtered and concentrated on the silicon dioxide. OST is OK purified using flash chromatography (gradient mixture of AcOEt:toluene 50:50 to 100:0 to + 0.5% AcOH, followed by a mixture of AcOEt/MeOH, 9:1). The appropriate fractions were concentrated and optionally purified using preparative HPLC (column: ACE 5 C8, 100×21,2 mm ACE-122-1020), flow rate = 15 ml/min, gradient of a mixture of 55% methanol/5% acetonitrile in 10 mm aqueous solution of ammonium acetate to 90% methanol for 10 minutes Appropriate fractions were concentrated, re-dissolved in methanol, concentrated and liofilizovane during the night, while receiving the solid is not quite white. In conclusion, the obtained material was subjected to processing using column chromatography (AcOEt/toluene, 1:1), while receiving 39 mg (32%) of the desired product23in the form of a white powder: m/z = 675 (M+H)+.

13C-NMR (125 MHz, CDCl3): 6,4, 6,5, 22,8, 24,0, 25,3, 28,0, 31,3, 33,4, 37,4, 43,0, 53,8, 56,2, 58,2, 63,7, 76,1, 98,9, 108,3, 115,4, 118,8, 123,3, 126,0, 127,4, 128,0, 128,9, 129,3, 129,6, 130,3, 131,2, 139,8, 151,4, 154,5, 158,5, 160,5, 161,6, 169,9, 175,6.

Example 6: Synthesis of 18-(7-methoxy-2-phenylindolin-4-yloxy)-2,15-dioxo-3,16-diaza-14-ocatillo[14.3.0.04,6]nonudes-7-ene-4-carboxylic acid (24)

Specified in the header of the connection24synthesized from the intermediate product19andO-(hept-6-enyl)-O-(4-nitrophenyl)carbonate, following the same procedure (stages C-E), which is described for the synthesis of 17-(7-methoxy-2-phenylindolin-4-yloxy)-2,14-dioxo-3,15-diaza-13-ocatillo[13.3.0.04,6]octadec-7-ene-4-carboxylic to the slots ( 22): m/z = 586 (M+H)+.

Example 7: Synthesis ofN-[18-(7-methoxy-2-phenylindolin-4-yloxy)-2,15-dioxo-3,16-diaza-14-ocatillo[14.3.0.04,6]nonudes-7-ene-4-carbonyl](cyclopropyl)sulfonamida (25)

Specified in the header of the connection25synthesized from compound24by following the same procedure described for the synthesis ofN-[17-(7-methoxy-2-phenylindolin-4-yloxy)-2,14-dioxo-3,15-diaza-13-ocatillo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (23): m/z = 689 (M+H)+.

Example 8: The synthesis of complextert-butyl ester 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid (27).

With stirring to a solution of26(180 mg, 1.15 mmol) in 2 ml of CH2Cl2in an inert atmosphere of argon at 0°C 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 mixture of 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, 9H), 1,90 (l,J=of 11.0 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 of27

Connection26(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 a cloudy solution". Added BF3× Et2O (5.6 ml, of 44.5 mmol, 0.5 EQ.) and the reaction mixture was left at approximately -10°C in nitrogen atmosphere. After 10 min was obtained a clear solution. The reaction mixture was monitored by TLC (mixture of 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 connection26,to the reaction mixture were added saturated aqueous solution of NaHCO3(200 ml) and then vigorously stirred mixture within 10 minutes the Organic layer was washed with saturated solution of NaHCO3(3×200 ml) and saturated salt solution (1×150 ml), then dried with sodium sulfite, filtered and concentrated in the form of small droplets of oil. Adding to the residue of hexane was released product. Adding an additional amount of hexane and heated to boiling under reflux received prozrachny solution from which the crystallized product. The crystals were collected during the filtration and washed with hexane (at room temperature), 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 9:Synthesis of hintline in the form of a structural element

P2 - complex methyl ester of 2-(4-perbenzoate)-4-methoxy-3-methylbenzoic acid (28)

