Thiophene derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula wherein each of R1 and R2 is independently selected from a group consisting of a hydrogen atom, nitro and NR6R7; R3 is C1-C8alkyl; each of R4 and R5 is independently selected from a group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylene)oxy; each of R6 and R7 is independently selected from a group consisting of a hydrogen atom, C1-C8alkyl, C(O)R8 and SO2R8;R8 is selected from a group consisting of a hydrogen atom, C1-C8alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkylsubstituted amino), C1-C8-alkyl, substituted with piperidine and C1-C8-alkyl, substituted with morpholine.

EFFECT: reduced PDE4 enzyme activity and treating PDE4 enzyme mediated diseases or conditions.

21 cl, 2 tbl, 32 ex

 

The technical field to which the invention relates

The present application relates to the field of organic chemistry and pharmaceutical chemistry.

The level of technology

TNFα is a cytokine produced primarily by mononuclear phagocytes in response to Immunostimulants. TNFα is able to participate in most processes, such as differentiation, aggregation, and cell proliferation, protein degradation, etc., With a low level of TNFα has protective effects aimed at preventing infectious substances, tumors and tissue damage. However, excessive release of TNFα to induce disease. For example, when TNFα enter the mammal or human, it will induce or exacerbate inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute reaction similar to acute infections and shock States. Excess or uncontrolled amount of TNFα produced in animals or humans, often indicates the presence of the following diseases: endotoxemia and/or toxic shock syndromes, cachexia, nervous, respiratory syndromes in adults, malignant tumors (such as solid tumors and tumors of the blood vessels), heart disease (such as acute heart failure), viral infections, G. the kinetic diseases, inflammatory diseases, allergic diseases or autoimmune diseases.

A malignant tumor is a particularly destructive disease. Elevated levels of TNFα in the blood indicates the risks of malignant tumors or spread of malignant tumors. Usually in a healthy subject's tumor cells can not survive in the circulation (blood). One of the reasons is that the inner vessel wall is an obstacle to extravasation of oncocytes. Studies show that ELAM-1 on endothelial cells may mediate the increased adhesion of tumor cells of the colon on the endothelium treated with cytokines.

Cyclic monophosphate (camp) is also involved in many diseases and disorders such as, but not limited to, asthma, inflammation and other disorders. When there is inflammation, increased concentration of camp in white blood cells is to inhibit the activation of leukocytes and then to release factors that regulate inflammation, including TNFα, NF-ΚB, etc., Elevated levels of camp also will cause the relaxation of smooth muscles of the respiratory tract.

The main cellular mechanism of inactivation of camp is that the family of isoenzymes known as phosphodiesterase cyclic nucleotide is in (PDE), destroys the camp. It is known that there are eleven members of the PDE family. To date, it has been shown that inhibition of release of mediators of inflammation and relaxation of smooth muscles of the respiratory tract is particularly effective inhibition of the PDE4 enzyme. Therefore, the PDE4 enzyme is a target for drug treatment of interest. Inhibition of PDE4 enzyme causes increased levels of camp and thereby regulates the level of TNFα, while the treatment of inflammation, such as septic shock, septicaemia, endocrinolgy bacterial toxic shock, hemicheskiy shock, sepsis syndrome disease, ischemia-reperfusion injury, mycobacterial malarial infection, meningitis, psoriasis, acute heart failure, fibrosing disease, cachexia, graft rejection, tumor, a disease associated with autoimmune disorders, possible AIDS infection, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other inflammatory disease, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, leprosy erythema nodosum, radiation damage, gipertoksicheskaya lung damage, etc., infectious disease, immune disease, or other malignant disease.

Sovr the Menno inhibitors of PDE4 enzyme have shown clinical efficacy against various inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, allergic dermatitis, etc., In animal models, they also show effectiveness against various diseases, including arthritis, septicemia, etc., But they have adverse reactions such as nausea, vomiting, etc. because they are not able to specifically inhibit the PDE4 enzyme, so that their clinical practice is limited. Therefore, in order to reduce adverse reactions of the medicinal product and to maintain its anti-inflammatory activity, possibly obtaining specific inhibitors of the PDE4 enzyme.

The invention

In one aspect the present invention relates to the compound of formula (I), its stereoisomer, enantiomer or tautomer, or the mixture of its stereoisomers, its pharmaceutically acceptable salts, its polymorphic modifications, MES, its prodrug or metabolite:

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, neobyazatel is substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8; and

R8selected from the group consisting Isotoma hydrogen and optionally substituted alkyl.

