Macrocyclic phenylcarbamates inhibiting hcv

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

 

The technical field to which the invention relates.

The present invention relates to macrocyclic compounds having inhibitory activity against NS3 semipretioase HCV (hepatitis C virus). It relates also to compositions comprising these compounds as active ingredients, and to methods of producing such compounds and compositions.

The level of technology

Hepatitis C virus (hepatitis C virus (HCV) worldwide is the main cause of chronic liver disease and has become the main subject of in-depth medical research. HCV is a member of the family flaviviruses (Flaviviridae) in the genus of hepaciviruses and closely connected with this generation of flaviviruses (flavivirus), which includes a number of viruses involved in diseases such as Dengue virus and yellow fever virus, and family pestiviruses animals, which includes virus bovine viral diarrhea (bovine viral diarrhea virus (BVDV). The genome of HCV includes both the 5'and 3' untranslated region, which perceive the secondary structure of the RNA, and the Central open reading frame, which encodes the only polyprotein. Polyprotein encodes ten gene products that are generated from the precursor of polyprotein with organized series of co - and post-transplantation endoproteolytically splits, oposreduemyh as the proteases of the host body, and the protease of the virus. Structural proteins of the virus include nucleocapsid protein core and two covering his glycoprotein E1 and E2. Non-structural non-structural - NS) proteins encode some enzymes of the virus vital functions (such as helicase, polymerase, protease), as well as proteins of unknown functions. Replication of the viral genome is mediated by RNA-dependent RNA polymerase, encoded nonstructural protein 5b (NS5B). It was shown, as well as the polymerase function of the virus, elikana and proteasa functions encoded in bifunctional NS3 protein are essential for replication of HCV RNA. In addition to the NS3 semipretioase HCV encodes the metalloproteinases in the NS2 region.

After the initial acute infection, most infected patients develop chronic hepatitis C, because HCV is reproduced preferentially in hepatocytes, but is not directly cytopathic. In particular, the absence of a strong T-limfotsitov response and high affinity of the virus to mutations, apparently, contributes to the high speed development of chronic infection. Chronic hepatitis may develop to liver fibrosis leading to cirrhosis, end-stage liver disease, and hepatocellular cancer (hepatocellular carcinoma - HCC), making it the leading cause of liver transplantation.

There are 6 main g is Natapov and more than 50 subtypes of HCV, which are distributed in different geographical areas. 1 type HCV is the dominant type in Europe and the USA. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, possibly explaining the difficulties in developing a vaccine and lack of response to modern therapy.

The transfer of HCV can occur through contact with infected blood, or drugs derived from infected blood, for example, as a result of blood transfusion or intravenous administration of drugs. The introduction of the diagnostic tests used in the selection of blood led to a decline in the incidence of post-transfusion HCV. However, due to the slow development of liver disease to end stage of the disease, the infection is already taking place at present, will continue to represent a serious medical and economic problem for decades.

Used in the present therapeutic methods of treating HCV are based on (paglinawan) interferon-alpha (IFN-α) in combination with Riboflavin. Such combination therapy leads to a stable virological response in more than 40% of patients infected with genotype 1 virus, and approximately 80% of patients infected with genotypes 2 and 3. In addition to limited effectiveness against the AI HCV type 1 such combined therapy is associated with significant side effects and is poorly tolerated by many patients. Main side effects include symptoms similar to the symptoms of influenza, hematologic abnormalities, and neuropsychiatric symptoms. Therefore, there is a need for more effective, more convenient and easier-tolerated treatments.

In the scientific and patent literature describes many of the inhibitors of HCV protease. Long-term administration of inhibitors of HCV protease usually leads to the emergence of resistant HCV mutants, the so-called "mutants, which disables the action of medicines. They have a characteristic mutation in protease the HCV genome, in particular D168V, D168Y and/or A165S. Therefore, there is a need for additional drugs with different resistance characteristics to provide patients with such disorders treatment choice. Such medicines can be used in combination therapy, which is expected to become the norm in the future, even as first-line therapy.

Practical experience in the use of HIV medicines, in particular inhibitors of the HIV protease, shows that sub-optimal pharmacokinetics and complex patterns dosage quickly lead to inadvertent violations of the regime and medication. This, in turn, means that the lower concentration (minimum plasma concentration for the respective drugs in the treatment of HIV often for long periods of time during the day falls below the threshold value IC 90or ED90. It is believed that when the minimum concentration within 24 hours, equal to at least the IC50more precisely IC90or ED90significantly slows down the development of mutants, "which disables the action of medicines.

Achieving the desired pharmacokinetics and metabolism drugs for such lower concentrations causes severe requirement for the development of medicines. Known inhibitors of HCV protease with many peptide bonds impose additional pharmacokinetic requirements effective dosage regimes.

Thus, there is a need for inhibitors of HCV, which can overcome such shortcomings of modern therapy of HCV, as side effects, limited efficacy, the development of resistance and treatment failure due to violation of the regimen of medicines.

The present invention relates to inhibitors of HCV replication, which show at least one improved property relative to the compounds of the prior art. In particular, the inhibitors according to the present invention are best on one or more of these related pharmacological properties as efficiency, reduced cytotoxicity, improved pharmacokinetics, improved prof is any resistance, acceptable dosage and content of active substance in the tablet.

The invention

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

including their stereoisomers, where

A represents-C(=O)OR1, -C(=O)-NH-SO2-R2, -C(=O)C(=O)NR3aR3b, -C(=O)-NH-SO2-NR3aR3b, -C(=O)NH-P(=O)(OR4a)(R4b) or-P(=O)(OR4a)(R4b),

where

R1represents hydrogen; aryl; Het; C3-7cycloalkyl, optionally substituted C1-6by alkyl; or C1-6alkyl, optionally substituted C3-7cycloalkyl, aryl or Het;

R2represents aryl; Het; C3-7cycloalkyl, optionally substituted C1-6by alkyl; or C1-6alkyl, optionally substituted C3-7cycloalkyl, aryl or Het;

R3aand R3beach independently represent hydrogen, C1-6alkyl, optionally substituted C1-6alkoxy-, hydroxyl group, halogen, C3-7cycloalkyl, aryl or Het; aryl; C2-6alkenyl; Het; C3-7cycloalkyl, optionally substituted C1-6by alkyl; or R3aand R3btogether with the nitrogen atom to which they are attached, form the group Het1; and R3acan also be a C1-6alkoxy;

R 4arepresents hydrogen, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, aryl or C1-6alkyl, optionally substituted C3-7cycloalkyl or aryl;

R4bis an R4b', OR4b'or other4b';

R4b'represents a C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, aryl or C1-6alkyl, optionally substituted C3-7cycloalkyl or aryl;

X represents N, CH and where X is connected by a double bond, then a is a C;

E represents NR5or, when X represents N, then E is NR5or CR6aR6b;

R5represents hydrogen, C1-6alkyl, C1-6alkoxyl1-6alkyl or C3-7cycloalkyl;

R6aand R6bindependently represent hydrogen or C1-6alkyl, or R6aand R6btogether with the carbon atom to which they are attached, form a C3-7cycloalkyl;

n is 3, 4, 5 or 6;

each dotted line ----- independently represents an optional double bond;

R7represents hydrogen or, when X is C or CH, R7can also be a C1-6alkyl;

R8represents a radical of the formula

R8aand R9aeach independent is about represents hydrogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, hydroxyl group, halogen, polyhalogen1-6alkyl, cyano, amino, mono - or C1-6dialkylamino;

each R9independently represents a C1-6alkyl, optionally substituted C1-6alkoxy, hydroxyl group or halogen; C3-7cycloalkyl; C2-6alkenyl; C1-6alkoxy, C3-7cycloalkane; aryloxy; Het-O-; hydroxyl group; cyano; polyhalogen1-6alkyl; mono - or C1-6dialkylamino;

each R10independently represents hydrogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, hydroxyl group, halogen, polyhalogen1-6alkyl, cyano, amino, mono - or C1-6dialkylamino;

each aryl independently represents a phenyl, optionally substituted one, two or three substituents selected from a halogen, hydroxyl group, nitro, cyano, carboxyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6of alkyl, C1-6alkylsulphonyl, amino, mono - or dis1-6alkylamino, azido, mercapto, C1-6alkylthio, polyhalogen1-6of alkyl, polyhalogen1-6alkoxy, C3-7cycloalkyl and Het1;

each Het independently represents a 5 - or 6-membered saturated, partially unsaturated or fully unsaturated heterocycle, containing the s 1, 2, 3 or 4 heteroatoms, each independently selected from nitrogen atoms, oxygen and sulfur, and said heterocycle is optionally substituted one, two or three substituents, each of which is independently selected from halogen, hydroxyl group, nitro, cyano, carboxyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6of alkyl, C1-6alkylsulphonyl, amino, mono - or dis1-6alkylamino, azido, mercapto, polyhalogen1-6of alkyl, polyhalogen1-6alkoxy, C3-7cycloalkyl, Het1;

each Het1independently represents pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6alkylpiperazine, 4-C1-6acylcarnitines and morpholinyl where morpholinyl and piperidinyl groups can be optionally substituted by one or two C1-6alkyl radicals;

or their N-oxides, pharmaceutically acceptable salt or pharmaceutically acceptable solvate.

The invention relates to compounds of formula (I) as such and their N-oxides, pharmaceutically acceptable additive salts and stereochemical isomeric forms, for use as a drug. The invention relates also to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. Pharmaceutical which such compositions can include combinations of the aforementioned compounds with other means, possessing antiviral activity against HCV.

The invention relates also to the use of compounds of formula (I), its N-oxide, pharmaceutically acceptable additive salt or a stereochemical isomeric form for the production of pharmaceuticals for inhibition of HCV replication. Or the invention relates to a method of inhibiting HCV replication in the body of warm-blooded animal, and this method includes the introduction of an effective amount of the compounds of formula (I), its N-oxide, pharmaceutically acceptable additive salt or a stereochemical isomeric form.

Detailed description of the invention

Used above and hereinafter, the terms have the following definitions (unless otherwise specified values).

The term "C1-4alkyl", when used in the description of the invention to define a group or part of a group, means a saturated hydrocarbon radicals with a straight or branched chain, containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl; the term "C1-6alkyl" includes C1-4alkyl 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. In the range of C1-6Akilov interest is predstavljaet C 1-4alkyl.

The term "C2-6alkenyl" in the definition of the group or part of a group means a hydrocarbon radicals with a straight or branched chain containing saturated carbon-carbon bonds, and, at least one double bond, and comprising 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. In the range of C2-6alkenyl interest represents C2-4alkenyl.

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

The term "C1-6alkoxy" means C1-6alkyloxy, in which "C1-6alkyl is a radical defined above and attached to the oxygen atom, i.e-O-C1-6alkyl. In a series of C1-6alkoxy interest methoxy, ethoxy and propoxy.

The term "halogen" is a General name atoms such as fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

The term "polyhalogen1-6alkyl" in the definition of the group or part of a group, for example, in the group "polyhalogen1-6alkoxy"means a mono - or polyhalogen C1-6alkyl, in particular C16 alkyl, substituted 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. The term also includes perftools1-6alkyl group, which represents C1-6alkyl group in which all hydrogen atoms substituted by fluorine atoms, for example, pentaverate. When more than one halogen atom attached to the alkyl group, which is defined as polyhalogen1-6alkyl, - halogen atoms may be the same or different.

Fragment (=O) or oxo mentioned above, forms a carbonyl group, when attached to a carbon atom, sulfoxide group, when attached to a sulfur atom, sulfonyloxy group, when two of the above fragment is attached to the sulfur atom. The carbon atom that is attached to the oxo-group is a saturated carbon atom regardless of the cycle or cyclic system is substituted by an oxo group.

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

Each of Het radicals mentioned in the description, may be optionally substituted varying number of different types of substituents provided in the definition of compounds of formula (I) or any subgroup of compounds of formula (I). Some of the Het radicals mentioned in the description, can be substituted by one, two or three hydroxy substituents. Such hydroxy-substituted cycles may exist in tautomeric forms, containing keto groups. For example, 3-hydroxypyridine can exist in tautomeric form as 2H-pyridazin-3-one. When Het represents piperazinil, it is preferably substituted in the 4-position of Deputy attached to the nitrogen atom through a carbon atom, for example, 4-C1-6the alkyl, 4-polyhalogen1-6the alkyl, C1-6alkoxyl1-6alkyl, C1-6alkylcarboxylic, C3-7cycloalkyl.

Interest Het is adically include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, 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 the above heterocycles condensed with the benzene ring cycle, for example, indolyl, indazoles (in particular 1H-indazole), indolinyl, chinoline, tetrahydroquinolines (in particular, 1,2,3,4-tetrahydroquinoline), ethenolysis, tetrahydroisoquinolines (in particular, 1,2,3,4-tetrahydroisoquinoline), hintline, phthalazine, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzoxadiazole, benzothiadiazole, benzofuranyl, benzothiazol.

Het radicals pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, piperazinil, 4-substituted piperazinil preferably attached via the included nitrogen atom (i.e. represent 1-pyrrolidinyl, 1-piperidinyl, 4-thiomorpholine, 4-morpholinyl, 1-piperazinil, 4-substituted 1-piperazinil).

It should be noted that the position of the radicals on any fragment of the molecule, referred to in the definitions, can be arbitrary, provided that the fragment is chemically stable.

The radicals used in the definitions of the variables included in the e possible isomers, if not stated otherwise. For example, the term "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl; the term "pencil includes 1 pencil, 2-pentyl and 3-pentyl.

When any variable occurs more than once on any fragments, each definition is independent.

It is assumed that the terms "compounds of formula (I)", "data connection" or similar terms used in the description, include the compounds of formula (I), their N-oxides, pharmaceutically acceptable salt additive and stereochemical isomeric form. One option for implementing the invention includes compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in the description, as well as their pharmaceutically acceptable salts and the possible stereoisomeric forms.

The compounds of formula (I) contain several centers of chirality and exist in stereochemical isomeric forms. The term "stereochemical isomeric forms, when used in the description means all possible compounds made up of the same atoms connected in the same sequence of relationships, but having different three-dimensional structures that cannot be combined with the imposition and which can have compound of formula (I).

As for examples of where to denote the absolute configuration of chiral atom in the Deputy used the symbol (R) or (S, the specified designation takes into account all the connection as a whole, not Deputy separately.

Except as specifically stated or highlighted cases, the chemical definition of a connection involves a mixture of all possible stereochemical isomeric forms, which may have the specified connection. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. Assumes that all stereochemical isomeric forms of the compounds according to the present invention, including pure form and a mixture of each one form with another, included in the scope of the present invention.

The term "stereoisomer pure forms of the compounds and intermediates", when referred to in the description, means isomers, essentially free from other enantiomeric or diastereoisomeric forms of the same basic structures of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate products with stereochemical excess in the range from at least 80% (i.e. at least 90% of one and a maximum of 10% of the other possible isomers) and 100% (i.e. 100% of one isomer and the absence of the other possible isomers), more specifically to compounds or intermediate products with a stereoisomeric excess of 90% to 100%, more than is right with the stereoisomeric excess from 94% to 100% and most accurately with stereometry excess from 97% to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood similarly, but with respect to the enantiomeric excess and diastereomeric excess of the considered mixture, respectively.

Pure stereoisomeric forms of the compounds and intermediates according to the present invention can be obtained in accordance with methods known in the art. For example, the enantiomers may be separated by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples of such acids are tartaric acid, dibenzoyltartaric acid, dItalia acid and camphorsulfonic acid. Alternatively, the enantiomers may be separated chromatographic methods using chiral stationary phases. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction proceeds in a stereospecific. Preferably, if a specific stereoisomer, the specified connection synthesize stereospecific methods of getting them. In such methods will mainly be used enantiomerically pure source materials.

Diastereomeric the racemates of the compounds of formula (I) can be obtained from the Department is but suitable methods. Suitable methods of physical separation that pre-emption may be used are, for example, selective crystallization and chromatography, for example, column chromatography.

For some of the compounds of formula (I), their N-oxides, pharmaceutically acceptable additive salts and solvate, as well as intermediates used in their preparation, the absolute stereochemical configuration was not experimentally determined. A qualified specialist in the art can determine the absolute configuration of these compounds using methods known in the art, such as, for example, diffraction of x-rays.

It is also understood that the present invention includes all isotopes of atoms, which contain compounds according to the present invention. Isotopes include atoms with identical atomic numbers but different mass numbers. As a General example, but without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Pharmaceutically acceptable salt additive include therapeutically active non-toxic acid - and basically-additive salt forms of the compounds of formula (I). Pharmaceutically acceptable acid salt additive can be traditionally obtained by the processing is basically the 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, for example, acetic, propanoic, hydroxyestra, dairy, peruvemba, oxalic (i.e. tanginoa), malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic (i.e. hydroxybutanone acid), tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, ciclamino, salicylic, p-aminosalicylic, Mamonova acid and other acids. Conversely, these salt forms can be converted into the free base by treatment with a suitable base.

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

p> It is also understood that the term "additive salt" includes a solvate, which is able to form compounds of formula (I)and their salts. These are solvate, for example, hydrates, alcoholate, for example, ethanolate, propanoate etc.

Assume that the N-oxide forms of the compounds according to the present invention include compounds of formula (I)in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

Some of the compounds of formula (I) may exist in their tautomeric form. Assume that such forms, although it is not indicated in the above formula, is included in the scope of the present invention.

As indicated above, the compounds of formula (I) contain several asymmetric centers. For a more precise definition of each of these asymmetric centers will use the numbering system represented by the following structural formula.

Asymmetric centers are in positions 1, 4 and 6 of the macrocycle, and when the carbon atom in the 3' to 5-membered cycle, when the carbon atom of 2', when the substituent R7represents a C1-6alkyl, and the carbon atom 1'when X represents CH. Each of these asymmetric centers may exist in the R or S configuration.

When X represents N stereochemistry at position 1 preferably corresponds to the configuration of L-amino acids, i.e. L-Proline, as shown below.