4-fermenting acid (700 mg, 5 mmol) was dissolved in dichloromethane (20 ml) and pyridine (2 ml). Was added methyl ester 2-amino-4-methoxy-3-methylbenzoic acid (878 mg, 4.5 mmol) and boil the mixture under reflux for 5 hours. Was added water and was extracted with a mixture of dichloromethane. The organic phase was dried, filtered, evaporated and the obtained residue was purified by column chromatography on silica gel, elwira a mixture of 1:1 simple ether-pentane, getting mentioned in the title compound in pure form (870 mg, 61%). MS (M+H)+318.

2-(4-perbenzoate)-4-methoxy-3-methylbenzoic acid (29)

To a solution of complex methyl ester of 2-(4-perbenzoate)-4-methoxy-3-methylbenzoic acid (28) (870 mg, 2.7 mmol) in tetrahydrofuran (15 ml), water (7.5 ml) and methanol (7.5 ml) was added LiOH (1M, 4 ml). The mixture is heated to 50°C for 4 hours. Then added water (30 ml) and reduced by half the volume. Upon acidification with acetic acid, followed by filtering of the received specified in the title compound in pure form (830 mg, 100%). MS (M+H+) 304.

2-(4-forfinal)-7-methoxy-8-methyl-hinzelin-4-ol (30)

2-(4-perbenzoate)-4-methoxy-3-methylbenzoic acid (29) (830 mg, 2.7 mmol) was heated to 150°C in formamide (20 ml) for 4 hours. The excess formamide was removed by distillation. Added water and the precipitated was filtered precipitate the product, while receiving specified in the title compound in pure form (642 mg, 83%). MS (MH+H+) 285.

Example 10:A General procedure for obtaining substituted hinzelin-4-tins

To a suspension of substituted 2-aminobenzamide [A] (1 EQ.) in dry THF (60 ml) was added pyridine (2 EQ.) and the mixture was cooled to 5°C. was Slowly added to the acid chloride [B] (1.25 EQ.) and stirred the mixture at room temperature over night. The mixture was evaporated under reduced pressure and then suspended in water. The connection was left in water for several hours, filtered and washed with cold water and simple diethyl ether. The product [C] was dried in vacuum. Output: 90-100%. When used, the acid chloride [B] represented hydrochloride nicotinamide, then used a 2.5 EQ. PI is Idina and instead of stirring overnight the mixture was stirred for 2-3 days at room temperature.

The obtained amide [C] (1 EQ.) was added to a suspension of sodium carbonate (2.5 EQ.) in a mixture of water and EtOH 1:1 and the mixture is boiled under reflux for two hours. EtOH was removed under reduced pressure, was added 5% citric acid solution and the mixture was left to stand over night. The product [D] allocated during the filtration, then washed with water and simple diethyl ether and dried in vacuum.

Example 11: 7-methoxy-8-methyl-2-pyridin-3-imaginaton-4-ol (31)

Followed the General procedure according to example 10, using 2-amino-4-methoxy-3-methylbenzamide as a benzamide derivative and hydrochloride nicotinamide as the acid chloride, thus obtaining specified in the title compound (2.5 g, 92%), [M+H]=268.

Example 12: 7-methoxy-8-methyl-2-pyridine-4-imaginaton-4-ol (32)

Followed the General procedure according to example 10, using 2-amino-4-methoxy-3-methylbenzamide as derived benzamide hydrochloride and isonicotinohydrazide as the acid chloride, thus obtaining specified in the title compound (1.6 g, 60%), [M+H]=268.

Example 13: 7-methoxy-8-methyl-2-utilisation-4-ol (33)

Followed the General procedure according to example 10, using 2-amino-4-methoxy-3-methylbenzamide as derived benzamide [A] and the acid chloride UKS the red acid as the acid chloride [B] while receiving specified in the title compound (2.2 g, 100%).