In yet another aspect, the present application relates to a method for obtaining compounds of formula (I), which includes the interaction of the compounds of formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I):

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted arylalkyl)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

In another aspect the present invention relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds of formula (I), its stereoisomer, enantiomer or tautomer, or a mixture of its stereoisomers, its pharmaceutically acceptable salts, its polymorphic modifications, MES, its prodrugs or its metabolite,

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R 7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

Each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

Each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which the ω X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

In yet another aspect, the present application relates to a method for decreasing the activity of PDE4 enzyme comprising contacting the enzyme PDE4 with a therapeutically effective amount of the compounds of formula (I), its stereoisomer, enantiomer, or tautomer, or a mixture of its stereoisomers, its pharmaceutically acceptable salts, its polymorphic modifications, MES, its prodrugs or its metabolite,

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

Each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally Zam is on alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

Each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

In yet another aspect, the present application relates to a method of treatment of diseases or conditions mediated by the PDE4 enzyme, comprising the administration to a subject in need of treatment a therapeutically effective amount of the compounds of formula (I), its stereoisomer, enantiomer or tautomer or a mixture of its stereoisomers, its pharmaceutically acceptable salts, E. what about polymorphic modifications his MES, its prodrugs or its metabolite,

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

Each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

Each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted is on aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

Detailed description of the invention

To provide understanding of the various described embodiments of the invention, in the following description, some specific details. However, the person skilled in the art will understand that embodiments of the invention can be applied in practice without one or more of these specific details or with other methods, components, materials, etc.

Unless the context requires otherwise, throughout the description and claims which follows, the term "contain" and variations such as "includes" and "include" shall be construed in an open, broad sense, which is understood as "includes, but is not limited to".

Throughout this specification reference to "one of the options for implementing the invented what I" or "variant implementation of the invention", or another variant implementation of the invention", or "some embodiments of the invention" means that the designated feature, structure or characteristic described in connection with the variants of the invention, included in at least one alternative embodiment of the invention. Therefore, the appearance of the phrases "in one of the embodiments of the invention", or "in the embodiment of the invention", or "in another embodiment of the invention", or "in some embodiments of the invention in various places throughout this specification are not necessarily refers only to the same variant embodiment of the invention. Moreover, individual characteristics, structure, or characteristic features can be combined in any suitable manner in one or more embodiments of the invention.

It should be noted that used in this description and the attached claims forms in the singular ("a", "an" and "the") include many of the designated objects, unless the context clearly indicates otherwise. Therefore, for example, the reaction mixture containing the catalyst contains a single catalyst, two or more catalysts. It should also be noted that the use of "or" means "and/or" unless stated otherwise.

Definition

Some here mentioned chemical groups is preceded by a symbol that indicates the total number of carbon atoms, which should be denoted by the chemical group. For example, C7-C12-alkyl describes alkyl, which is shown below, containing generally from 7 to 12 carbon atoms, and C4-C12-cycloalkenyl describes cycloalkenyl listed below, contains in General from 4 to 12 carbon atoms. The total number of carbon atoms in the callout does not include the carbon atoms that may be present in the substituents described groups.

Respectively, used in the description and the attached claims, unless the opposite, the following terms have the meanings specifies:

"Hydroxy" refers to the group-OH.

"Cyano" refers to the group-CN.

"Nitro" refers to the group-NO2.

Used here, the term "alkyl" refers to aliphatic hydrocarbon group. The alkyl part may be a "saturated alkyl" group, which means it does not contain any alkenovich or alkenovich fragments. The alkyl fragment may also be an "unsaturated alkyl" fragment, which means that it contains at least one Allenby or alkyne fragment. "Allenby" fragment Rel is referring to the hydrocarbon group with a straight or branched chain, containing from two to eight carbon atoms and at least one double bond in the carbon-carbon that is attached to the residue of the simple molecule by a single bond, for example ethynyl, prop-1-enyl, but-1-enyl, Penta-1-enyl, Penta-1,4-dienyl, etc. "Alkyne" fragment refers to a hydrocarbon group with a straight or branched chain, containing from two to eight carbon atoms and at least one triple bond carbon-carbon that is attached to the residue of the simple molecule by a single bond. The alkyl fragment, both saturated and unsaturated, may be branched chain or straight chain.