When X represents CH, 2 carbonyl group substituted in positions 1' and 5' cyclopentane cycle, preferably are in the TRANS configuration. Carbonyl substituent in position 5' is preferably in a configuration that matches the configuration of L-Proline. Carbonyl group substituted in positions 1' and 5', preferably located in positions that are presented below on the structure of the following formula:

The compounds of formula (I) include cyclopropyl group, which is represented by structural fragment below:

where C7is the carbon at position 7, and the carbon atoms in position 4 and 6 represent the asymmetric carbon atoms in tsiklopropanovom cycle. The presence of these two asymmetric centers means that the compounds can exist as mixtures of diastereomers, such as diastereomers of the compounds of formula (I), where the carbon at position 7 is in CIS-configuration relative to the carbonyl or in the CIS-configuration relative to the amide, as shown below.

One way of carrying out the invention relates to compounds of the formula I, in which the carbon atom in position 7 on titsa in the CIS-configuration relative 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 is R-configuration. A particular subgroup of compounds of formula (I) is a subgroup of compounds in which the carbon atom in position 7 is in CIS-configuration relative to the carbonyl and the configuration at the carbon atom in position 4 is R-configuration.

In accordance with another embodiment of the invention cyclopropyl group (C4-C5-C6) joined the group, which is a phosphonate group-P(=O)(OR4a)(R4b). Under this option, the carbon atom in position 7 is in CIS-configuration relative to the phosphonate group or relative to the amide group, as shown on the structural fragment below:

Another variant embodiment of the invention relates to compounds of formula (I), in which the carbon atom in position 7 is in CIS-configuration relative to the phosphonate group. Another variant embodiment of the invention relates to compounds of formula (I), in which the configuration at the carbon atom in position 4 is S-configuration. A particular subgroup of compounds of formula (I) is a subgroup of compounds in which the carbon atom in position 7 of the local is seeking in the CIS-configuration relative to the phosphonate group and the configuration at the carbon atom in position 4 is S-configuration.

The compounds of formula (I) may include polynomy balance (i.e. X is a (N), cyclopentenyl or cyclopentadienyl balance (i.e. X represents CH or C, respectively). In accordance with one embodiment of the present invention compounds include the following structural fragments:

Other embodiments of the invention are compounds of formula (I) or any subgroup of compounds of formula (I), where R7represents methyl, E is an NR5That X is connected through a double bond with a carbon atom bearing an R7.

Preferred are the compounds of formula (I), in which the substituent in position 1 (or 5') and the pyrimidine substituent in position 3', attached through ether linkage, are in the TRANS configuration. Of particular interest are compounds of formula (I), in which position 1 has the configuration corresponding L-Proline, and the pyrimidine substituent in position 3', attached via ether bond is in the TRANS configuration relative to position 1.

Preferably the compounds of formula (I) have the stereochemistry shown in the structures of the formulas (I-a) and (I-b) below:

One variant of implementation of the present invention relative to the tsya 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) R7represents hydrogen;

(b) X represents nitrogen;

(C) E is an NR5;

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

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

(a) R7represents hydrogen;

(b) X represents nitrogen;

(C) E is a CR6aR6b;

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

Another variant 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) R7represents hydrogen;

(b) X represents CH;

(C) E is an NR5where R5takes the values defined above, in particular R5represents hydrogen or C1-6alkyl;

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

Particular subgroups of compounds of formula (I) are the subgroups of compounds represented by structural formulas(I-c), (I-d) and (I-e) below:

Among the compounds of formula (I-c), (I-d) and (I-e) connection with the stereochemical configuration shown in formula (I-a) and (I-b), respectively, are of particular interest.

The double bond between atoms 7 and 8 in the compounds of formula (I) or any subgroup of compounds of formula (I) may be CIS - or TRANS-configuration. Preferably, the double bond between carbon atoms 7 and 8 has the CIS-configuration, as shown in formulas (I-c), (I-d) and (I-e).

Other specific subgroups of compounds of formula (I) include compounds represented by the following structural formulas:

Of particular interest among the compounds of formula (I-f), (I-g) or (I-h) are compounds with the stereochemical configuration of the compounds of formula (I-a) and (I-b).

In the compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or (I-h)when applicable, A, E, X, n, R5, R7, R8and R9take the values specified in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description.

You should imagine that the above subgroups of compounds of formula (I-a), (I-b), (I-c), (I-d) or (I-e), as well as any other subgroup defined in the description, also includes any N-oxide, salt additive and stereochemical isomeric forms of such compounds.

Whenin the compounds of formula (I) or any subgroup of compounds of formula (I) n is 2, fragment-CH2-enclosed in brackets with the index “n”corresponds ethandiyl. When in compounds of formula (I) or any subgroup of compounds of formula (I) n is 3, the fragment-CH2-enclosed in brackets with the index “n”corresponds propandiol. When in compounds of formula (I) or any subgroup of compounds of formula (I) n is 4, the fragment-CH2-enclosed in brackets indecom “n”corresponds butandiol. When in compounds of formula (I) or any subgroup of compounds of formula (I) n is 5, the fragment-CH2-enclosed in brackets indecom “n”corresponds pentandiol. When in compounds of formula (I) or any subgroup of compounds of formula (I) n is 6, the fragment-CH2-enclosed in brackets with the index “n”corresponds hexandiol. Of particular interest is the subgroup of compounds of formula (I)in which n is 4 or 5.

Variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which a represents a-C(=O)OR1in particular, where R1represents a C1-6alkyl, such as methyl, ethyl or tert-butyl, most preferably where R1represents hydrogen.

Another embodiment of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), in which is And represents-C(=O)-NH-SO 2-R2in particular, where R2represents a C3-7cycloalkyl, phenyl or the group Het, for example, thiazolyl or pyridyl, which is optionally substituted by one or more substituents, such as one or two substituent selected from C1-6of alkyl, C1-6alkoxy, trifloromethyl and halogen, or, in particular, one or two substituent selected from methyl, fluorine and chlorine. For example, R2can be a 1-methylcyclopropyl.

Another embodiment of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where a represents-C(=O)C(=O)NR3aR3bin particular, where R3aand R3bindependently selected from hydrogen, C1-6the alkyl, optionally substituted aryl, and C2-6alkenyl. In one embodiment of the invention one of R3aand R3brepresents hydrogen and the other is a 3-propenyl, cyclopropylmethyl or cyclopropyl. In yet another embodiment of the invention R3aand R3bboth represent hydrogen.

Another embodiment of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which a represents a-C(=O)-NH-P(=O)(OR4a)(R4b), in particular, where R4arepresents a C1-6alkyl, in person the particular ethyl or isopropyl, R4bis a OR4b'and R4b'represents a C1-6alkyl, such as ethyl or isopropyl.

Another embodiment of the invention are the compounds of formula (I), in which a represents-P(=O)(OR4a)(R4b), in particular, where R4arepresents a C1-6alkyl, especially ethyl or isopropyl, R4bis a OR4b'and R4b'represents a C1-6alkyl, especially ethyl or isopropyl.

Another embodiment of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(a) R5represents hydrogen; C1-6alkyl; C1-6alkoxyl1-6alkyl or C3-7cycloalkyl;

(b) R5represents hydrogen or C1-6alkyl;

(C) R5represents hydrogen.

Preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where R5represents hydrogen or C1-6alkyl, more preferably hydrogen or methyl.

Another variant embodiment of the invention relates to compounds of formula (I), (I-e), or any subgroup of compounds of formula (I), where R6aand R6bindependently represent hydrogen or C1-6alkyl, for example methyl. Preferred is compulsory R 6arepresents hydrogen, and R6brepresents methyl, or, more preferably, R6aand R6bboth represent hydrogen.

Variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(a) R8represents a radical of the formula

(b) R8represents a radical of the formula

(C) R8represents a radical of the formula

Variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where

(d) R8represents a radical of the formula

(e) R8represents a radical of the formula

(f) R8represents a radical of the formula

Variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which R9and R10or one of R9and R10accept(et) the following values:

R9represents a C1-6alkyl (e.g. methyl, ethyl or isopropyl);1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy); aryloxy; Het-O-; cyano; or R9is sobeys 1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy) or aryloxy (for example, phenoxy or 4 methoxyphenoxy);

R10represents hydrogen; C1-6alkyl (e.g. methyl, ethyl or isopropyl);1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy); cyano.

In the paragraph above aryl and Het are set as described above or hereinafter, in particular, the aryl is a phenyl, optionally substituted C1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy), more precisely, a 4-substituted phenyl; and Het, in particular, represents a pyridyl or pyrimidinyl.

Preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which one of R9represents hydrogen, methoxy or cyano.

Preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where R9represents cyano, C1-6allyloxycarbonyl, mono - and di(C1-6alkylamino), halogen, amino, C1-6alkoxy, aryloxy,1-6alkyl, Het; or where R9represents cyano, C1-6allyloxycarbonyl (for example, methoxycarbonyl), mono(C1-6alkylamino) (for example, methylamino), halogen (e.g. chlorine)1-6alkoxy (e.g. methoxy), phenoxy,1-6alkyl (for example, ethyl), thiazolyl, optionally substituted C1-6the alkyl (for example, 2-methyl-4-thiazolyl).

Preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which R10represents hydrogen, C1-6alkoxy (e.g. methoxy) or halogen.

Preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which one of R9and R10represents halogen (in particular fluorine or trifluoromethyl. Other preferred variants are compounds in which R9represents halogen (in particular fluorine or trifluoromethyl, and R10represents hydrogen.

Preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which R8represents a radical of the formula

where R9represents cyano or methyl and R10represents hydrogen or methoxy; or R9represents cyano or methoxy and R10represents hydrogen.

Other preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), where R8the stand is made by a radical of the formula

or formulaor of the formula

where either or both of the following conditions (a) and (b):

(a) R9represents cyano, C1-6allyloxycarbonyl, mono - and di(C1-6alkylamino), halogen, amino, C1-6alkoxy, aryloxy,1-6alkyl, Het; or where R9represents cyano, C1-6allyloxycarbonyl (for example, methoxycarbonyl), mono(C1-6alkylamino) (for example, methylamino), halogen (e.g. chlorine)1-6alkoxy (e.g. methoxy), phenoxy,1-6alkyl (e.g. methyl), thiazolyl, optionally substituted C1-6the alkyl (for example, 2-methyl-4-thiazolyl);

(b) R10represents hydrogen, C1-6alkoxy (e.g. methoxy) or halogen.

Variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), whererepresents a group

which has the following structure:

Variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), wheretakes the values defined in the previous paragraph, and R8a, R9aand R10or athe R 8a, R9aand R10in particular, take the following values:

R8aand R9aindependently represent hydrogen, C1-6alkyl (e.g. methyl, ethyl or isopropyl);1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy); aryloxy; Het-O; cyano; or R10represents hydrogen, C1-6alkoxy (for example methoxy, ethoxy or isopropoxy) or aryloxy (for example, phenoxy or 4 methoxyphenoxy);

R8aand R9aindependently represent hydrogen; C1-6alkyl (e.g. methyl, ethyl or isopropyl);1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy); cyano; or R10represents hydrogen, C1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy).

Variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I)in which R8represents hydrogen.

In the previous paragraphs, aryl and Het take the values defined previously, in particular, the aryl is a phenyl, optionally substituted C1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy), more precisely, a 4-substituted phenyl; and Het, in particular, represents a pyridyl or pyrimidinyl.

Preferred variants of the invention are the compounds of formula (I) or any subgroup of compounds of formula (I), in the which one of R 9represents hydrogen, methoxy or cyano.

The compounds of formula (I) consist of three structural blocks P1, P2, P3. Structure-forming unit P1 further comprises an end portion (tail) P1'. Carbonyl group marked with an asterisk in the compound (I-i), below, may be part of a structure-forming unit P2 or structural unit P3. From a chemical point of view it is clear that the structure-forming unit P2 of the compounds of formula (I), where X represents S, includes a carbonyl group attached to position 1'.

Linking structural units P1 to P2, P2 to P3 and P1 with P1' (when R1represents-NH-SO2R2occurs with the formation of amide linkages. Linking blocks P1 and P3 occurs with formation of a double bond. Linking structural units P1, P2 and P3 to obtain the compounds (I-i) or (I-j) can be performed in any sequence. One of the stages includes cyclization, which is formed macrocycle.

Below shows the compound (I-i), which are compounds of formula (I), in which the carbon atoms C7 and C8 are connected by a double bond, and the compound (I-j), which are compounds of formula (I), in which the carbon atoms C7 and C8 are connected by a single bond. The compounds of formula (I-j) can be obtained from the corresponding connection the settings of the formula (I-i) restoration of the double bond in the macrocycle.

It is understood that the methods of synthesis described below, applicable to racemate, pure stereochemical intermediate or final products or any stereoisomeric mixtures. The racemate or stereochemical mixture can be divided into stereoisomeric forms at any stage of the methods of synthesis. In one embodiment of the invention intermediate products and final products have the stereochemistry as defined above in the compounds of formula (I-a) or (I-b).

In the discussion below, R11represents a radical

In one embodiment, the invention compound (I-i) receive via the formation of amide linkages with the subsequent formation of a bridge of a double bond between P3 and P1 with simultaneous cyclization to the macrocycle.

In yet another embodiment of the invention the compound (I), in which the bond between C7and C8is a double bond, i.e. compounds of formula (I-i), defined above, can be obtained in accordance with the following synthesis scheme:

The formation of the macrocycle can be done through the exchange reaction of olefins in the presence of a suitable metal catalyst, such as catalyst based on ruthenium described in the publications Miller, S.J., Blackwell, H.E., Gubbs, R.H. J. Am. Chem. Soc. 118, (1996), 9606-9614; Kingsbury, J. S., Harrity, J. P. A., Bonitatebus, P. J., Hoveyda, A. H., J. Am. Chem. Soc. 121, (1999), 791-799; and Huang et al., J. Am. Chem. Soc. 121, (1999), 2674-2678; for example, catalyst Howeidy-verification (Hoveyda-Grubbs).

May apply stable in air 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 generations, 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 Howeidy-verification of the first and second generations, which are dichloro(o-isopropoxyphenyl)(tricyclohexylphosphine)ruthenium(II) and 1,3-bis-(2,4-trimetilfenil)-2-imidazolidinone)dichloro(o-isopropoxyphenyl)ruthenium, respectively. In this reaction can also be applied to other catalysts containing other transition metals such as Mo.

The exchange reaction can be conducted in a suitable solvent, such as, for example, ethers, in particular THF, dioxane; halogenated hydrocarbons such as dichloromethane, CHCl3, 1,2-dichloroethane and the like, hydrocarbons, for example, the thickness of the ol. In a preferred embodiment of the invention, the exchange reaction is carried out in toluene. Such reactions are conducted at elevated temperatures in an atmosphere of nitrogen.

The compounds of formula (I), in which the link between 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) restoration of the C7-C8 double bond in compounds of formula (I-i). Such recovery can be performed by catalytic hydrogenation with hydrogen in the presence of a catalyst of a noble metal such as Pt, Pd, Rh, Ru or Raney Nickel. Of particular interest is the Ph on aluminum. The hydrogenation reaction is preferably conducted in a solvent such as, for example, alcohols, in particular methanol, ethanol, or an ether, such as THF, or mixtures thereof. These solvents or mixtures of solvents can be added to water.

Group And may join structure-forming unit P1 at any stage of the synthesis, i.e. before or after the cyclization, either before or after cyclization with recovery, as described above. The compounds of formula (I)in which a represents a-CO-NHSO2R2, i.e. the compounds of formula (I-k-1), can be obtained by joining the group And to P1 through the formation of amide linkages between the two fragments. Similarly, connected to the I of the formula (I), in which R1represents-C(=O)OR1, i.e. the compounds of formula (I-k-2), can be obtained by joining the group R1to P1 through the formation of ester bonds. In one embodiment of the invention, the group-C(=O)OR1, introduced at the last stage of the synthesis of compounds (I), as shown in the following synthesis scheme, where G is a group

Intermediate (2A) can be combined with a sulfonamide (2b) via the formation of amide, for example in accordance with any of the methods of amide bond formation as described below. In particular, (2A) can be handled by the agent combinations, for example, N,N'-carbonyl diimidazol (CDI), EEDQ, IIDO, EDCI or benzotriazol-1 yloxy-Tris-pyrrolidineethanol hexaflurophosphate (commercially available as PyBOP®), in a solvent such as a simple ether, for example THF, or a halogenated hydrocarbon, e.g. dichloromethane, chloroform, dichloroethane, and are subject to interaction with the target sulfonamide (2b), preferably after the interaction (2A) with the agent combinations. Interaction (2A) with (2b) is preferably conducted in the presence of a base, for example, trialkylamine, such as triethylamine or diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The intermediate compound (2A) can also build Atisa in activated form, for example, the activated form of the General formula G-CO-Z, where Z represents halogen or the residue of an active complex ester, for example, Z represents aryloxy group, such as phenoxy, p-nitrophenoxy, Pantothenate, trichlorophenoxy, pentachlorophenoxy and the like; or Z may represent a remnant of the mixed anhydride. In one embodiment of the invention G-CO-Z is an acid chloride (G-CO-Cl) or a mixed acid anhydride (G-CO-O-CO-R or G-CO-O-CO-OR R in the last formula represents a C1-4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or benzyl). An activated form of G-CO-Z undergoes interaction with the sulfonamide (2b).

The compounds of formula (I)in which A represents-C(=O)-NH-P(=O)(OR4a)(R4b), i.e. the compounds of formula (I-k-3), can be obtained by forming amide linkages between the intermediate product (2A) and phosphoramidate (2d) in accordance with the methods of amide bond formation, described next. In particular, (2A) may be processed by an agent combination in a suitable solvent and subsequent interaction with phosphoramidates (2d) preferably in the presence of a base such as sodium hydride, preferably after the interaction (2A) with the agent combinations. The intermediate compound (2A) can also be excellent is asenio in activated form, for example, the activated form of the General formula G-CO-Z, where 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 embodiment of the invention G-CO-Z is an acid chloride (G-CO-Cl) or a mixed acid anhydride (G-CO-O-CO-R or G-CO-O-CO-OR, where R represents a C1-4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or benzyl). An activated form of G-CO-Z is subjected to interaction with the target compound (2b). Agent combination, the solvent and base may be such as described in the General description of the receiving amide bonds.