1H-NMR, DMSO-D6δ 1,2 (m, 3H), of 2.38 (s, 3H), and 2.6 (m, 2H), 3,90 (s, 3H), 7,18 (d, 2H), of 7.96 (d, 2H), 11,88 (s, 1H).

Example 14: 7-methoxy-8-methyl-2-(4-methoxyphenyl)hinzelin-4-ol (34)

Followed the General procedure according to example 10, using 2-amino-4-methoxy-3-methylbenzamide as derived benzamide [A] and the acid chloride 4-methoxybenzoic acid as the acid chloride [B], while receiving specified in the title compound (5.5 g, 92%).

1H-NMR, DMSO-D6δ of 2.38 (s, 3H), 3,82 (s, 3H), 3,92 (s, 3H),? 7.04 baby mortality (d, 2H), 7,20 (m, 1H), 8,00 (d, 1H), to 8.20 (d, 2H), 12,18 (s, 1H).

Example 15: 8-methoxy-2-phenylpyrazole-4-ol (35)

Followed the General procedure according to example 10, using 2-amino-4-methoxy-3-methylbenzamide as derived benzamide [A] and benzoyl chloride as the acid chloride [B], while receiving specified in the title compound (2.0 g, 80%), [M+H]=253.

1H-NMR, DMSO-D6δ of 3.97 (s, 3H), 7,39-7,72 (m, 6H), 8,19 (m, 2H), 12,48 (s, 1H).

Example 16: 2-(3-forfinal)-7-methoxy-8-methylpyrazole-4-ol (36)

Followed the General procedure according to example 10, using 2-amino-4-methoxy-3-methylbenzamide as derived benzamide [A] and 3-perbenzoate as the acid chloride [B], while receiving specified in the title compound (21 g, 73%), [M+H]=271.

Example 17: 2-(3,5-differenl)-7-methoxy-8-methylpyrazole-4-ol (37)

Followed the General procedure according to example 10, using 2-amino-4-methoxy-3-methylbenzamide as derived benzamide [A] and 3,5-differentiald as the acid chloride [B], while receiving specified in the title compound (2.1 g, 85%), [M+H]=303.

Example 18: 7-methoxy-8-methylpyrazole-4-ol (38)

When the reaction ring closure (stage [B]-[C]) in the General procedure was carried out in DMF, and not in EtOH specified in the title compound was obtained in the form of byproduct.

Example 19: 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 the publication 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 upon naemul as 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 cultivation of the replicon-containing cells in the presence of G418 (neoRdepends 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). The replicon-containing cells in the control cultures in the absence of any inhibitors was characterized by high expression of luciferase. Carried out onitoring inhibitory activity of compounds against luciferase activity in cells Huh-Luc, getting the curve of the dependence of 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 vitroconsisted in determining the extent 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 basically as described in the publication Poliakov, Prot Expression & Purification 25 363371 (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 (Ake 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 30°C for 10 min, after which initiated the reaction by adding 0.5 µm substrate. Inhibit the s was dissolved in DMSO, subjected to the action of ultrasound for 30 seconds and stirred. Between measurements the solutions were stored at -20°C.

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

The following table lists compounds that are obtained according to any of the above-mentioned examples. Compounds are numbered as in examples 1-7. The table also shows the activity of the tested compounds.

1. The compound of the formula

its pharmaceutically acceptable salts and stereochemical isomeric forms, where
R1represents a
the radical (d-1) formula

the radical (d-2) formula

Rlais a halogen;
Rlb, Rlb'each independently represents hydrogen or-OR8;
R8the stand is made With a 1-6alkyl;
Rld, Rld'represent hydrogen;
R2represents-OR5, -NR4aSOpR7;
n is 4 or 5;
p is 2;
R4arepresents hydrogen;
R5represents hydrogen or C1-6-alkyl;
R7represents a C3-7-cycloalkyl.

2. The compound according to claim 1, where the compound has formula (I-b)

3. The compound according to claim 1, in which
R1is a radical (d-1) formula

4. The compound according to claim 1, in which
(a) R2represents-OR5where R5represents methyl, ethyl, tert-butyl or hydrogen; or
(b) R2represents-NHS(=O)2R7where R7is cyclopropyl.