Activation of the carboxylic acid in (2A), as described in the reactions described above can lead to intermediate cyclization reaction with intermediate azlactone formula

where X, E, R7, R11and n take the values described above, and where the stereogenic centers may have the stereochemical configuration described above, for example, as in (I-a) or (I-b). Intermediate compounds (2A-1) can be isolated from the reaction mixture using the traditional methods, and selected intermediate compound (2A-1) then undergoes interaction with (2b), or the reaction mixture containing (2A-1) subject to interaction with (2b) or (2d) without selection (2A-1). In one embodiment of the invention, where the interaction with the agent combination is not miscible with water, the solvent, the reaction mixture containing (2A-1)can be cleaned with water or weakly padmalochan water to remove all insoluble in water and by-products. Thus obtained leaching solution may then be subjected to interaction with (2b) or (2d) without additional purification stages. On the other hand, the allocation of intermediate compounds (2A-1) can provide certain advantages in that the isolated product after an optional additional purification may be subjected to interaction with (2b) or (2d), which reduces the formation of by-products and facilitates the reaction.

Intermediate (2A) can be combined with alcohol (2C) via the formation of ester. For example, (2A) and (2C) are interacting with the removal of water, which is either physically, e.g., azeotropic removal of water, or chemically using a dehydrating agent. The intermediate compound (2A) can also become activated in the form G-CO-Z, such as activated forms mentioned above, and further interact with alcohol (2C). The formation of ester is preferably conducted in the presence of a base such as a carbonate or bicarbonate of an alkali metal, e.g. sodium bicarbonate or potassium, or a tertiary amine, such as amines mentioned in the description of reactions of formation of amide, in particular, trialkylamine, for example, triethylamine. Solvents that can be used in the reaction of formation of ester include ethers such as THF; halogenated Uglevodorody, such as dichloromethane, CH2Cl2; hydrocarbons such as toluene; polar aprotic solvents such as DMF, DMSO, DMA; and other solvents.

The compounds of formula (I)in which E represents NH, i.e. the compounds of formula (I-l), can also be obtained by removing group PG, which is a protective group of nitrogen, from the corresponding intermediate compound (3A) in accordance with the following reaction scheme. The protective group PG, in particular, is any protective group of the nitrogen atom of the above-mentioned hereinafter and can be removed using techniques, also described below:

The original substance (3A) in the above reaction can be obtained in accordance with methods of the AMI obtain compounds of formula (I), but using intermediate compounds in which the group R5represents a protective group for the nitrogen atom of PG are as defined above.

The compounds of formula (I) can be obtained by the interaction of the intermediate compound (4A) with the amine (4b-1), (4b-2) or (4b-3) in the presence of the carbamate-forming reagent, as shown in the following synthesis scheme, where different radicals take the values defined above:

The interaction of intermediate products (4A) with a carbamate-forming reagent is carried out in the same solvents and bases that are used for the formation of amide linkages, as described below.

The reaction of formation of the carbamate can be carried out using various methods, in particular, the interaction of amines with alkylchlorosilanes; the interaction of alcohols with carbamylcholine or isocyanates; through reactions involving metal complexes or reagents transferring acyl groups (see, for example, Greene, T. W. and Wuts, P. G. M., "Protective Groups in Organic Synthesis"; 1999; Wiley and Sons, p. 309-348). For the synthesis of carbamates from some starting compounds, including amines, can be used carbon monoxide and some metal catalysts. As catalysts may be used such metals as palladium, iridium, uranium, and platinum. Can use the camping methods for the synthesis of carbamates using carbon dioxide, described in the literature (see, for example, Yoshida, Y., et al., Bull. Chem. Soc. Japan 1989, 62, 1534; Aresta, M., et al., Tetrahedron, 1991, 47, 9489).

One approach includes the use of carbamates intermediates

where Q represents a removable group, such as halogen, in particular chlorine and bromine, or a group used in the active esters for the formation of amide linkages, such as those mentioned above, for example, phenoxy or substituted, phenoxy group, such as p-chloro - or p-nitrophenoxy, trichlorophenoxy, pentachlorophenoxy, N-hydroxysuccinimidyl etc. Intermediate compound (4d) can be obtained from alcohols (4A) and phosgene with obtaining, thus, chloroformate or displacement of chlorine from the last intermediate in the intermediate (5A)i.e. the intermediate compounds of formula (4d), in which Q represents Q1. In this method and the methods of subsequent reactions Q1is any of the active fragments of esters, such as fragments mentioned above. Intermediate products (4d) are subjected to interaction with amines (4b-1), (4b-2) or (4b-3) obtaining thus compounds of formula (I).

Intermediate compound (4E), which are intermediate compounds (4d), in which Q represents Q1can also be obtained from Samadashvili alcohol (4A) with carbonates Q 1-CO-Q1such as, for example, bisphenol a, bis-(substituted phenol) or bis-N-hydroxysuccinimidyl:

The above reactions produce an intermediate compound (4d) can be carried out in the presence of bases and solvents mentioned above for the synthesis of amide bonds, in particular, triethylamine as base and dichloromethane as solvent.

Alternatively, to obtain the compounds of formula (I) first, the reaction of formation of amide linkages between structural blocks P2 and P1 with the following combination of structural unit P3 fragment P1 P1-P2, and then the reaction of the formation of urethane or ether linkages between fragments P3 and P2 in P2-P1-P3 with the simultaneous closing of the cycle.

Another alternative method of synthesis consists in the formation of amide linkages between structural blocks P2 and P3, followed by a combination of structure-forming unit P1 P3 fragment in P3-P2 and forth with the formation of amide bond between P1 and P2 in P1-P3-P2 with the simultaneous closing of the cycle.

Structure-forming units P1 and P3 may contact in the sequence of P1-P3. If necessary, the double bond linking R1 and R3, may be subject to recovery. The resulting sequence of P1-P3, restored or not, the mod is should be combined with structure-forming unit P2 with education thus the sequence P1-P3-P2, ciclismo further through the formation of amide linkages.

Structure-forming units P1 and P3 in any of the above approaches can be combined by forming the double bond, for example, through exchange reactions of olefins, described below, or by using the Wittig reaction. If necessary, the thus obtained double bond may be subject to recovery by the method similar to that described above for the conversion of (I-i) (I-j). The double bond may also be subject to recovery at a later stage, i.e. after the accession of the third structural unit, or after the formation of the macrocycle. Structural blocks P2 and P1 are connected through the formation of amide linkages, and P3 and P2 are connected through the education group of the carbamate or ether complex.

The remainder of the P1' can join structure-forming unit P1 at any stage of the synthesis of compounds of formula (I), for example, before or after connecting structural units P2 and P1; before or after attaching structural unit P3 to P1; or before or after the closing cycle.

First can be obtained separate structural blocks, which can then be combined together, or, alternatively, the precursors of the structural units can be combined together and then modified at last the stage of obtaining molecules desirable patterns.

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

The formation of amide bonds can be carried out using standard techniques, such as techniques used for the combination of amino acids in the synthesis of peptides. The latter includes dehydrative combination of carboxyl group of one reagent with the amino group of another reagent with the formation of the amide bond connecting. The formation of the amide bond can be carried out through the interaction of initial substances in the presence of the agent or combination by turning the carboxyl functionality in the active form, such as an active ester, mixed anhydride or acid chloride or bromohydrin carboxylic acid. General description of such reactions and reagents used in them, can be found in textbooks of peptide chemistry, for example, M. Bodanszky, “Peptide Chemistry”, 2ndrev. ed., Springer-Verlag, Berlin, Germany, (1993).

Examples of reactions combination with amide bond formation include the azide method, the method of the mixed anhydride of carboxylic acid (isobutylparaben), carbodiimide method (using dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide, such as N-ethyl-N'-[(3-dimethylamino)propyl]carbodiimide), the way Akti is tion of ester (for example, p-nitrophenylthio, p-Hohenlohe, trichloranisole, pentachlorphenol, pentafluorophenyl, N-hydroxysuccinimide etc. esters), the method of reagent-To Woodward, the way 1,1-carbonyldiimidazole (CDI or N,N'-carbonyldiimidazole), methods using a phosphorus-containing reagents or oxidation-reduction. Some of these methods can be improved by the addition of suitable catalysts, for example, carbodiimide method can be improved by adding 1-hydroxybenzotriazole, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or 4-DMAP. Additional agents combinations are hexaflurophosphate (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium (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 extortive O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea. These reactions combinations can be held in solution in the liquid phase or in solid phase.

The preferred amide bond formation is carried out using N-ethoxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEDQ) or N-isobutylketone-2-isobutoxy-1,2-dihydroquinoline (IIDQ). Unlike classical techniques anhydride, using EEDQ and IIDQ requires no base or low temperature reactions. Typically the method includes the interaction e is violari amounts of carboxyl and amine components in the organic solvent can be used in a variety of solvents). Then, the excess is added EEDQ or IIDQ and the mixture was incubated at room temperature with stirring.

Of combination reaction is preferably conducted in an inert solvent, such as halogenoalkane hydrocarbons such as dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO, NMRT, ethers, such as tetrahydrofuran (THF).

Many examples of combination reaction is conducted in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine, 4-DMAP or 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction temperature is in the range from 0°C to 50°C and the reaction time may be from 15 minutes to 24 hours.

Functional groups in the structural units, which are connected together, can be protected to prevent unwanted connections. Suitable protective groups that can be used, see, for example, in the publications Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1999) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1987).

Carboxyl groups can be protected with getting groups of ester, which can be converted to obtain the carboxylic acid group. Protective groups which can be used in luchot 1) group of complex alilovic esters, such as methyl, trimethylsilyloxy or tert-butyl; 2) group of complex arylalkyl esters, such as benzyl and substituted benzyl; or 3) the group of esters, which can be split under the action of a weak base or a weak reductant, such as the group of complex trichlorethylene and ventilago esters.

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

1) acyl groups such as formyl, trifluoracetyl, Tallina and p-toluensulfonyl;

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

3) aliphatic urethane groups, such as tert-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 or tert-butyldimethylsilyl; and

7) group containing Tilney group, such as phenylthiocarbamyl and datasection.

Protective groups of particular interest are the BOC and Fmoc.

Preferably a protective group of the amine the group split before the next stage combination. Removal of N-protecting groups may be carried out in accordance with well-known in the art techniques. When using the BOC-group, selected methods are the use of triperoxonane acid (pure or in dichloromethane) or HCl in dioxane or ethyl acetate. The obtained ammonium salt is then neutralized before combination or in situ using basic solutions, such as aqueous buffers or tertiary amines in dichloromethane, acetonitrile or dimethylformamide. When using Fmoc-group-selected reagents are piperidine or substituted piperidine in dimethylformamide, but can be used and any secondary amine. Removing the protection is carried out at a temperature in the range from 0°C to room temperature, typically in the range of about 15-25°C or 20-22°C.

Other functional groups that can influence the reaction of a combination of structural units, can also be protected. For example, hydroxyl groups can be protected with getting groups of ordinary benzyl or substituted benzyl ethers, for example, a simple 4-methoxybenzylthio ether complex benzilovogo or substituted benzilovogo esters, for example, complex 4-nitrobenzoate ether, or using trialkylsilyl groups (for example, trimethylsilyloxy or tert-butyldimethylsilyloxy group).

Further the s amino group can be protected with protective groups, able to be selective cleavage. For example, when the α-aminoamide groups are used Vos, suitable are the following protective groups of the side chains of the p-toluensulfonyl (tselnye) fragments can be used to protect more amino groups; simple benzyl (Bn) ethers can be used to protect hydroxyl groups; and complex benzyl esters can be used to protect additional carboxyl groups. When to protect the α-amino group selected Fmoc, suitable protective groups usually are tert-butyl groups. For example, the EGM can be used for additional amine groups; group a simple tert-butyl ester to hydroxyl groups; and groups of complex tert-butyl ester for additional carboxyl groups.

Any of the protective groups can be removed at any stage of the synthesis procedures, but preferably a protective group of any functional groups not involved in the stage of synthesis reactions are removed after formation of the macrocycle.

Removing the protective groups can be carried out in any manner determined by the choice of protective groups, which are well known specialist in this field of technology.

Intermediate products of the formula (1a), in which X represents N, i.e. intermediate products of the formula (1A-1), can be is derived from intermediates (5A), which are subject to interaction with alkeneamine (5b) in the presence of the agent, the introduction of carbonyl as shown in the following reaction scheme.

Agents the introduction of a carbonyl group (CO) include phosgene or phosgene derivatives such as carbonyldiimidazole (CDI) and the like In one embodiment of the invention, the compound (5A) is subjected to interaction with an agent introducing CO-group in the presence of a suitable base and in a solvent, which can be a base and the solvent used in the reaction of formation of amide linkages described above. In a specific embodiment of the invention the base is a carbonate, for example, NaHCO3or tertiary amine, such as triethylamine and the like, and the solvent is a simple ether or halogenated hydrocarbon, for example, THF, CH2Cl2, CHCl3etc. After this is added the amine (5b) to obtain intermediate products (1A-1), as shown in the diagram above. An alternative way using similar reaction conditions includes a first interaction agent introduction with alkeneamine (5b) and the subsequent interaction of the thus obtained intermediate product with a compound (5A).

Intermediate products (1A-1) can be an alternative receiving the s as follows:

PG1represents a O-protecting group, which can be any of the groups mentioned in the description, and in particular, is benzoyloxy or substituted benzoyloxy group, such as 4-nitrobenzoyl. In the last example, this group can be removed by interaction with the alkali metal hydroxide (LiOH, NaOH, KOH), in particular, when PG1is a 4-nitrobenzoyl, interaction with LiOH in aqueous medium comprising water and water soluble organic solvent, such as alkanol (methanol, ethanol and THF.

Intermediate compound (6A) subject to interaction with alkeneamine (5b) in the presence of the agent, the introduction of the carbonyl group, as described above, and this reaction leads to the production of intermediate products (6C). From the obtained compounds are removed protective group, in particular, using the reaction conditions described above. The resulting alcohol (6d) subject to interaction with intermediates (4b-1), (4b-2) or (4b-3), as described above in the description of the interaction of (4A) with (4b-1), (4b-2) or (4b-3), and this reaction leads to the production of intermediates (1A-1).

Intermediate products of the formula (1A), where X represents S, i.e. intermediate products of the formula (1A-2), can be obtained is through the formation of amide, based on the intermediates (7a), which are subject to interaction with alkeneamine (5b)as shown in the following reaction scheme, using the reaction conditions obtaining amides, which are described above.

Alternatively, intermediates (1A-2) can be obtained as follows:

PG1represents a O-protecting group, as described above. Can be used reaction conditions described above: amide formation as described above, deleting PG1in accordance with the description of the protective groups and the introduction OR11as in reactions (4A) with amines (4b-1), (4b-2) or (4b-3).

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

PG2represents a protective group of carboxyl group, for example, one of the protective group of carboxyl group, mentioned above, in particular, the group of complex1-4alkylboron or benzyl ether, for example, a complex methyl, ethyl or tert-butyl methyl ether. The reaction conversion (9a) (9b) is the exchange reaction and is carried out as described above. Group PG2delete what is in accordance with the methods also described above. When PG2is a group With1-4Olkiluoto ether, it is removed by alkaline hydrolysis, for example with NaOH or preferably LiOH in aqueous solvent, for example, a mixture With1-4alkanol/water. The benzyl group can be removed by catalytic hydrogenation.

In an alternate synthesis of intermediate compound (2A) can be obtained as follows:

PG1the group is selected such that it selectively was cut with education PG2. PG2can represent, for example, the group of complex methyl or ethyl esters, which can be removed by treatment with a hydroxide of an alkali metal in the aquatic environment, in this case PG1represents, for example, tert-butyl or benzyl. PG2the group may be a group of complex tert-butyl ether, which can be removed in a weak acidic conditions, or PG1can be a group of simple benzyl ester, which can be removed using a strong acid or by catalytic hydrogenation, in the latter two cases PG1represents, for example, the group of complex benzoic ether, such as group 4-nitrobenzoyl ether.

First intermediate compound (10A) podvergaut the cyclization to complex macrocyclic ethers (10b), to remove protection from the latest remove PG1groups receiving (10C), which is subjected to interaction with (4b) in accordance with the reaction of formation of carbamate as described above, with the subsequent removal of the group PG2protecting the carboxyl group. Cyclization, removing the protective groups PG1and PG2and the reaction of formation of carbamate from (4b-1), (4b-2) or (4b-3) described above.

Group can be introduced at any stage of the synthesis, or at the last stage, as described above, either prior to the formation of the macrocycle. The following diagram introduces the group And which represents a-CO-NH-SO2R2or-CO-OR5(as defined above):

In the above diagram PG2takes the values defined above, and L1is a P3 group

where n and R5take the values defined above, and X represents N, L1can also represent a group-COOPG2awhere the group PG2arepresents a protective group of carboxyl group, similar to PG2but the group PG2acapable of selectively split with obtaining group PG2. In one embodiment of the invention PG2arepresents tert-butyl, and PG2represents methyl or those who.

Intermediate products (11C) and (11d), where L1represents a group (b)correspond to intermediate products (1A) and may be processed as defined above.

The combination of structural units P1 and P2

Structural blocks P1 and P2 are associated with the use of the reaction of formation of amide in accordance with the techniques described above. Structure-forming unit P1 may contain group PG2protecting the carboxyl group (as in (12b)), or may already be connected to P1' group (as in (12C)). L2represents an N-protecting group (PG) or group (b)as described above. L3represents a hydroxyl group, -OPG1or a group-O-R11that defined above. When any of the following schemes reactions L3represents a hydroxyl group, before each reaction stage it can be protected and can be represented as a group-OPG1and if you want, then the protective group can be removed with the free hydroxyl functional groups. Similarly, as described above, the hydroxyl functional group can turn to the group-O-R11.

In the method presented above, the scheme cyclopropylamine (12b) or (12C) is combined with the acid functional g is POI P2 structural unit (12A) with the formation of the amide bridge in accordance with the methods described above. Thus obtained intermediate products (12d) and (12E). When was the last L2represents a group (b), the resulting products represent a sequence P3-P2-P1, including some of the intermediate products (11C) and (11d) in the previous reaction scheme. The removal of the protective group of the acid in (12d) using suitable conditions for used protective group and subsequent combination with a sulfonamide H2N-SO2R2(2b), phosphoramidon (2d) or HOR1(2c), as described above, again leads to the production of intermediate products (12E), where-A is an amide group or a group of ester. When L2represents an N-protecting group, it may be deleted from obtaining intermediates (5A) or (6A). In one embodiment of the invention PG in this reaction is a BOC group, and PG2represents methyl or ethyl. When L3represents a hydroxyl group, the original connection (12A) is a BOC-L-hydroxyproline. In a specific embodiment of the invention PG is a BOC group, PG2represents methyl or ethyl, L3represents-O-R11.

In one embodiment, the invention L2represents a group (b), and presents the reaction in luchot combination of P1 with P2-P3, that leads to the production of intermediates (1A-1) or (1A)described above. In another embodiment, the invention L2represents an N-protecting group PG, which is defined above, and the reaction mix leads to the production of intermediate products (12d-1) or (12E-1), from which the group PG may be removed using the reaction conditions described above, to obtain the intermediate products (12-f) or (12-g), respectively, which include intermediate products (5A) and (6A)defined above:

In one embodiment of the invention, the group L3in the above diagrams represents a group-O-PG1that can be entered in the source substance (12A), where L3represents a hydroxyl group. In this example, PG1selected in such a way that it is capable of selectively split to obtain group L2that is a PG.

In a similar way structural blocks P2, in which X represents s and which are derived cyclopentane or cyclopentene, can contact with structure-forming units P1 as shown in the following diagram, where A, R7L3take the values defined above, and PG2and PG2arepresent a protective group of carboxy who enoy group. PG2ausually chosen so that it could be selectively split with obtaining group PG2. Delete group PG2ain (13C) leads to the production of intermediates (7a) or (8A), which can be subjected to interaction with (5b), as described above.

In a specific embodiment of the invention, where X represents S, R7represents N and X and the carbon attached to R7connected by a single bond (P2 represents a cyclopentane fragment), PG2aand L3together form a bond, and structure-forming unit P2 corresponds to the formula

Bicyclic acid (14a) is subjected to interaction with (12b) or (12C), as described above, obtaining (14b) and (14C), respectively, where the lactone is revealed with intermediate products (14C) and (14). The lactones may be subject to disclosure using methods of hydrolysis of esters, for example, in the conditions described above for alkali removal PG1group in (9b), in particular, using basic conditions, such as alkali metal hydroxide, for example NaOH, KOH, particularly LiOH.

Intermediate products (14C) and (14) can be further processed, as described below.

The combination is their structural blocks P3 and P2

When structural units P2 contain pyrolidine fragment, structure blocks P3 and P2 or P3 and P2-P1 is combined with the formation of carbamate in accordance with the methods described above for the combination of (5A) with (5b). A General method of combining P2 blocks containing pyrolidine fragment represented by the following reaction scheme, where L3takes the values defined above, and L4represents a group-O-PG2group

In one embodiment, the invention L4in (15A) is a group-OPG2where PG2the group may be removed and the resulting acid may be combined with cyclopropylmagnesium (12A) or (12b) to obtain intermediate products (12d) and (12E), in which L2is a radical (d) or (e).

A General method of combining blocks P3 unit P2 or with block P2-P1, where P2 is a cyclopentane or cyclopentene presented on the following scheme. L3and L4take the values defined above.

In a specific embodiment, the invention L3and L4together form lackenby bridge, as in (14a), and a combination unit P3 unit P2 is as follows:

Bi is Ilichevsky lactone (14a) is subjected to interaction with (5b) in accordance with the reaction of the formation of amide with getting amide (16C), lackenby bridge which reveals obtaining (16d). The conditions of reaction of formation of amide and opening of the lactone described above or below. The intermediate product (16d), in turn, can be combined with a group R1 as described above.

The reaction shown in the above schemes are carried out using methods that are described above for the reactions (5A), (7a) or (8A) with (5b), in particular, the reaction described above, where L4is a group (d) or (e), consistent reactions (5A), (7a) or (8A) with (5b), as described above.

Structure-forming units P1, P1', P2 and P3 used in the preparation of compounds of formula (I)can be obtained from known in the art of intermediate products. Some of these syntheses are described in more detail below.

First can be obtained separate structural blocks, which can then be connected together or, alternatively, the precursors of the structural units can be connected together and be modified at a later stage to the molecules of the desired structure.

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

Synthesis of structural blocks P2

Structural blocks P2 contain pyrolidine, cyclopentane or cyclopentenone fragment, substituted gr is POI-O-R 11.

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

Obtaining structural blocks P2, which contain a cyclopentane ring, can be carried out in accordance with the scheme below.

Bicyclic acid (17b) can be obtained, for example, 3,4-bis(methoxycarbonyl)Cyclopentanone (17A), as described in the publication Rosenquist et al., Acta Chem. Scand. 46 (1992) 1127-1129. The first stage in this method includes the restoration of the keto-group in such a reducing agent as borohydride sodium in a solvent such as methanol, followed by hydrolysis of esters and, finally, the closure ring of the bicyclic lactone (17b) in accordance with the methods of formation of the lactone, in particular, through the application of acetic anhydride in the presence of a weak base such as pyridine. The functional group of carboxylic acid in (17b) can then be protected through the introduction of a suitable protective group, such as group PG2defined above, obtaining thus a complex bicyclic ether (17c). Group PG2in particular, is acid-labile, such as tert-bucilina group, and is, for example, by treatment with Isobutanol in the presence of Lewis acid is or di-tert-BUTYLCARBAMATE in the presence of a base, such as a tertiary amine, for example, dimethylaminopyridine or triethylamine, in a solvent such as dichloromethane. Disclosure of lactone (17c) in the conditions described above, in particular, in the presence of lithium hydroxide, results in acid (17d), which can be used later in the reactions combination with structure-forming units P1. The free acid group in (17d) can also be protected, preferably a protective group of the acid PG2athat is selectively cleaved to group PG2and hydroxyl function can be transformed into the group-OPG1or the group-O-R11. Intermediate products (17g), and (17i)obtained after removal of the group PG2correspond to intermediate products (13A) or (16A), as defined above.

Intermediate products with specific stereochemistry can be obtained by separation of the intermediates in the above-described sequence of reactions. For example, (17b) can be divided in accordance with known methods, for example by interaction of the salt form with an optically active base or by chiral chromatography and the stereoisomers can be further processed, as described above. Group IT and COOH in (17d) are in the CIS-position. TRANS-analogues can be obtained by inverting the stereochemistry at the carbon atom that is attached to the functional group-HE, with the use of specific reagents in reactions introduction-OPG1or-O-R11when there is inversion of stereochemistry, such as, for example, the reaction Mitsunobu.

In one embodiment of the invention intermediate products (17d) combined with blocks P1 (12b) and (12C) reaction combinations that correspond to the combination of (13A) or (16A) with the same blocks P1 using the same conditions. Sequential introduction-O-R11Deputy, as described above, and then removing the protective group of the acid group PG2leads to the production of intermediate products (8A-1), which are a subset of intermediate products (7a) or part of the intermediate products (16A). The reaction products removal PG2it may further be combined with structure-forming unit P3. In one embodiment of the invention PG2in (17d) represents tert-butyl, which can be removed in acidic conditions, for example, when processing triperoxonane acid.

Unsaturated structure-forming unit P2, i.e. cyclopentenone ring, can be obtained as shown in the diagram below.

The reaction of the synthesized-removal of 3,4-bis(methoxycarbonyl)Cyclopentanone (17A), as described in the publication Dolby et al., J. Org. Chem. 36 (1971)1277-1285, with the subsequent restoration of the keto functional group in such a reducing agent as borohydride sodium results of Cyclopentanol (19a). Selective hydrolysis of ester using, for example, lithium hydroxide, in a solvent such as a mixture of dioxane and water, leads to the production of hydroxy-substituted complex monoamino of Cyclopentanol (19b).

Unsaturated structure-forming unit P2, where R7also possible is different from hydrogen, can be obtained as shown in the diagram below.

Oxidation of commercially available 3-methyl-3-butene-1-ol (20A), in particular oxidizing agent, as chlorproma pyridinium, results in (20b), which is converted into the corresponding methyl ester, for example, by treatment with acetylchloride in methanol, followed by reaction of the synthesized bromine to obtain a complex of α-Brumaire (20C). The latter then may be subjected or complex alkenilovyh ether (20E), obtained from (20d) via the formation of ester. Ester (20E) preferably represents a tert-butyl ether, which can be obtained from the corresponding commercially available acid (20d), for example, by treatment with di-tert-BUTYLCARBAMATE in the presence of a base, such as dimethyl shall aminopyridin. The intermediate product (20E) is treated with base, such as diisopropylamide lithium, in a solvent such as tetrahydrofuran, and interacts with (20C) to obtain the complex alkenilovyh diapir (20f). Cyclization of (20f) via exchange reactions of olefins carried out as described above, provides the derivative cyclopentene (20g). Stereoselective epoxidation (20g) can be carried out using the method of asymmetric epoxidation of Jacobsen (Jacobsen) obtaining epoxide (20h). Finally, the reaction of the disclosure epoxide in basic conditions, for example, by adding a base, in particular DBN (1,5-diazabicyclo-[4.3.0]non-5-ene), leads to the production of alcohol (20i). The double bond in the intermediate product (20i) may optionally be subjected to recovery, for example, catalytic hydrogenation using a catalyst such as palladium on carbon, to obtain the corresponding cyclopentane compounds. The group of complex tert-butyl ether can be removed and obtaining the corresponding acid, which is consistently combined with structure-forming unit P1.

The group-O-R11can be entered in pyrolidine, cyclopentane or cyclopentenone cycles at any convenient stage of the synthesis of compounds according to the present invention. One approach is in is the primary introduction-O-R 11groups in these loops, and sequential addition of other necessary structural units, i.e. P1 (optional with tail P1'and P3 and then the formation of the macrocycle. Another approach is the combination of the structural units P2, does not contain-O-R11the Deputy, with each of the blocks P1 and P3 and introduction-O-R11group before or after the formation of the macrocycle. In the latter method fragments P2 contain a hydroxyl group which may be protected by a protective group of hydroxyl group PG1.

R11groups can be introduced into structural blocks P2 through interaction of hydroxy-substituted intermediates (21A) or (21b) with intermediates (4b) in the same way as described above for the synthesis of (I), from (4A). These reactions are represented in the diagrams below, where L2takes the values defined above, and L5and L5aindependently from each other represent a protective group of hydroxyl or carboxyl group-OPG2or-OPG2arespectively, or L5may also be a P1 group, such as group (d) or (e)defined above, or L5amay also be an R3 group, such as group (b), which is defined above. Group PG2and PG2atake the values defined above. When group L5/sup> and L5arepresent PG2or PG2athey are chosen so that each group could be subjected to selective cleavage to get another. For example, one group of L5and L5acan be a methyl or ethyl group and the other represents a benzyl or tert-boutelou group.

In one embodiment of the invention in (21A) L2represents-OPG2or in (21d) L5arepresents-OPG2and L5represents-OPG2and group PG2removed, as described above.

In another embodiment, the group of L2represents VOS, L5represents a hydroxyl group, and the original substance (21A) is a commercially available BOC-hydroxyproline or any other stereoisomeric form, for example, BOC-L-hydroxyproline, in particular, its TRANS-isomer. When L5in (21b) is a protective group of carboxyl group, it may be removed in accordance with the techniques described above for (s). In yet another embodiment of the invention PG in (21b-1) represents the Vos, and PG2is an ester of lower alkyl, in particular methyl complex or Adilov the second ether. Hydrolysis last of ester to acid can be carried out in accordance with standard techniques, for example, by acid hydrolysis using hydrochloric acid in methanol or alkali metal hydroxide, such as NaOH or, more preferably, using LiOH. In yet another embodiment of the invention hydroxy-substituted cyclopentane or cyclopentenone analogues (21d) are turning in (e), where L5and L5arepresent-OPG2or-OPG2aand the resulting product can be subjected to conversion into the corresponding acid (21f) by removing group PG2. Remove PG2ain (e-1) yields a similar intermediate products.

Synthesis of structure-forming units P1

Cyclopropanecarboxylate used to obtain fragment P1, is commercially available or can be obtained in accordance with methods known in the art.

In particular, complex aminobenzylpenicillin ester (12b) can be obtained in accordance with the methodology described in WO 00/09543, or as shown in the following diagram, where PG2represents a protective group of carboxyl group, which is defined above:

Treatment of commercially available or easily Sintesi what has been created imine (31A) 1,4-dehalogenation in the presence of a base results in (31b), which after hydrolysis provides getting cyclopropylamine (12b)containing the allyl substituent in the syn-position to the carboxyl group. The separation of the enantiomeric mixture of (12b) results in (12b-1). The separation is performed in accordance with known methods, such as enzymatic separation; crystallization with a chiral acid; chemical derivatization; or chiral column chromatography. Intermediate products (12b) or (12b-1) can be combined with suitable derivatives of P2, as described above.

Structure-forming units P1 to obtain the compounds according to General formula (I)in which a represents a-COOR1, -CO-NH-SO2R2or-CO-NH-PO(OR4a)(OR4b), can be obtained by the interaction of amino acids (32A) with a suitable alcohol, sulfonamide or phosphoramidon, respectively, under standard conditions of education receive ester or amide. Cyclopropylamine (32A) is obtained by introduction of N-protecting groups PG and removing PG2and the resulting PG-protected amino acids (32A) are subject to conversion into amides (12C-1) or esters (12C-2), which are subgroups of intermediate products (12C), as shown in the following diagram, where PG takes the values defined above.

Interaction (2A) with the amine (2b) or (2d) represents a method of formation of the amide. The analogous reaction with (2C) represents the reaction of the formation of ester. Both types of reactions can be carried out in accordance with the methods described above. This reaction leads to the production of intermediate products (32b), (32b-1) and (32C), from which the protective group of the amino group is removed by standard methods such as the methods described above. This, in turn, leads to obtain the desired intermediate product (12C-1), (12C-1A) or (12C-2). The original substance (32A) can be obtained from the above-mentioned intermediate products (12b). The original substance (32A) can be obtained from the above-mentioned intermediate products (12b) first, the introduction of the N-protecting group PG and the subsequent removal of the group PG2.

In one embodiment of the invention the interaction (32A) with (2b) or (2d) is carried out by treatment of the amino acid agent combinations, for example, N,N'-carbonyl diimidazol (CDI) or the like, in a solvent such as THF, followed by interaction with (2b) or (2b-1) in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively, the amino acid may be processed (2b) or (2d) in the presence of a base, such as diisopropylethylamine, or sodium hydride in case (2d) with subsequent processing agent combinations, such as hexaphosphate benzotriazol-1 yloxy-Tris-pyrrolidino one (commercially available as PyBOP®) for injection sulfonamidnuyu group.

Structure-forming units P1 to obtain the compounds according to General formula (I), where a represents-C(=O)C(=O)NR3aR3bconveniently receive in accordance with the following schema.

PG2ain the original substance (32d) represents an alkyl group, in particular, With1-6alkyl, such as methyl or ethyl. (32d) can be obtained from the reaction of formation of ester (32A) with a suitable alkanol or the introduction of nitrogen-protecting group PG in (12b), as described above. The reduction of the ester group in the derived amino acid (32d) to the appropriate hydroxymethylene intermediate product (e)conducted, for example, using lithium borohydride, followed by oxidation of the obtained hydroxymethylene group using a moderate oxidant, such as, for example, peridinin dessa-Martin, provides the aldehyde (32f). The interaction of the aldehyde (32f) with a suitable derivative of isonitrile in the presence of carboxylic acids, such as triperoxonane acid (TFOC), in the presence of a base, e.g. pyridine, in accordance with the reaction Passerini (which is described, for example, in Org. Lett., Vol. 2, No. 18, 2000) leads to the production of ester carboxylic acid obtained α-hydroxyamide, for example, in the case of TFWC to receive triftoratsetata of ester carboxylic acid thus obtained α-hydroxyamide can be removed using standard techniques, for example, using the basic conditions such as LiOH, resulting in the formation of α-hydroxyamide (32g). Delete group PG leads to the production of intermediate products (32h), which can be combined with the P2 group. Hydroxyl functional group (32g) can undergo oxidation to the corresponding α-ketoamide, but to prevent adverse reactions in subsequent reactions (such as removing the N-protecting group, the combination with the P2 fragment and so on) used α-hydroxyamide or its predecessor an ester of carboxylic acid. Oxidation of α-hydroxyl group P1 fragment is then carried out at any convenient stage of the synthesis, for example, after combination with the P2 fragment or at later stages of the synthesis, for example, at the last stage, with the use of weak oxidizing agent, such as, for example, peridinin dessa-Martin, thus obtaining the compounds of formula I or intermediates, in which a represents-C(=O)C(=O)NR3aR3b.

The above-described method, i.e. the recovery of ester, oxidation to the aldehyde, interaction with isonitriles, can also be carried out at later stages, methods of synthesis, for example, after the formation of the macrocycle.