5. 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 4.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula l where R1 represents CH2CI, CH2F or-C1-2alkyl-R3R4; R3 represents -O-; R4 represents phenyl, where said R4 group is optionally substituted by 0-5 groups J where J represents halogen; R2 represents C6-10aryl; or a group: where Y represents CH, AA2 represents C1-C7alkyl, R8 and R9 represents hydrogen or halogen; or a group: where Y represents CH, AA2 represents C1-C7alkyl, and R6 represents hydrogen, P4 represents -(T)p-R, where T represents -C(O)O-group, R represents C1-C12alkyl, and p is equal to 1; or a group: where A2 represents O, R7 and R8 together with atom whereto attached form a (10-14)members tricyclic unsaturated ring, e.g. carbazole; or a group: where AA2 represents C1-C7alkyl, and R15 represents 2-tert-butylphenyl. The declared compounds are caspase inhibitor prodrugs which under certain conditions can be transformed into biologically active compounds, particularly caspase inhibitors. Also, said invention refers to methods of producing said compounds and to a pharmaceutical composition exhibiting caspase inhibitory action on the basis of the said compounds.

EFFECT: what is produced are new compounds and based pharmaceutical composition which can find application in medicine for treating the diseases associated with inflammatory or degenerative conditions.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 4-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6,7-dicarbonitriles of general formula: where R=H (a); CH3 (b); OCH3 (c); CI (d) which can be used as biologically active substances, fluorescent materials and for synthesis of phthalocyanines. The method involves synthesis of substituted 4-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6,7-dicarbonitriles through a reaction which takes place in two steps, where at the first step 4-bromo-5-nitrophthalonitrile reacts with sodium salts of substituted 3-phenylpropanoates in molar ratio 1:2, respectively, at temperature 19…25°C for 12-20 hours in dimethyl formamide (DMF) solution, after which the reaction mass is diluted with tenfold excess water with T=0…25°C. The released resinous residue is extracted with dichloromethane, thoroughly washed with water and chromatographed on silica gel. The eluent (solvent) is evaporated. The residue of the intermediate product is filtered and re-crystallised from alcohol. At the second step of the method, tin dichloride solution in concentrated hydrochloric acid is mixed with the solution of the obtained intermediate product in ethyl alcohol in molar ratio 3.5-4.5:1, respectively, at temperature 30...50°C and reaction time of 1-2 hours, after which the reaction mixture is diluted with tenfold excess water with T=0…25°C, and the precipitate is filtered and re-crystallised from alcohol.

EFFECT: obtaining novel heterocyclic dicyano-derivatives of benzoxazines.

1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

,

where R1 is selected from formulae

, and ,

n equals 0; R6 and R7 are independently selected from hydrogen, C1-C6alkyl, cyanoC1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; or R6 and R7 together with a carbon atom to which they are bonded form a 6-member heterocycloalkyl with one nitrogen atom; wherein any alkyl in R6 and R7 can optionally contain a methylene group substituted with an O atom; wherein any aryl in R6 and R7 or formed by a combination of R6 and R7 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, -XC(O)OR10; where X denotes a bond; R10 is independently selected from C1-C6alkyl; R8 is selected from C5-C9heteroarylC0-C4alkyl containing 2-3 heteroatoms independently selected from N, O and S; wherein any heteroaryl in R8 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, C3-C6cycloalkyl; R2 denotes hydrogen; R3 and R4 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; wherein any alkyl in R3 and R4 can optionally contain a methylene group substituted with a S(O)2 group; R5 is selected from C5-C6heterocycloalkyl with 1-2 heteroatoms selected from N and O, and NR12R13; where R12 and R13 are independently selected from C1-C6alkyl; as well as pharmaceutically acceptable salts and isomers thereof. The invention also relates to use of compounds of formula (I) in preparing a medicinal agent, and to a pharmaceutical composition having cathepsin S inhibiting properties, which contains a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable filler.