Structure-forming units P1, which can be used to obtain the compounds of General formula (I), where a is the battle-C(=O)NH-P(=O)(OR 4a)(R4b) or-P(=O)(OR4a)(R4b)phosphonate, can be obtained in accordance with the methods described in WO 2006/020276. Specific examples of compounds of formula (I), where a is a-P(=O)(OR4a)(R4b), can be obtained in the following way:

Source 32i is subjected to interaction with the bottom, in particular with CsOH, preferably in the presence of a catalyst phase transition, such as a chloride of triethylenediamine, and added 32j forming cyclopentene ring with vinyl side chain, i.e. cyclopropylboronic 32k. Protective groups, phenyl-CH= removed in acidic conditions (for example, HCl in dichloromethane) to give the 32l. The latter substance can be separated into the stereoisomers using known techniques, for example, obtaining a salt with an optically active acid, for example, with Dibenzoyl-L-tartaric acid, and removing groups of tartaric acid salt results in 32m. Analogues other than ethylphosphonate, can be obtained from the original substances 32i, the group containing esters, other than group a complex of ethyl ether. Source 32i are known compounds or can be easily obtained using known methods.

Intermediate products (12C-1) or (12C-2), in turn, can be combined with suitable derivatives of PR is Lina, cyclopentane or cyclopentene, as described above.

Synthesis of structural units P3

Structural blocks P3 are commercially available or can be obtained in accordance with methods known to the expert of the art. One of such methods is presented in the diagram below, which uses monosilane amines, such as triptorelin or BOC-protected amine.

In the above scheme, R together with the group forms a N-protecting group, in particular, R represents tert-butoxy, trifluoromethyl; R5and n take the values defined above and LG represents a removable group, in particular halogen, for example chlorine or bromine.

Monosilane amines (33a) is treated with a strong base such as sodium hydride, and successively subjected to interaction with the reagent LG-C5-8alkenyl (33b), in particular Halogens5-8alkenyl, to obtain the corresponding protected amines (33C). To remove protection from (33) results in (5b), which are structure blocks P3. Removal of protection will be determined by the functional group R; thus, if R is a tert-butoxy, remove protection from the corresponding BOC-protected amine can be carried out by sour the Noi processing, for example, processing triperoxonane acid. Alternatively, when R represents, for example, trifluoromethyl, removal of the R group is carried out by treatment with a base, such as sodium hydroxide.

The following diagram illustrates another method of obtaining structural unit P3, namely the synthesis of primary5-8alkenylamine Gabriel method that may be performed by processing phthalamide (34a) base, such as NaOH or KOH, and (33b), which is defined above, followed by hydrolysis of the intermediate N-alkenylamine to obtain primary5-8alkenylamine (5b-1).

In the above scheme, n takes on the values defined above.

Each of the compounds of formula (I) may be subjected to transformation into any other in accordance with known transformation reactions of functional groups. For example, amino groups can be subjected to N-alkylation, nitro recovered to amino groups, one halogen atom may be replaced by another halogen atom.

Intermediate products used to produce compounds of formula (I)are known compounds or analogues of known compounds which can be obtained by modification of known techniques which may be implemented by a qualified technician.

Connection fo the formula (I) can undergo transformation into the corresponding N-oxide forms in accordance with known methods of transformation of trivalent nitrogen into its N-oxide form. This reaction N-oxidation can usually be carried out by reaction of starting compound 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 oxyacids, such as, for example, benzolkarbonovyh hydroxy acid or halogen-substituted benzolkarbonovyh hydroxy acid, for example, 3-chlorobenzylamino hydroxy acid, paracalanidae acid, for example, peroxidasa acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

Stereochemical pure isomeric forms of the compounds of formula (I) can be obtained in accordance with methods known in the art. The diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques, for example, by the method of countercurrent distribution, liquid chromatography and the like

The compounds of formula (I) may be the Holocene in the form of racemic mixtures of enantiomers, which may be separated using known in the art techniques. Racemic compounds of the formula (I), which are sufficiently basic or acidic, can undergo transformation into the corresponding diastereomeric salt form by interaction with a suitable chiral acid or a suitable chiral basis, respectively. These diastereomeric salt forms are then separated, for example, selective or fractional crystallization, and the enantiomers are released with alkali or acid. Alternative methods of separating the enantiomeric forms of the compounds of formula (I) include liquid chromatography, in particular liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, provided that the reaction proceeds in a stereospecific. Preferably, if you want to get specific stereoisomer, this connection can be synthesized stereospecific methods of getting. In these methods can mainly be used enantiomerically pure source materials.

In accordance with an additional aspect, the present invention relates to a pharmaceutical composition and, comprising a therapeutically effective amount of the compounds of formula (I)as defined in the description, or the connection of any of the subgroups of compounds of formula (I)as defined in the description, and pharmaceutically acceptable carrier. The term "therapeutically effective amount" in this context means a quantity sufficient for preventive actions against viral infections, to stabilize or reduce viral infection, in particular HCV infection, we infected subjects or subjects at risk of infection. In accordance with another aspect, the present invention relates to a method for producing a pharmaceutical composition, as defined in the description, which includes a thorough mixture of the pharmaceutically acceptable carrier with a therapeutically effective amount of the compounds of formula (I)as defined in the description, or connection of any of the subgroups of compounds of formula (I)as defined in the description.

Therefore, the compounds according to the present invention or any of its subgroups for easy application can be entered in various pharmaceutical forms. As appropriate compositions can be listed all the songs that are commonly used for systemic administration of drugs. To prepare the pharmaceutical compositions according infusion is his invention of an effective amount of a particular compound, not necessarily in the form of additive metal salt or complex of the metal, as the active ingredient is combined in a homogeneous mixture with a pharmaceutically acceptable carrier, the form of which may depend on the desired form of the drug. Such pharmaceutical compositions preferably are standard dosage form suitable for administration orally, rectally, transdermally, or parenterally by injection. For example, in the preparation of compositions in a dosage form for oral administration may be used any conventionally used pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like, in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja additives, etc. in the case of powders, pills, capsules and tablets. Due to the ease of administration, tablets and capsules represent the most advantageous dosage forms standard doses for oral administration, which use standard solid pharmaceutical carriers. Media for the preparation of compositions for parenteral administration will typically include sterile water, at least in the most part,though can be entered and other ingredients for example, additives to increase the solubility. For example, can be prepared solutions for injection, in which the carrier comprises saline solution (saline)solution, glucose solution or a mixture of salt solution and a glucose solution. Can be prepared suspension for injection, which can suitable liquid carriers, suspendresume agents and other Compositions also include drugs in solid form intended to become immediately before use in preparations in liquid form. In the compositions suitable for percutaneous administration, the carrier optionally includes an additive that improves the penetration and/or a suitable wetting agent, optionally combined with minimal amounts of suitable additives of any nature, which does not have significant adverse effects on the skin.

Compounds according to the present invention can also be administered by oral inhalation or insufflate using the methods and drugs used for such an introduction. Thus, typically, the compositions according to the present invention can be introduced into the lungs in the form of a solution, suspension or dry powder, and is the preferred solution. Any system designed for the delivery of solutions, suspensions or dry powders for oral inhalation or in what Uppsala, is suitable for the introduction of compounds according to the present invention.

Therefore, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflate through the mouth and including a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds according to the present invention are introduced by inhalation solution in a spray or spray dosage forms.

It is particularly convenient to prepare the above-described pharmaceutical compositions in the form of standard dosage forms for ease of administration and uniform dosage. The term "standard dosage form", when used in the description refers to physically discrete particles (units), suitable for use as single doses, each unit contains a predetermined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms standard doses are tablets (including tablets with notches and coated tablets), capsules, pills, suppositories, packaged powders, wafers, solutions or suspensions for injection and the like, as well as their individual set.

The connection form is s (I) possess antiviral properties. Viral infections and associated diseases can be treated using compounds and methods according to the present invention, including infections caused by HCV and other pathogenic flaviviruses, such as yellow fever virus, Dengue virus (types 1-4), the causative agent of encephalitis St. Lewis, the causative agent of Japanese encephalitis virus encephalitis Murray valley, West Nile virus and virus Kunjin. Diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, liver failure end stage and NSS; 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 are active against mutant lines HCV. Moreover, many of the compounds according to the present invention show favorable pharmacokinetic profile and have attractive properties in terms of bioavailability, including acceptable half-life, the amount of area under the curve (area under curve - AUC) and peak values, and the absence of unfavorable phenomena, such as slow onset of action and retention in the tissues.

Antiviral activity of compounds of the formula (I) is against HCV in vitro can be tested in the cellular system of the HCV replicon, as described in the publication Lohmann et al. (1999) Science 285:110-113, with the additional modifications described in the publication Krieger et al. (2001) Journal of Virology 75:4614-4624 (introduced in the description by reference), a typical example of which is given in the "Examples"section. This model, although it is not a full model for HCV infection, is widely used as the most reliable and effective model of Autonomous replication of HCV RNA, are currently available. The compounds exhibiting antiviral activity against HCV in this cellular model, are considered as potential drugs for the treatment of HCV infections in mammals, subject to further study. You should know that it is important to distinguish compounds that specifically affect the function of HCV, from compounds that cause cytotoxic or cytostatic effects in models of HCV replicon and consequently cause a decrease of the concentration of HCV RNA or related reading enzymes. Analysis methods known in the field of cell cytotoxicity, based on, for example, on the activity of mitochondrial enzymes and include the application of fluorogenic redox dyes such as resazurin. In addition, there are filter counting cells for evaluation of selective inhibition-related activity of the reporter gene, that the CSOs as Firefly luciferase. Cells suitable types can be supplied with stable transfection of luciferase gene reporter whose expression is dependent on constitutive active gene-promoter, and such cells can be used as a filter-counter to eliminate non-selective inhibitors.

Thanks antiviral properties, in particular antiviral activity against HCV, the compounds of formula (I) or any subgroup, their N-oxides, pharmaceutically acceptable salt additive and stereochemical isomeric forms may be used to treat patients infected with a virus, particularly a virus, which is a HCV, and for the prevention of viral infections, in particular HCV infection. Usually the compounds according to the present invention can be used for the treatment of warm-blooded animals infected with viruses, in particular, flaviviruses, such as HCV.

Thus, the compounds according to the present invention or any subgroup can be used as a drug. The specified application 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 for suppressing conditions associated with viral infection, in particular HCV infection.

The present invention relates also to the use of compounds according to the present invention or any subgroup in the production of pharmaceuticals 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, and this method includes the introduction of antiviral effective amount of the compounds of formula (I)as defined in the description, or compounds of any of the subgroups of compounds of formula (I)as defined in the description.

It is generally understood that the daily antiviral effective amount should be from 0.01 mg/kg to 500 mg/kg body weight, from 0.1 mg/kg to 50 mg/kg body weight or from 0.5 mg/kg to 5 mg/kg Maxy body. It may be acceptable to provide the required dose in the form of two, three, four or more smaller doses at appropriate intervals throughout the day. These smaller doses can be prepared in dosage forms standard dose, for example, containing from 1 to 1000 mg, in particular from 5 to 200 mg, of active ingredient in the medicinal form of the standard dose.

The invention relates also to the combination of the compounds of formula (I), including its stereoisomeric form, headlight is asepticheski acceptable salt or pharmaceutically acceptable MES, and other antiviral compounds, in particular other compounds with antiviral activity against HCV. The term "combination" may refer to a product containing (a) compound of formula (I)defined above, and (b) optional other antivirals against HCV compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections.

Compounds with antiviral activity against HCV, which can be used in such combinations include drugs selected from an inhibitor of HCV polymerase inhibitor of HCV protease, an inhibitor of another target in the HCV life cycle, and immunomodulatory drug, and combinations thereof. Inhibitors of HCV polymerase include NM283 (valopicitabine), R803, JTK-109, JTK-003, HCV-371, HCV-086, HCV-796 and R-1479. Inhibitors of HCV proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors) include compounds described in WO 02/18369 (see, for example, page 273, lines 9-22 and page 274 line 4 to page 276 line 11); BILN-2061, VX-950, GS-9132 (ACH-806), SCH-503034 and SCH-6. Additional agents that can be applied, are medicines that are described in WO 98/17679, WO 00/056331 (Vertex); WO 98/22496 (Roche); WO 99/07734, (Boehringer Ingelheim), WO 2005/073216, WO 2005/073195 (Medivir) and structurally similar agents.

Inhibitors of other targets in vital the cycle of HCV include inhibitors of NS3 helicase; inhibitors metalloprotease; inhibitors antisense-oligonucleotides, such as ISIS-14803, AVI-4065, etc.; small interfering RNA (siRNA), such as SIMPLEX-140-N; vector encodename short RNA, forming a hairpin (shRNA); Decimi; HCV specific ribozymes, such as heptazyme, RPI.13919 and the like; inhibitors of penetration, such as HepeX-C, HuMax-HepC and the like; alpha-glucosidase inhibitors, such as celgosivir, UT-231B, etc.; KPE-02003002; and BIVN 401.

Immunomodulators include isoforms connection of natural and recombinant interferon, 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; polietilenglikolya (paglierani) derivatives of interferon, such as PEG-interferon-α-2A (Pegasys®), PEG interferon-α-2b (PEG-Intron®), targeted IFN-α-con1, etc.; preparations of interferons long-acting derivatives of interferon compounds such as interferon, fused to albumin - Albuferon-α etc.; compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the production response of helper T cell type 1, such as SCV-07 and the like; agonists of TOLL-like receptors, such as CpG-10101 (actilon), isatoribine etc.; thymosin α-1; ANA-245; ANA-246; histamine-dihydrochloride; propagermanium; tetrachlorodecaoxide is d; ampligen; IMP-321; KRN-7000; antibodies, such as civacir (civacir), XTL-6865 and the like; and prophylactic and therapeutic vaccines such as InnoVac C, HCV E1E2/MF59 and the like

Other antiviral agents include ribavirin, amantadine, viramidine, nitazoxanide; telbivudine; NOV-205; taribavirin; inhibitors of internal penetration of ribosomes; inhibitors of viruses with a wide range of actions, such as IMPDH inhibitors, and mycophenolate acid and its derivatives, including, but without limitation, VX-950, merimepodib (VX-497), VX-148, and/or VX-944); or a combination of any of the above antiviral agents.

Special tools, suitable for use in the above combinations are interferon-α (IFN-α), targeted interferon-α or ribavirin, as well as a therapeutic agent on the basis of antibodies against HCV epitopes, small interfering RNA (siRNA), ribozymes, Decimi, antisense DNA, antagonists, small molecules, for example, the NS3 protease, NS3 of helicase and NS5B polymerase.

In accordance with another aspect provided by the combination of the compounds of formula (I)defined above, and compounds with antiviral activity against HIV. The latter preferably is an inhibitor of HIV that have a positive impact on drug metabolism and/or pharmacokinetics, which improves its biologists who definition availability. An example of such an inhibitor of HIV is ritonavir. In itself, the present invention also provides a combination comprising (a) an inhibitor of HCV NS3/4A protease formula (I) or its pharmaceutically acceptable salt; and (b) ritonavir or its pharmaceutically acceptable salt. Connection ritonavir, its pharmaceutically acceptable salts and methods for their preparation are described in WO 94/14436, in U.S. Patent 6037157, and the links in them; in U.S. Patent No. 5484801, Application for U.S. Patent 08/402690, WO95/07696 and WO95/09614 disclosed preferred dosage forms of ritonavir. One way of carrying out the invention relates to combinations comprising (a) an inhibitor of HCV NS3/4a protease formula (I) or its pharmaceutically acceptable salt; and (b) ritonavir or its pharmaceutically acceptable salt; including optional additional compounds having antiviral activity against HCV and selected from the compounds mentioned above.

The invention also relates to a method for the combination that is defined above, including the stage of combining the compounds of formula (I)defined above, and other drugs such as antiviral, including antivirals against HCV or HIV, drug, in particular an antiviral agent mentioned above.

These combinations can be found prima is giving in the production of drugs for treating HCV infection or infection with other pathogens, flavi or pestivirus the mammal, infected them, this combination, in particular, includes the compound of formula (I)defined above, and interferon-α (IFN-α), targeted interferon-α or ribavirin. Or the invention provides a method of treating a mammal, in particular humans infected with HCV or other pathogens, flavi or pestiviruses, the method includes the introduction of the specified mammal an effective amount of the combination that is defined in the description. In particular, the method of treatment comprises the systemic introduction of this combination in such a quantity that is effective in the treatment of clinical conditions associated with HCV infection.

In one embodiment of the invention the above-mentioned combinations are presented in the form of a pharmaceutical composition, which includes the active ingredients described above, and the media, which is described above. Each of the active ingredients can be represented in the form of a separate drug and these drugs can be administered together, or the active ingredients can be represented in the form of a single preparation containing both the active ingredient and, if necessary, additional active ingredients. In the first example, the combination can also be represented in the form of a combined preparation for simultaneous, separate or sequential with the change in HCV therapy. This composition may also take any of the forms described above. In one embodiment of the invention both ingredient introduced into a single dosage form, such as a combined dosage form of a fixed dose. In a particular embodiment, the present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of the compounds of formula (I), its stereoisomeric forms, pharmaceutically acceptable salt or pharmaceutically acceptable MES, (b) a therapeutically effective amount of ritonavir or its pharmaceutically acceptable salt and (C) the media.

The individual components of the combinations according to the present invention can be administered separately at different times during the course of therapeutic treatment, at the same time as multiple doses, administered at intervals, or in one dose. Understood that this invention includes all such schemes of simultaneous or alternating treatment and the term "introduction" should be interpreted accordingly. In a preferred variant of the invention, the separate dosage forms are entered simultaneously.

In one embodiment of the invention the combination according to the present invention contain an amount of ritonavir or its pharmaceutically acceptable the Oli, sufficient for clinical improvement bioavailability of the inhibitor of HCV NS3/4A protease formula (I) compared with the bioavailability of the inhibitor of HCV NS3/4A protease formula (I), administered separately. Or combination according to the present invention contain an amount of ritonavir or its pharmaceutically acceptable salt, sufficient to improve at least one of the pharmacokinetic variables of an inhibitor of HCV NS3/4A protease formula (I)selected from t1/2CminCmaxCSSthe area under the curve for the period, equal to 12 hours, or area under the curve for the period, equal to 24 hours, relative to the specified at least one pharmacokinetic variable inhibitor of HCV NS3/4A protease entered separately.

Combination according to the present invention can be administered to humans in doses that are within the range of values specific to each component contained in the specified combinations, for example, the compound of formula (I)as defined above, and ritonavir or its pharmaceutically acceptable salt can have levels of dosages in the range of from 0.02 to 5.0 g/day.

The mass ratio of the compounds of formula (I) and ritonavir may be in the range from about 30:1 to about 1:15, from about 15:1 to about 1:10, from about 15:1 to about 1:1, from about 10:1 to about 1:1, the example is about 8:1 to about 1:1, from about 1:5 to 1:1 or up to about 5:1, from about 3:1 to about 1:1 or from about 2:1 to about 1:1. The compound of formula (I) and ritonavir can be together once or twice a day, preferably orally, where the amount of the compounds of formula (I) per dose is in the range from about 1 to about 2500 mg, from about 50 to about 1500 mg, from about 100 to about 1000 mg, from about 200 to about 600 mg, or from about 100 to about 400 mg; and the amount of ritonavir per dose is in the range from 1 to about 2500 mg, from about 50 to about 1500 mg, from about 100 to about 800 mg, from about 100 to about 400 mg, or from 40 to 100 mg of ritonavir.

Examples

The following examples are intended to illustrate the present invention but do not limit its scope. In some examples retrieves structural blocks that can be combined with any other suitable structural unit described in the invention, not only from structural units typical examples of the final products of formula I.

Example 1

Stage a: ethyl ester of 1-[(3-oxo-2-oxabicyclo[2.2.1]heptane-5-carbonyl)amino]-2-vinylcyclopropanes acid (1a)

To a solution of 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid (857 mg, 5.5 mmol who) in DMF (14 ml) and DHM (25 ml) at room temperature add ethyl ester of 1-amino-2-vinylcyclopropanes acid (1,15 g, 6.0 mmol), HATU (to 2.29 g, 6.0 mmol) and DIPEA (3,82 ml, 22 mmol). The reaction mixture was stirred in an atmosphere of N2at ambient temperature for 1 hour. LC/MS analysis shows complete conversion, after which the reaction mixture was concentrated in vacuo. The residue is again dissolved in DHM (100 ml) and 0.1 M HCl (aq.) and the layers separated. The organic phase is washed with NaHCO3(aq.) and a solution of salt, dried (MgSO4) and filtered. The solvent is removed in vacuum, obtaining the connection specified in the title (1.6 g, 99%). LC/MS (method A): tR=2,46 min, >95%, m/z (ESI+)=294(MH+).

Stage b: diisopropylethylamine salt of 2-(1-etoxycarbonyl-2-vinylcyclopropyl)-4-hydroxycyclohexanone acid (1b)

To a solution of ester (1a) (800 mg, 2,73 mmol) in water (15 ml) in a vessel microwave reactor with a volume of 20 ml added DIPEA (1.2 ml, 6.8 mmol) and a magnetic stirrer. Capacity, sealed and received immiscible suspension vigorously shaken before inclusion in the microwave cavity. After pre-mixing for 1 min, the reaction mixture was irradiated for 40 minutes at a set temperature of 100°C. After cooling to 40°C. a clear solution was concentrated in vacuo and the resulting brown oil is evaporated 3 times with acetonitrile to remove residual water. The resulting crude compound, which asanee in the title, in the form of DIPEA salt immediately used in the next stage. LC/MS (method A): tR=1,29 min, >95%, m/z (ESI+)=312(MH+).

Stage c: ethyl ester of 1-{[2-(Gex-5-animationname)-4-hydroxycyclohexanone]amino}-2-vinylcyclopropanes acids (lc)

The crude acid (1b) (5.5 mmol) dissolved in DHM (50 ml) and DMF (14 ml), and then at room temperature is added HATU (2,09 g, 5.5 mmol), Gex-5-animationen (678 mg, 6.0 mmol) and DIPEA (is 3.08 ml, 17.5 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. LC/MS analysis shows complete conversion, after which the reaction mixture was concentrated in vacuo. The residue is again dissolved in EtOAc (100 ml) and the organic layer was washed with 0.1 M HCl (aq.), K2CO3(aq.) and a solution of salt, dried (MgSO4) and filtered. The solvent is removed in vacuum to obtain an oil, which was purified flash chromatography (silica, EtOAc:MeOH)to give specified in the title compound (1.65 g, 74%). TLC (silica): MeOH:EtOAc 5:95, Rf=0,5; LC/MS (method A): tR=3,44 min, >95%, m/z (ESl+)=407(MH+).

Stage d: ethyl ester of 1-{[4-ethoxyethoxy-2-(Gex-5-animetal-carbarnoyl)cyclopentanecarbonyl]amino}-2-vinylcyclopropanes acid (1d)

To a solution of diene 1c (7,94 g, 0.02 mol) in DHM and DIPEA (9.7 ml, 6 EQ.) with stirring at 0°C (ice bath) add chloromethylmethylether (2,79 g, equ.). The reaction mixture was stirred at room temperature overnight, concentrated on a rotary evaporator and purified column chromatography on silica gel (elution with gradient: EtOAc/petroleum ether, 1:1->1:0)to give a pure compound indicated in the title, in the form of a yellowish syrup in (6.67 g, 74%).

Stage e: ethyl ester of 17-ethoxyethoxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid (1e)

The diene (1d) (1.75 g) was dissolved in dry dichloroethane (800 ml, 0,0046 M solution). Through the resulting solution for 10 minutes bubbled argon, then add the catalyst Hoveyda-verification of the 1st opening. (20 mg 3,5% (mol)and the reaction mixture was stirred at 95°C during the night. The reaction mixture was added an additional portion of catalyst (25 mg) (when bubbling argon and the reaction mixture was stirred at 97°C. the Reaction mixture is cooled to room temperature, add the absorber (100 mg) and the reaction mixture is stirred for 4 hours at room temperature. The reaction mixture is filtered, the filtrate concentrated on a rotary evaporator and the residue is purified column chromatography on silica gel, receiving net connection specified in the title (1.23 g, 75%yield).

Stage f: 17 ethoxyethoxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carboxylic acid (1f)

Complex EF the R 1e (of 2.26 g) is mixed with THF (20 ml), MeOH (20 ml) and a solution of LiOH (1N, 20 ml) and stirred at 55°C for ~17 hours. The reaction mixture was concentrated on a rotary evaporator, diluted with water (30-50 ml) and acidified with 10% citric acid to pH 3-4. A cloudy solution is extracted with ethyl acetate (3x50 ml). The combined organic extracts washed with water and salt solution and dried over magnesium sulfate. The desiccant is removed by filtration and the ethyl acetate removed on a rotary evaporator. The residue is dried in high vacuum, receiving 2 g specified in the title compound as a white foam. The resulting product is used in the next stage without additional purification.

Stage g: (17 ethoxyethoxy-13-methyl-2,14-dioxo-3.13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl)amide cyclopropanemethanol acid (1g)

Acid 1f dissolved in dry DHM (20 ml). To the solution was added EDC (1.2 equiv.) and the reaction mixture is stirred for 3 hours at room temperature. LC-MS shows complete conversion of the educt. The solution was diluted with DHM and washed with water (3×20 ml). The aqueous phase is extracted with DHM and the United DHM extracts are washed with salt solution, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator, getting brownish syrup, which is used in the next stage without additional purification.

The syrup was dissolved in dry DHM (20 ml), obtained Rast is oru add cyclopropanesulfonyl (1.1 EQ.) and then DBU. The solution was stirred at room temperature for 17 hours. The progress of the reaction is followed LC-MS. The reaction mixture was diluted with DHM (70 ml), washed with 10% citric acid (2 x 20 ml) and a solution of salt, dried over magnesium sulfate, concentrated on a rotary evaporator and purified column chromatography on YCM the silicon dioxide (approximately 50 g, elution: ether), getting mentioned in the title compound as a white foam (83%), (M+H)+512.

Stage h: (17-hydroxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl)amide cyclopropanemethanol acid (1h)

Detoxify 1g dissolved in a mixture of THF/MeOH/water (1:1:1, total volume 30 ml), then with stirring, add 2.5 ml conc. of hydrochloric acid. The reaction mixture was stirred over night at room temperature, controlling the course of the reaction using LC-MS. Then the reaction mixture is poured into a feast upon. an aqueous solution of NaHCO3(50 ml) and evaporated to half volume on a rotary evaporator. The resulting mixture was acidified with 10% citric acid and extracted with DHM (3×20 ml). The combined organic phases are washed with salt solution, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and dried under high vacuum over night. The resulting product is then used without further purification.

Stage i: 4-cyclopropanecarbonyl-13-IU the Il-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (2-cyanophenyl)carbamino acid (1i)

Alcohol 1h (11 mg) was dissolved in dry dichloromethane (2 ml), the resulting solution was added 2-sozialarbeiter (2 EQ.) and then triethylamine (5 μl). The reaction mixture was stirred over night at room temperature and then concentrated on a rotary evaporator. Purification of the residue preparative HPLC (water/acetonitrile with addition of 0.1% TFUK, elution gradient: 30-80) results specified in the title compound (5 mg, 27%), [M+H]+598.

Example 2

(4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (2-phenoxyphenyl)carbamino acid (2)

Alcohol 1h (11 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 2-isocyanatoacetate ether instead of 2-isocyanatomethyl, getting mentioned in the title compound (10 mg, 63%), [M+H]+665.

Example 3

(4-cyclopropanecarbonyl-13-methyl-

2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (2-methoxyphenyl)carbamino acid (3)

Alcohol 1h (11 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 2-isocyanatomethyl ester instead of 2-isocyanatomethyl, receiving specified in the header with the Association (9 mg, 58%), [M+H]+603.

Example 4

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.0*4.6*]octadec-7-ene-17-silt ether (3-cyano-5-methoxyphenyl)carbamino acid (4)

Alcohol 1h (15 mg) was dissolved in dry EDC, to the resulting solution was added 20 mg of sodium bicarbonate and then 2 ml of a solution of phosgene in toluene (20%). The reaction mixture was stirred at room temperature for 3 hours (full conversion to chlorimide in accordance with the data of LC-MS), then concentrated on a rotary evaporator and dried from an excess of phosgene in high vacuum (1.5 hours). The dry reaction mixture is transferred into a test tube microwave reactor (2-5 ml), mixed with dry EDC (3 ml), 3-amino-5-methoxybenzonitrile (2 equiv.) potassium carbonate (9 mg, 1.5 EQ.), sprayed molecular sieves (4Å, 5 mg) and incubated in a microwave oven at 100°C for 45 minutes, the Reaction mixture was passed through a layer of silica (elution: DHM, then 10% methanol in DHM). The obtained fractions containing the target urethane compound are pooled, concentrated on a rotary evaporator and purified column chromatography on YMC-silicon dioxide (15 g, elution: a mixture of ethyl acetate/petroleum ether (1:3) to remove excess aniline, then dichloromethane and then 2% methanol in dichloromethane)to give specified in the header is VCE connection in the form of a powder (15 mg, 8%), [M+H]+628.

Example 5

Methyl ester of 3-(4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-eloxierarbeiten)benzoic acid (5)

Alcohol 1h (20 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using the methyl ester of 3-aminobenzoic acid instead of 3-amino-5-methoxybenzonitrile and getting mentioned in the title compound (10 mg, 36%), [M+H]+631.

Example 6

Stage a: (17 ethoxyethoxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl)amide 1-methylcyclopropane acid (6a)

Acid 1f subjected to interaction in accordance with the procedure described in example 1 (stage g), but using methylcyclopentanone instead of cyclopropanesulfonyl, getting listed at the beginning of the connection.

Stage b: (17-hydroxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl)amide 1-methylcyclopropane acid (6b)

Detoxify 3a process in accordance with the procedure described in example 1 (stage h), receiving specified in the header of the connection.

Stage c: 13-methyl-4-(1-methylcyclopentadienylmanganese)-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (5-cyano-2-methoxyphenyl is)carbamino acid (6c)

Alcohol 3b (30 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 3-amino-4-methoxybenzonitrile instead of 3-amino-5-methoxy-benzonitrile, getting mentioned in the title compound (12 mg, 33%), [M+H]+642.

Example 7

13-methyl-4-(1-methyl-cyclopropanecarbonyl)-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (3-methylcarbamoylmethyl)carbamino acid (7)

Alcohol 3b (34 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 3-amino-N-methylbenzamide instead of 3-amino-5-methoxybenzonitrile, getting mentioned in the title compound (8 mg, 19%), [M+H]+644.

Example 8

4-(1-methylcyclopentadienylmanganese)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (3-chlorophenyl)carbamino acid (5)

Alcohol 3b (35 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 3-Chloroaniline instead of 3-amino-5-methoxybenzonitrile, getting mentioned in the title compound (27 mg, 66%), [M+H]+622.

Example 9

13-methyl-4-(1-methyl-cyclopropanecarbonyl)-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt the IDF (3-dimethylaminophenyl)carbamino acid (6)

Alcohol 3b (80 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 3-dimethylaminopyridine instead of 3-amino-5-methoxybenzonitrile, getting mentioned in the title compound (50 mg, 40%), [M+H]+63.

Example 10

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (3-methoxyphenyl)carbamino acid (10)

Alcohol 1h (6 mg) is dissolved in dry dichloromethane (2 ml) and the resulting solution was added first 3-isocyanatoacetate (2 equiv.) then triethylamine (5 μl). The reaction mixture was stirred over night at room temperature and then concentrated on a rotary evaporator. Purification of the residue preparative HPLC (elution: water/acetonitrile with 0.1% TFUK, gradient 30-80) results specified in the title compound (2 mg, 27%), [M+H]+603.

Example 11

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (3-phenoxyphenyl)carbamino acid (11)

Alcohol 1h (10 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 3-isocyanatobenzene instead of 3 isocyanatoacetate, getting mentioned in the title compound (11 mg, 2%), [M+H]+665.

Example 12

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (3-cyanophenyl)carbamino acid (12)

Alcohol 1h (10 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 3-solanoentre instead of 3 isocyanatoacetate, getting mentioned in the title compound (10 mg, 75%), [M+H]+598.

Example 13

13-methyl-4-(1-methylcyclopentadienylmanganese)-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (3-cyanophenyl)carbamino acid (13)

Alcohol 3b (20 mg) is subjected to interaction in accordance with the procedure described in example 7 (stage i), but using 3-solanoentre instead of 3 isocyanatoacetate, getting mentioned in the title compound (13 mg, 51%), [M+H]+612.

Example 14

13-methyl-4-(1-methyl-cyclopropanecarbonyl)-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (3-methoxyphenyl)carbamino acid (14)

Alcohol 3b (18 mg) is subjected to interaction in accordance with the procedure described in example 7 (stage i) receiving specified in the title compound (14 mg, 59%), [M+H]+617.

Example 15

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether m-tailormaking acid (15)

Alcohol 1h (17 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 3-isocyanatopropyl instead of 3 isocyanatoacetate, getting mentioned in the title compound (6 mg, 26%), [M+H]+587.

Example 16

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (2-fluoro-5-were)carbamino acid (16)

Alcohol 1h (23 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 4-fluoro-3-isocyanatopropyl instead of 3 isocyanatoacetate, getting mentioned in the title compound (14 mg, 46%), [M+H]+605.

Example 17

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-EN-l7-silt ester [3-(2-methylthiazole-4-yl)phenyl]carbamino acid (17)

Alcohol 1h (30 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 4-(3-isocyanates)-2-methylthiazole instead of 3 isocyanatoacetate, getting mentioned in the title compound (19 mg, 49%), [M+H]+670.

Example 18

4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-17-silt ether (2-cyano-5-were)carbamino acid (18)

Alcohol 1h (30 mg) is subjected to interaction in accordance with the procedure described in example 1 (stage i), but using 2-amino-4-methylbenzonitrile instead of 3-amino-5-methoxy-benzonitrile, getting mentioned in the title compound (25 mg, 70%).

Example 19

Stage a: tert-butyl methyl ether (1-hydroxymethyl-2-vinylcyclopropyl)carbamino acid (19a)

To a solution of ethyl ester 1-tert-butoxycarbonylamino-2-vinylcyclopropanes acid (0.51 g, 2.0 mmol) in THF (10 ml) at 0°C is added 2M solution of lithium borohydride (4 ml, 8 mmol). The reaction mixture was analyzed TLC (hexane-ethyl acetate (7:3), tinted using sulfate ammoniummolybdate-cerium in an aqueous 10% sulfuric acid and after stirring over night at room temperature the reaction is carefully quenched with aqueous 10% citric acid (25 ml, added dropwise at 0°C). The resulting mixture was washed with dichloromethane (3×10 ml) and the combined organic layers are dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue (elution: hexane-ethyl acetate (1:1)) followed by concentration of the appropriate fractions and drying of the residue in vacuum is during the night leads to obtain the product as a colourless syrup (0,407 g, at 1.91 mmol, 96%).

1H NMR (400 MHz, CDC13): δ 0,98 (m, 1H)and 1.15 (m, 1H), of 1.44 (s, 9H), of 1.84 (m, 1H), 3,20 (ush. s, 1H), 3,60 (DD, 1H), 3,78 (USM, 1H), 5,10-of 5.26 (m, 3H), 5,70 (m, 1H).

Stage b: tert-butyl methyl ether (1-formyl-2-vinylcyclopropyl)carbamino acid (19b)

To a solution of alcohol 19a (0.152 g, 0.71 mmol) in dichloromethane (5 ml) at room temperature with stirring periodinane dessa-Martin (0.33 g, 0.78 mmol). The progress of the reaction is controlled TLC (hexane-ethyl acetate (3:2), UV visualization and the application of stains, using the molybdate of ammonium cerium sulfate in aqueous 10% hydrochloric acid solution). Staining indicates a fairly pure interaction, but UV control indicates the presence of several side products. 1 hour later obtained a yellowish-red solution was diluted with dichloromethane (20 ml), then washed with a mixture (1:1) 10% aqueous sodium thiosulfate solution/saturated aqueous solution of sodium bicarbonate (3×20 ml), then dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue using elution with a stepwise gradient (ethyl acetate in hexane 20-30%), followed by concentration of the appropriate fractions and drying of the residue in vacuum over night results specified in the title compound in the form of a colorless oil (0,054 g, 0,255 mmol, 36 %).