EFFECT: obtaining compounds which can be used as cathepsin S inhibitors.

10 cl, 12 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

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

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

7 cl, 2 tbl, 4 ex

FIELD: chemistry.

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

EFFECT: high effectiveness of derivatives.

11 cl, 20 ex

FIELD: chemistry.

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

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

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzoxazines

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

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

9 cl, 14 ex

FIELD: chemistry.

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

,

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

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

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

Kinase inhibitors // 2440352

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula : a pharmaceutically acceptable salt or solvate thereof, having Syk kinase inhibiting properties. The invention also relates to a pharmaceutical composition containing said compound, methods of treating diseases whose development is aided by c-kit receptor activity, such as arthritis, rheumatoid arthritis, tumours, mantle cell lymphoma, as well as a method of inhibiting angiogenesis.

EFFECT: improved method.

13 cl, 4 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula in which is or (values of radicals are given in the claim), a method of producing said compounds, a pharmaceutical composition containing said compounds and therapeutic application thereof.

EFFECT: compounds are cysteine protease inhibitors and can be used in medicine.

25 cl, 1 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (glycoluril). The reaction takes place at 80°C for 60 minutes, where concentrated sulphuric acid is used in an aqueous medium and reagents are taken in the following molar ratios: glyoxal 2.0; urea 4.0; sulphuric acid 0.4; water 12, and the freshly prepared glyoxal solution is added while stirring for 20 minutes, after which the mixture is stirred for 40 more minutes.

EFFECT: novel method of producing glycoluril, which increases output of the end product and is simpler.

1 cl, 1 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of formulae pharmaceutically acceptable salts or stereoisomers thereof, where R1 = -OR5, -NH-SO2R6; R2 = hydrogen; R3 = C1-6-alkyl; R4 = isoquinolinyl, possibly substituted; n equals 4 or 5; R5 = hydrogen; R6 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: novel compounds have hepatitis C virus replication inhibitory action and can be used in medicine.

6 cl, 32 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes a compound of general formula where A1 is selected from the following formula R1c denotes a hydrogen atom, a lower alkenyl group or a -Q3-A3(R1d)R1e group; A3 denotes a methane or lower alkyl group; Q3 denotes a single bond; R1d and R1e independently denote a hydrogen atom, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1 denotes a lower alkenyl group or a lower alkynyl group; R2 denotes a phenyl, pyridyl or thienyl group, which can contain a -Q4-A4(R1g)R1h group; A4 denotes a nitrogen atom, a lower alkyl group optionally substituted with a hydroxy-lower alkyl group, or a methane group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q denotes a single bond or a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1g and R1h independently denote a hydrogen atom, a lower alkyl group or a lower alkylsulphonyl group; R5 and R6 independently denote a hydrogen atom, a lower alkyl group or a hydroxyl-containing lower alkyl group, or a pharmaceutically acceptable salt thereof. The invention also describes a pharmaceutical composition based on compounds of formula I, having anti-cancer activity, an anticancer agent, a codrug, as well as an exposure sensitising agent containing the pharmaceutical composition.

EFFECT: novel compounds are obtained and described, having excellent Well-kinase inhibitory action and can therefore be used in medicine, especially when treating different malignant tumours.

13 cl, 21 ex

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

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: medicine.

SUBSTANCE: group of inventions is referred to the area of medicine, namely to the area of virusology, and is related to virosomes containing hemagglutinin extracted from influenza virus produced in the cell lines, compositions, containing said virosomes, means of manufacturing and applications. The essence of the invention including virosomes containing hemagglutinin extracted from influenza virus produced in the bird cell lines, compositions, containing said virosomes, application of virosome as a vessel, set, methods of vaccination, methods of treatment and methods of virosome production.

EFFECT: production of virosomes having improved merging capability and increased immunogenicity.

21 cl, 3 tbl, 5 dwg

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