Stage c: tert-butyl ether [1-(tert-butylcarbamoyl is methyl)-2-vinylcyclopropyl]carbamino acid (19c)

To a solution of aldehyde 19b (0,054 g, 0,255 mmol) and tert-utilityfree (0,043 ml, 0.38 mmol) in dichloromethane (1 ml) and pyridine (0,083 ml of 1.02 mmol) under nitrogen atmosphere add triperoxonane acid (0,039 ml, 0.51 mmol). The mixture was incubated for 30 minutes at room temperature and further stirred for 2 days. After TLC (7:3 hexane-ethyl acetate) and LC-MS shows about 60% conversion, the reaction mixture was diluted with ethyl acetate (10 ml). The solution is successively washed with aqueous 10% citric acid (3×5 ml) and saturated aqueous sodium hydrogen carbonate (3×5 ml), then dried (Na2SO4), filtered and concentrated. The residue is treated with a mixture (1:1:1) aq. 1M LiOH/THF/MeOH (1.5 ml) for 10 minutes at room temperature, then diluted with aqueous 10% citric acid and transferred into ethyl acetate, then dried (Na2SO4), filtered and concentrated. Column chromatography of the residue (elution: hexane-ethyl acetate (7:3)) followed by concentration of the appropriate fractions and drying of the residue in vacuum during the night leads to obtain the product as a colorless solid matter (0,027 g 0,086 mmol, 34%).

1H NMR (400 MHz, CDCl3): δ 1,24 (m, 1H), 1,33-of 1.40 (m, 10 H), the 1.44 (s, 9H), to 1.87 (m, 1H), 3,65 (d, 1H), total of 5.21 (m, 3H), of 5.50 (d, 1H), of 5.89 (m, 1H), 7,03 (ush. s, 1H).

α-Hydroxyamide-derivatives of compounds of formula (I) according to the present izopet is to get the removal of N-BOC specified in the header of the connection with the subsequent combination of the obtained amine with the acid, such as acid 1f, in accordance with the procedure described in example 1 (stage g), with the subsequent removal of the hydroxyl protecting group and reaction carbamylcholine in accordance with the methods of example 1 (stages h and I, respectively).

A General method of oxidation of α-hydroxyamides to α-ketoamide:

Usually α-hydroxyamide dissolved in dichloromethane (20-30 ml/g) at room temperature, then add periodinane dessa-Martin (1.1 EQ.) and the composition of the reaction mixture analyzed by TLC and LC-MS. After completion of the reaction, or close to completion the reaction mixture is diluted with dichloromethane and then washed with a mixture of aq. 10% sodium thiosulfate/feast upon. aq. a solution of sodium bicarbonate (1:1) (X3), dried (Na2SO4), filtered and concentrated. The residue is purified column chromatography or preparational LC.

Example 20

Stage a: 1-{[2-(Gex-5-animationname)-4-hydroxycyclohexanone]amino}-2-vinylcyclopropanes acid (20a)

Compound 1c (493 mg, 1,21 mmol) dissolved in DMF (1 ml) and the resulting solution was transferred into a reaction chamber of the microwave reactor with a volume of 20 ml were Then added an aqueous solution of LiOH (2 M, 10.5 ml) and a magnetic stirrer (stirbar). A reaction chamber sealed and received a suspension vigorously shaken before entering into o the new reactor. The reaction mixture is treated with microwaves for 30 minutes at a temperature of 130°C. the Reaction mixture is cooled to 40°C, the obtained clear solution is acidified to pH 2 with aqueous HCl (1 M, 24 ml) and extracted with EtOAc (3x20 ml). The combined organic layers are washed with salt solution, dried (MgSO4) and filtered. The solvent is evaporated in vacuum, obtaining mentioned in the title compound (410 mg, 90 %). LC/MS >95%, m/z (ESI+)=379(MH+).

Stage b: (1-cyclopropanecarbonyl-2-vinylcyclopropyl)amide 2-(Gex-5-animationenabled)-4-hydroxycyclohexanone acid (20b)

The crude acid 20a (410 mg, of 1.09 mmol) dissolved in DMF (1.5 ml) and DHM (4,5 ml) and to the resulting solution at room temperature add EDAC (417 mg, to 2.18 mmol). The mixture was kept with stirring at room temperature for 10 minutes. To the mixture is added DMAP (133 mg, of 1.09 mmol) and again incubated the mixture at room temperature for 20 minutes. Then to the mixture is added a pre-mixed solution of amide cyclopropanemethanol acid (527 mg, 4,36 mmol) and DBU (663 mg, 4,36 mmol) in DMF (2 ml) and DHM (2 ml) and the mixture was incubated in a microwave oven at 100°C for 30 minutes. The resulting red solution was concentrated in vacuo and again dissolved in EtOAc (20 ml). The organic phase is washed with 1 M HCl (aq.) (3×10 ml) and a solution of salt 10 ml), dried (MgSO4) and filtered. The solvent is evaporated in vacuum, obtaining the crude sulfonamide, which is then purified by chromatography (silica, EtOAc/MeOH, 97,5:2,5), getting mentioned in the title compound (403 mg, 77%); LC/MS, >95%, m/z (ESI+)=482(MH+).

The compounds of formula (I) can be obtained from intermediate products (20b) via reaction carbamylcholine conducted by any of the methods described above, for example, in accordance with the techniques described in example 1 (stage i) or in example 10, followed by reaction of the closing cycle in accordance with the procedure described in example 1 (stage e).

Example 21

Stage a: tert-butyl ether 2-(1-etoxycarbonyl-2-vinylcyclopropyl)-4-hydroxypyrrolidine-1-carboxylic acid (21a)

Boc-protected 4-hydroxyproline (4 g, 17.3 mmol), HATU (6,9 g, 18.2 mmol) and ethyl ester of 1-amino-2-vinylcyclopropanes acid obtained in accordance with the method described in WO03/099274, (3.5 g, and 18.3 mmol), dissolved in DMF (60 ml) and cooled to 0°C in an ice bath. To the mixture add diisopropylethylamine (DIPEA) (6 ml). The ice bath removed and the mixture is left overnight at ambient temperature. Then add dichloromethane (~80 ml), the organic phase is washed with an aqueous solution of sodium bicarbonate, citric acid is the water, salt solution and dried over sodium sulfate. Purification with flash chromatography (elution: ether →7% methanol in ether) yields a net connection specified in the title (6,13 g, 96%)

Stage b: tert-butyl ether 2-(1-etoxycarbonyl-2-vinyl-cyclopropanecarbonyl)-4-(4-nitrobenzyloxy)pyrrolidin-1-carboxylic acid (21b)

Compound 21a (11.8 g, 32,0 mmol) and pyridine (27 ml, 305 mmol) was dissolved in DHM (200 ml) and cooled to 0°C, add 4-nitrobenzoate (6.6 g, a 35.6 mmol) and the resulting solution was stirred at room temperature overnight. The reaction mixture was washed with NaHCO3(aq.), aqueous solution of citric acid and salt solution, dried over MgSO4and evaporated on the silicon dioxide. The crude product is purified column chromatography on silica gel (EtOAc/n-heptane: 50:50), receiving 11,84 g (72%) specified in the connection header.

Stage c: 5-(1-etoxycarbonyl-2-vinylcyclopropyl)pyrrolidine-3-silt ether 4-nitrobenzoic acid (21c)

Of compound 21b (11,84 g is 22.9 mmol) remove the protective group using TFOC (30 ml), dissolved in DHM (100 ml)and then treated by a method known in the art, receiving specified in the header connection (9,37 g, 98%).

Stage d: 5-(1-etoxycarbonyl-2-vinylcyclopropyl)-1-[hept-6-enyl-(4-methoxybenzyl)carbarnoyl]pyrrolidin-3-silt ether 4-nitrobenzol the Oh of the acid (21d)

Amin 21c (4.68 g, and 11.2 mmol) dissolved in THF (100 ml), add NaHCO3(saturated solution) (approx. 5 ml) and then a solution of phosgene (20% in toluene, of 11.6 ml of 22.5 mmol). The reaction mixture was vigorously stirred for 1 hour and then filtered, evaporated and dissolved again in DHM (100 ml). To the mixture is added NaHCO3(saturated solution) (approx. 5 ml) and then hept-6-enyl-(4-methoxybenzyl)Amin (to 3.92 g, a 16.8 mmol). The reaction mixture was stirred at room temperature over night, filtered and evaporated on the silicon dioxide. The crude product is purified column chromatography on silica gel (EtOAc/n-heptane: 25/75), getting mentioned in the title compound (6.9 g, 91%).

Stage e: ethyl ester of 14-(4-methoxybenzyl)-18-(4-nitrobenzyloxy)-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.0*4,6*]nonudes-7-ene-4-carboxylic acid (21e)

Dien 21d (406 mg, 0.6 mmol) dissolved in EDC (250 ml) and Tegaserod. To the solution was added the catalyst Howeidy-verification of the 2nd generation (26 mg, 0,042 mmol) and the solution refluxed for 3 hours. After that, the mixture is evaporated and the residue used directly in the next stage.

Stage f: ethyl ether 18-hydroxy-14-(4-methoxybenzyl)-2,15-dioxo-3,14,16-diazatricyclo-[14.3.0.0*4,6*]nonudes-7-ene-4-carboxylic acid (21f)

The crude compound 21e (445 mg) dissolved in a mixture of THF (20 ml), MeOH (10 ml) and water (10 ml). After cooling the mixture to 0°C EXT is make 1M LiOH (2 ml). After 1.5 hours the hydrolysis is complete, to the mixture is added HOAc (1 ml) and the solution evaporated to a volume of about 10 ml. of water is Added and the mixture extracted with DHM (2x30 ml). The combined organic extracts washed with NaHCO3(aq.), water, salt solution and dried over MgSO4. The crude product is purified column chromatography on silica gel (elution with gradient: DHM/MeOH from 100/0 to 80/20), getting mentioned in the title compound (201 mg, 67%).

Stage g: ethyl ether 18-ethoxyethoxy-14-(4-methoxy-benzyl)-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.0*4.6*]nonudes-7-ene-4-carboxylic acid (21g)

To a solution of alcohol 21f (1.35 g, 2,70 mmol, 75% purity) and N-ethyldiethanolamine (1,42 ml, 8.1 mmol) in dichloromethane (15 ml), cooled to 0°C, with stirring, add chloromethylmethylether (0.5 ml, 5.4 mmol). The mixture allow to warm with stirring to room temperature, after which the mixture is cooled to 0°C, add an additional amount of N-ethyldiethanolamine (1 ml, 5.7 mmol) and chloromethylmethylether (0.3 ml, 3.2 mmol) and the resulting mixture is stirred for 16 hours at room temperature. Next, the reaction mixture is transferred into a column with silica gel (graded elution gradient: ethyl acetate in hexane 50-80%). Concentration of appropriate fractions results specified in the title compound in the form of syrup brownish color, to the which crystallizes in the air (0.8 g, 53%). LR-MS: C30H44N3O7- calculated: 558; found: 558 [M+H].

Stage h: 18 ethoxyethoxy-14-(4-methoxybenzyl)-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.0*4,6*]nonudes-7-ene-4-carboxylic acid (21h)

A solution of ester 21g (0,775 g of 1.39 mmol) in a mixture of THF-methanol-aqueous 1M LiOH (1:1:1) (36 ml) was stirred at room temperature for 3.5 hours, after which TLC (95:5 and 9:1 dichloromethane-methanol) and LC-MS shows complete conversion of the original substance in a carboxylic acid. Then the reaction mixture was evaporated to approximately 1/3 of the volume, then diluted with water (10 ml) and acidified to about pH 4 using 10% citric acid (60 ml), during which a precipitate. The mixture is washed with ethyl acetate (3×25 ml) and the combined organic layers are washed with salt solution (2×50 ml), then dried (Na2SO4) filtered and evaporated. The residue concentrated from toluene (3×10 ml)to give crude compound indicated in the title, as not quite white foam (0.75 g, quantitative yield). LR-MS: C28H40N3O7: computed 530; found 530 [M-H].

Stage i: compound 21i

To a solution of carboxylic acid 21h (approximately of 1.39 mmol) in dichloromethane (10 ml) at room temperature add N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide × HCl (0.32 g, 1,67 mmol), then stirred overnight, after which LC-MS shows complete con the version of acid in the product. After the reaction mixture is diluted with dichloromethane (10 ml), washed with water (3×10 ml), then dried (Na2SO4) filtered and evaporated to obtain a colorless solid matter (crude yield: 0.7 g), which are immediately used in the next stage. LR-MS: C28H38N3O6: computed 512; found 512 [M+H].

Stage j: [18 ethoxyethoxy-14-(4-methoxy-benzyl)-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.0*4,6*]nonudes-7-ene-4-carbonyl]amide cyclopropanemethanol acid (21j)

To a solution of crude oxazolinone 21i (0,328 g, 0.64 mmol) in dichloromethane (4 ml) was added with stirring cyclopropylalanine (0,117 g, 0.96 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (to 0.19 ml, 1.3 mmol), then stirred at room temperature overnight. The reaction mixture was analyzed LC-MS, then diluted with dichloromethane (20 ml), washed sequentially aqueous 10% citric acid (3×15 ml) and salt solution (1×15 ml), then dried (Na2SO4), filtered and concentrated, gaining not quite white foam. Column chromatography of the residue (stepwise elution gradient: ethyl acetate in toluene 60-100%), followed by concentration and drying of the appropriate fractions results specified in the title compound as a colourless foam (0.27 g, 66% for 3 stages).

1H NMR: (500 MHz, DMSO-d6): δ 0,9-1,6 (m, 14H), of 1.80 (m, 1H), 1,90 (m, 1H), 2,0-2,2 (who, 3H), of 2.25 (m, 1H), 2.95 and (m, 1H), 3,05 (m, 1H), 3,3-3,4 (m, 2H), 3,50 (kV, 2H), of 3.7-3.8 (m, 4H), of 3.97 (d, 1H), from 4.3 to 4.4 (m, 2H), 4,55 (d, 1H), 4,63 (m, 2H), 5,12 (m, 1 H), 5,70 (m, 1H), to 6.88 (d, 2H), 7,19 (d, 2H), 8,12 (s, 1H). LR-MS: C31H45N4O8S: calculated 633; found 633 [M+H].

Stage k: (18-hydroxy-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.0*4,6*]nonudes-7-ene-4-carbonyl)amide cyclopropanemethanol acid (21k)

A solution of acetal 21j (0,038 g, 0.06 mmol) in a mixture of THF-methanol-2M aq. hydrochloric acid (1:1:1) (1.5 ml) was stirred at room temperature for 30 minutes, then add additional portion of hydrochloric acid (0.1 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture is neutralized using a saturated aqueous solution of sodium bicarbonate, then concentrate on silicon dioxide. Flash chromatography of the residue (elution: ethyl acetate/methanol 9:1) yields the product as a colourless foam (0,020 g, 73%). LR-MS: C20H29N4O6S: calculated 453; found 453 [M-H].

The inhibitors according to the present invention is obtained from an intermediate product 21k by reaction carbamylcholine using any of the methods described above, for example, in example 1 (stage i) or in example 10.

Example 22

Stage a: [18 ethoxyethoxy-14-(4-methoxybenzyl)-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.0*4,6*]n nadec-7-ene-4-carbonyl]amide 1-methylcyclopropane acid (22a)

To a solution of oxazolinone 21i (0,372 g, 0.73 mmol) in dichloromethane (4 ml) was added with stirring cyclopropylacetylene (0,147 g of 1.09 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0,22 ml of 1.45 mmol). The resulting mixture was stirred at room temperature overnight. Processing and chromatography of the reaction mixture as described in example 19 (stage j) leads to obtain the target product as a colorless syrup which crystallized in the air (0.31 g, 65% for 3 stages).1H NMR (500 MHz, DMSO-d6): δ 0,92 (m, 2H), 1,1-1,6 (m, 15H), of 1.78 (m, 1H), of 1.88 (m, 1H), 2,0-2,1 (m, 3H), and 2.26 (m, 1H), to 3.02 (m, 1H), 3,2-3,4 (m, 2H), 3,49 (kV, 2H), of 3.7-3.8 (m, 4H), 3,95 (d, 1H), from 4.3 to 4.4 (m, 2H), 4,54 (d, 1H), 4,6-4,7 (m, 2H), is 5.06 (m, 1H), 5,69 (m, 1H), to 6.88 (d, 2H), 7,19 (d, 2H), by 8.22 (s, 1H), 11,23 (s, 1H). LR-MS: C32H47N4O8S: calculated 647; found 647 [M+H].

Stage b: (18-hydroxy-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.0*4,6*]nonudes-7-ene-4-carbonyl)amide 1-methylcyclopropane acid (22b)

From acetal 22a (0,301 g, 0,465 mmol) remove the protective group using a mixture of dichloromethane/triperoxonane acid/H2O (2:1:0,1) (6.2 ml)at room temperature for 4 hours, then concentrated on silica and purified flash chromatography (elution: ethyl acetate/methanol 9:1)to give the product as a colourless foam (0,065 g, 30%). LR-MS: C21H33N4O6S. Calculated 469; found 469 [M+H].

The compounds of formula (I) receive the C intermediate 22b in accordance with the reaction carbamylcholine using any of the methods described above, for example, in example 1 (stage i) or in example 10.

Example 23

Stage i: 4-cyclopropanecarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-17-silt ether 6H-phenanthridine-5-carboxylic acid (1i)

5,6-dihydropteridine (1k) receive, in accordance with the following procedure: into a round bottom flask with a volume of 500 ml, equipped with a magnetic stirrer and reflux condenser, load 6(5H)-phenanthridinone (1000 mg, 5123 mmol), THF (250 ml) (thin suspension). Through the contents of the flask bubbled nitrogen, the mixture was added 2M solution of BH3-dimethylsulfide complex in THF (10 ml). The resulting mixture was refluxed under stirring for 24 hours. After this time TLC shows that the reaction is not yet completed (ethyl acetate/heptane 1/1). The solvents are removed under reduced pressure. To the residue water is added (50 ml) and ethyl acetate (100 ml). The aqueous layer was washed with ethyl acetate (3×100 ml). The organic layers are combined, dried (sodium sulfate), the solid precipitate is removed by filtration and the solvents removed under reduced pressure. The residue is purified column chromatography with silica (elution gradient: heptane to 50% ethyl acetate in heptane). The target fractions are combined and the solvents removed under reduced pressure, obtaining the product in the form of solid n is completely white matter (270 mg, yield: 29%). LC-MS: 182 (M+E)+.

Alcohol 1h (15 mg) was dissolved in dry EDC, to the resulting solution was added 20 mg of sodium bicarbonate and then 2 ml of a solution of phosgene in toluene (20%). The reaction mixture was stirred at room temperature for 3 hours, then concentrated on a rotary evaporator and the excess phosgene is removed in high vacuum (1.5 hours). The dry reaction mixture is transferred into a reaction chamber of a microwave reactor (2-5 ml), mixed with dry EDC (3 ml), 5,6-dihydropteridine (1k) (2 equiv.) potassium carbonate (9 mg, 1.5 EQ.), sprayed molecular sieves (4Å, 5 mg) and the mixture was incubated in a microwave reactor at 100°C for 45 minutes. The reaction mixture was passed through a small layer of silica (elution: DHM, then 10% methanol in DHM). The obtained fractions containing the target urethane compound are pooled, concentrated on a rotary evaporator and purified column chromatography on YMC-silicon dioxide (15 g, elution: ethyl acetate/petroleum ether (1:3) to remove excess 5,6-dihydropteridine (1k), then dichloromethane and then 2% methanol in dichloromethane)to give specified in the title compound in the form of powder.

Example 24

(17-hydroxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0*4,6*]octadec-7-ene-4-carbonyl)amide 1-methylcyclopropane acid (24)

The compound (6b), polucen the e in accordance with the described methodology, subjected to interaction with a cyclic amine (23k), as described in example 23, receiving methylcyclopropyl similar compounds (23i).

The activity of compounds of the formula (I)

Assessment of biological effects on replicon

The compounds of formula (I) examine the activity of inhibiting HCV RNA replication in cell analysis. This experience shows that the compounds of formula (I) are active against HCV replicons, functional in cell culture. Cellular analysis based on the design of the expression of bicistronic, as described in the publication Lohmann et al. (1999) Science vol. 285 pp. 110-113 with modifications described in the publication Krieger et al. (2001) Journal of Virology 75: 4614-4624, in the multipurpose screening strategies. Essentially, the method consists in the following.

In the experience using a stable transfectional cell line Huh-7 luc/neo (hereinafter in the description called Huh-Luc). This cell line carries the design of the RNA encoding the expression of bicistronic, including area NS3-NS5B wild-type HCV type 1b, translated from the website of the internal ribosome binding (Internal Ribosome Entry Site (IRES) virus encephalomyocarditis (encephalomyocarditis virus (EMCV), which precedes area reading (FfL-luciferase) and select the area of the marker (neoR, neomycinphosphotransferase). Design limited untranslated regions 5' and 3' non-translated regions - NTR) of HCV type 1b. ararauna cell culture replicon in the presence of G418 (neo Rdepends on replication of HCV RNA. Stable transfection replicon cells that Express HCV RNA can be played offline and up to high levels and encode inter alia the luciferase used for screening of antiviral compounds.

Replicalouis cells placed in 384-well microplates in the presence of the test and control compounds, which are added in various concentrations. The microplates are incubated for three days, after which quantify the replication of HCV by analysis of luciferase activity (using standard test substrates and luciferase reagents and microplate Visualizer Perkin Elmer ViewLuxTmultraHTS). Replicalouis cells in the control cultures have high expression in the absence of any inhibitor. Inhibitory activity of compounds against luciferase activity monitor on Huh-Luc cells, receiving a curve dose-effect for each test compound. Then calculate values of EC50, which is the amount of compound required for 50% reduction determined luciferase activity, or, more precisely, the ability of the genetically linked HCV replicon RNA replication.

Analysis of inhibition

The objective of this analysis in vitro consists in quantifying the inhibition of complexes of HCV NS3/4A protease and the compounds according to the present invention. This analysis provides a definition of how effective compounds according to the present invention should inhibit HCV NS3/4A proteolytic activity.

Enzyme inhibition the NS3 protease of hepatitis C full length quantitatively determined essentially in accordance with the method described in the publication Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of depsipeptide substrate, Ac-DED(Edans)EEAbuψ[COO]ASK(Dabcyl)-NH2(AnaSpec, San Jose, USA), determined spectrophotometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Äke Engström, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nm) incubated in 50 mm HEPES, pH 7.5, 10 mm DTT, 40% glycerol, 0.1% of n-octyl-D-glucoside in the presence of 25 μm NS4A cofactor and inhibitor at 30°C for 10 minutes, after which the reaction initiated by addition of 0.5 μm of the substrate. Inhibitors dissolved in DMSO, is treated with ultrasound for 30 seconds with a vortex mixing. Between measurements, the solutions stored at -20°C.

The final concentration of DMSO in the test sample was adjusted to 3.3%. The rate of hydrolysis correct for the effects of the internal filter in accordance with published methods [Liu, Analytical Biochemistry, 1999, vol. 267, pp. 331-335]. The values of Ki are determined by nonlinear regression analysis (GraFit, Erithacus Software, Staines, MX, UK), using the model of competitive inhibition and fix the automatic value Km (0,15 µm). For all measurements carried out at least two replication.

Compounds according to the present invention preferably have a high efficacy against virus HCV nematanthus and mutant type, in particular in respect of the virus, including mutations "off drugs". Mutations shutdown "medicines" are mutations that occur in patients due to selective anti-virus exposure at the previous level and give greater resistance to this antiviral agent.

Inhibition of some mutant HCV shown by the compounds according to the present invention, determined in accordance with the method described in WO2004/039970.

A156T and D168V are especially relevant mutants "off drugs" in the context of a therapeutic treatment of HCV using NS3 protease inhibitors, and compounds according to the present invention preferably have low Ki values for these mutants.

The following table 1 shows the compounds that were obtained in accordance with the method of any of the above examples. Activity of the test compounds is also presented in table 1. Legend A, B, C, D, E, and F correspond to the following values:

A which correspond EC 50>10 μm;

B corresponds EC50in the range from 10 μm to 1 μm;

C corresponds EC50in the range of from 0.99 μm to 200 nm;

D is EC50in the interval from 199 nm to 0.5 nm.

E corresponds to Ki>100 nm;

F corresponds to Ki in the range from 100 nm to 30 nm;

G corresponds to Ki in the range of from 29,9 nm to 0.1 nm;

Example No.EC50
Evaluation of replication
Ki
Enzyme analysis
1AF
2BG
3BG
5B
6cA
9B
10B
11B
12C
13D
14C
15A
16B
17B
18C

1. The compound of formula (I):

including its stereoisomers, where
A represents-C(O)OR1or-C(=O)-NH-SO2-R2,
where R1represents hydrogen or C1-C6alkyl;
R2represents a C3-7cycloalkyl, phenyl, thiazolyl or pyridyl, each of which is optionally substituted by one or more substituents selected from C1-6of alkyl, C1-6alkoxy, trifloromethyl and halogen;
X represents N or CH;
E represents NR5;
R5represents hydrogen, C1-6alkyl, C1-6alkoxyl1-6alkyl or C3-7cycloalkyl;
n is 4 or 5;
where the dotted line-----adjacent to the fragment -(CH2)n-represents the FDS is the first double bond; and
where the dotted line ----- in the five-membered cycle, including X represents a simple bond, and R7represents hydrogen;
R8represents a radical of the formula

or grouprepresents a group:

which has the following structure


where R8aand R9aeach independently represents hydrogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, hydroxyl group, halogen, polyhalogen C1-6alkyl, cyano, amino, mono - or dis1-6alkylamino;
each R9independently represents a C1-6alkyl, optionally substituted C1-6alkoxy, hydroxyl group or halogen; C3-7cycloalkyl; C2-6alkenyl; C1-6alkoxy, C3-7cycloalkane; aryloxy; Het-O-; hydroxyl group; cyano;
polyhalogen C1-6alkyl; mono - or di (C1-6alkylamino;
each R10independently represents hydrogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, hydroxyl group, halogen, polyhalogen1-6alkyl, cyano, amino, mono - or di (C1-6alkylamino;
where each aryl independently represents a phenyl, optionally substituted one, two or three what zamestitelyami, selected from a halogen, hydroxyl group, nitro, cyano, carboxyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6of alkyl, C1-6alkylsulphonyl, amino, mono - or di (C1-6alkylamino, azido, mercapto, C1-6alkylthio, polyhalogen C1-6of alkyl, polyhalogen C1-6alkoxy, C3-7cycloalkyl and Het1;
each Het independently represents a 5 - or 6-membered saturated, partially unsaturated or fully unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms, each independently selected from nitrogen atoms, oxygen and sulfur, and said heterocycle is optionally substituted one, two or three substituents, each of which is independently selected from halogen, hydroxyl group, nitro, cyano, carboxyl, C1-6of alkyl, C1-6alkoxy, C1-6alkoxyl1-6of alkyl, C1-6alkylsulphonyl, amino, mono - or di (C1-6alkylamino, azido, mercapto, polyhalogen C1-6of alkyl, polyhalogen C1-6alkoxy, C3-7cycloalkyl, Het1;
each Het1independently represents pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6alkylpiperazine, 4-C1-6acylcarnitines and morpholinyl where morpholinyl and piperidinyl groups can be optionally substituted by one or two C1-6alkyl for Alamy;
or its N-oxide, pharmaceutically acceptable additive salt or pharmaceutically acceptable MES.

2. The compound according to claim 1, where X represents N.

3. The compound according to claim 1, where R8represents a radical of the formula
; or
R8represents a radical of the formula
; or
R8represents a radical of the formula

4. Compounds according to claim 1, where R8represents a radical of the formula

5. The compound according to claim 3 or 4, where R9represents a C1-6alkyl (e.g. methyl, ethyl or isopropyl); C1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy); aryloxy; Het-O-;
cyano; or R9represents a C1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy) or aryloxy (for example, phenoxy or 4 methoxyphenoxy).

6. The compound according to claim 3 or 4, where R10represents hydrogen, C1-6alkyl (e.g. methyl, ethyl or isopropyl); C1-6alkoxy (e.g. methoxy, ethoxy or isopropoxy); cyano.

7. The compound according to claim 1, where the group

has the structure

8. The connection according to claim 7, where R8, R8a, R9represent hydrogen.

9. The compound according to claim 1, where aryl represents Fe is Il, optionally substituted C1-6alkoxy group, and Het represents a pyridyl or pyrimidinyl.

10. The compound according to claim 1, where A represents-C(=O)-NH-SO2R2in particular, where R2represents a C3-7cycloalkyl, phenyl or the group Het, for example, thiazolyl or pyridyl, each of which is optionally substituted by one or more, for example one or two, substituents selected from C1-6of alkyl, C1-6alkoxy, trifloromethyl and halogen, or in particular one or two substituents selected from methyl, fluorine or chlorine; or A represents C(=O)OR1where R1represents hydrogen or C1-6alkyl, such as methyl.

11. Pharmaceutical composition having antiviral activity comprising as an active ingredient a compound of the formula (I) according to any one of claims 1 to 10, and the media.

12. The compound according to claim 1 for use as a drug with antiviral activity.

13. The use of compounds according to any one of claims 1 to 10 to obtain drugs for treatment or prophylaxis of viral infections.

14. Use item 13, where the viral infection is HCV infection.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel intermediate epoxy compound of general formula (2), where R1 represents hydrogen or a lower alkyl group; and R2 represents a piperidinyl group of general formula (A1), where R3 represents a phenoxy group, having a halogen-substituted lower alkoxy group, substituted with a phenyl group, and other similar groups; and n is an integer from 1 to 6, to obtain 2,3-dihydroimidazo[2,1-b]oxazole. The invention also relates to specific epoxy compounds, a method of producing epoxy compounds of formula (2) and a method of producing 2,3-dihydroimidazo[2,1-b]-oxazole using a novel intermediate epoxy compound.

EFFECT: obtaining 2,3-dihydroimidazo[2,1-b]oxazole with high output and high purity.

4 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1, or their pharmaceutically acceptable salts showing the properties of incretin secretagogues, preferentially the properties of a bile acid receptor TGR5 agonist. The compounds are applicable for treating metabolic diseases associated with glucose metabolism, such as diabetes, obesity, metabolic syndrome, etc. In formula 1 R1, R2 and R3 independently represent a cyclic system substitute specified in: hydrogen, C1-C3alkyl, halogen, a trifluoromethyl group, C1-C3alkoxy, a cyano group, a trifluoromethoxy group; an amino group substituted by C1-C3alkyl; or two radicals R3, found at carbon neighbours in a benzene ring, together with the benzene ring bound therewith form 3,4-methylene dioxyphenyl; R4 represents hydrogen, C1-C5alkyl, a carboxyl group, C1-C3alkoxycarbonyl or an amide group CONHR5; R5 is an optionally substituted by C1-C3alkyl, C5-C6cycloalkyl optionally substituted by phenyl, benzyl, pyridyl; X and Y represent two hydrogen atoms or an oxygen atom, provided Y=O, then X=2H, provided Y=2H, then X=O or X=Y=2H; the sign (N) shows the possibility of bioisosteric substitution of the benzene ring by the pyridine, pyrimidine, pyridazine, triazine or pyrazine ones.

EFFECT: preparing the pharmaceutical composition and the combined drugs with the use of the compounds of formula 1 or the based pharmaceutical composition and a protein kinase DPP-IV inhibitor specified in Vildagliptin or Sitagliptin, and/or an endogenous bile acid or mied bile acid secretagogues.

53 cl, 7 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (R)-N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide substantially free from (S)-N-(3-amino-propyl)-N[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methypropyl]-4-methyl-benzamide, or its pharmaceutically acceptable salt which shows the properties of Eg5 inhibitor.

EFFECT: invention also refers to a pharmaceutical composition containing said compound and its pharmaceutically acceptable salt.

4 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole- 2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, where R means hydrogen; R1 means phenyl, substituted with 1, 2 or 3 substitutes, each of them is independently selected from a group containing halogen, cyano, C1-4alkyl, perfluoroC1-4alkyl and perfluoroC1-4alkoxy; R2 means hydrogen or C1-4alkyl; R3 means hydrogen, trifluoromethyl or cyano; X means N or CR4, where R4 is trifluoromethyl. Also the invention relates to a pharmaceutical composition containing compounds of the formula as an active ingredient. The following derivatives are presented: derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole-2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) representing quick-dissociating antagonists of dopamine 2 receptors and used as medicinal agents for treatment or prevention of central nervous system.

EFFECT: improved properties of compounds.

7 cl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic 5-nitropyridin-2-yl-thioalkenyl-4-dithiocarbamate derivatives of general formula (I) or pharmaceutically acceptable acid- or base addition salts thereof. The compounds have antifungal activity even in case of deep, subcutaneous and surface mycoses in humans, caused by strains (including those resistant to existing drugs) of mycosis causative agents. In general formula , R denotes nitro, cyano, halide-substituted C1-C6 alkyl group, n=1, 2 or 3. The invention also relates to use of compounds of formula (I), a method of producing said compounds, a pharmaceutical composition and a method for treatment using said compounds.

EFFECT: improved method.

12 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrrol derivatives of formula (1): or a pharmaceutically acceptable salt thereof wherein the values A, R1-R3, n are specified in clause 1 of the patent claim.

EFFECT: compounds (1) inhibit activity against the interleukin IL-6 production that allows using them both in pharmaceutical compositions, and in a prophylactic drug for ocular inflammatory disease.

23 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to substitute nicotine-amide compounds of general formula , where n=0, 1 or 2, p=0 or 1, q=0 or 1, R1 is aryl or heteroaryl or heterocyclyl, non-substitute or mono- or polysubstitute; C1-6-alkyl, C3-10-cycloalkyl, non-substitute or mono- or polysubstitute; R2 is H or C1-6-alkyl; R3 is aryl or pyridyl, non-substitute or mono- or polysubstitute; C1-6-alkyl or C3-10-cycloalkyl, in each case non-substitute or mono- or polysubstitute; R4, R5, R6 and R7 independently from each other represent H; C1-6-alkyl; R8, R9 and R10 independently from each other represent H, F, Cl, Br, CF3, C1-6-alkyl; where "substitute alkyl", "substitute heterocyclyl" and "substitute cycloalkyl" stands for substitution of hydrogen radical for F, Cl, Br, I, C1-6-alkyl, SH, S-C1-6-alkyl, O-C1-6-alkyl, O-C1-benzyl, -OH, O-C1-6-alkyl-OH, phenyl, phenoxy, morpholynyl or benzyl; and "substitute aryl" and "substitute heteroaryl stands for single or multiple substitution of one or several atoms of circular system for F, Cl, Br, I, SH, S-C1-6-alkyl, OH, O-C1-6-alkyl, O-C1-6aryl-OH, CH2SO2-phenyl, OCF3, SCF3, CF3, , , C1-6-alkyl, morpholynyl, phenoxy, phenyl or pyrazolyl; provided that if R3 is 3-trifluoromethylphenyl or 4-trifluoromethyl-2-pyridyl, R2, R4 and R5 are H, and n is 0, then R1 is not 2-pyridyl or 2-thienyl; and if R3 is or methyl, R2, R4 and R5 are H, and n is 0, then R1 is not 2-thienyl; in the form of racemate; enantiomers, diastereisomers, mixtures of enantiomers or diastereisomers or a separate enantiomer or diastereisomer; bases and/or salts of physiologically acceptable acids. Besides, the invention relates to a pain killer containing specified compounds and to application of the specified compounds for preparation of medicinal agents.

EFFECT: new compounds were produced and described, which may find their application in pain treatment.

13 cl, 150 ex, 8 tbl, 1 dwg

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