An alkyl group can contain from 1 to 20 carbon atoms (whenever this expression appears herein, a numerical range such as "1 to 20" refers to each integer from a specified range of numbers; for example, from 1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to 20 carbon atoms and including 20 carbon atoms, although this definition also applies to the case of the term "alkyl", when the numerical range is not defined). An alkyl group may also be an alkyl medium in size, containing from 1 to 10 carbon atoms. The alkyl group can also represent ISSI alkyl, containing from 1 to 5 carbon atoms. The alkyl group of the compounds according to the present application can be defined as "C1-C4-alkyl" or using similar definitions. As the only example, "C1-C4-alkyl" means that the alkyl chain is from one to four carbon atoms,that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl,nbutyl, isobutyl,second-butyl andtbutyl.

Alkyl group optionally may be substituted, there may be substituted or unsubstituted. When an alkyl group is substituted, the group-Deputy (deputies) is selected individually and independently from cycloalkyl, aryl, heteroaryl, heteroalicyclic groups, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, cyano, halogen atom, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, Silla, trihalomethane, -NR'r R", or amino, including mono - and disubstituted an amino group and a protected derivative. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, Penta is l, hexyl, ethyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., whenever the Deputy described as "optionally substituted", the Deputy may be substituted for one of the above substituents.

"C1-C4-alkyl" refers to an alkyl group as defined above containing one to four carbon atoms. C1-C4is an alkyl group optionally may be substituted therefore, as described for alkyl groups.

"C1-C6-alkyl" refers to an alkyl group as defined above containing one to six carbon atoms. C1-C6is an alkyl group optionally may be substituted therefore, as described for alkyl groups.

"C1-C12-alkyl" refers to an alkyl group as defined above containing one to twelve carbon atoms. C1-C12is an alkyl group optionally may be substituted therefore, as described for alkyl groups.

"C2-C6-alkyl" refers to an alkyl group as defined above containing two to six carbon atoms. C2-C6is an alkyl group optionally may be substituted therefore, as described for alkyl groups.

"C3-C6-alkyl" refers to an alkyl group that is definitely the Lena higher containing three to six carbon atoms. C3-C6is an alkyl group optionally can be substituted as described for alkyl groups.

"C3-C12-alkyl" refers to an alkyl group as defined above containing three to twelve carbon atoms. C3-C12is an alkyl group optionally can be substituted as described for alkyl groups.

"C6-C12-alkyl" refers to an alkyl group as defined above containing from six to twelve carbon atoms. C6-C12is an alkyl group optionally can be substituted as described for alkyl groups.

"C7-C12-alkyl" refers to an alkyl group as defined above containing from seven to twelve carbon atoms. C7-C12is an alkyl group optionally can be substituted as described for alkyl groups.

Used here, the term "alkoxy" refers to the formula-OR, where R is an alkyl group as defined above, for example,methoxy, ethoxy,npropoxy, 1-methylethoxy (isopropoxy),nbutoxy, isobutoxy,second-butoxy,tbutoxy, amoxy,tamoxi etc.

Used herein, the term "alkylthio" refers to the formula-SR, in which R represents an alkyl group, Kotor is defined above, for example, methylmercapto, ethylmercaptan,npropylmercaptan, 1-methylethylacetate (isopropylmalate),nbutylmercaptan, isobutylparaben,second-butylmercaptan,tbutylmercaptan etc.

Used here, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting of atoms of carbon and hydrogen and containing from one to eight carbon atoms, for example, methylene, ethylene, propylene,nbutylene, ethenylene, propenylidene,nbutenolide. Allenova circuit can join the rest of the molecule and to the radical group through one carbon atom within the chain or through any two carbons within the chain.

Used here, the term "aryl" refers to a carbocyclic (only carbon atoms) ring or two or more condensed rings (rings, which together two adjacent carbon atoms) which have the system fully delocalized π-electrons. Examples of aryl groups include, but are not limited to, fluorenyl, phenyl and naphthyl. Aryl group, for example, may contain from five to twelve carbon atoms. Aryl group according to the present application may be substituted or unsubstituted. When the aryl group is substituted, the atoms in Dorada substituted by a group-Deputy (deputies), which represents one or more groups independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy groups, alkoxy, aryloxy, mercapto, alkylthio, aaltio, cyano, halogen atom, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C-carboxyl protected C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silila, trihalomethane, -NR'r R" (R' and R" represent alkyl groups that are specified in this application) or a protected amino group.

Used here, the term "halogen" refers to an atom of bromine, chlorine, fluorine or iodine.

"Cycloalkyl" refers to non-aromatic monocyclic or bicyclic hydrocarbon group containing only atoms of carbon and hydrogen, containing from three to fifteen carbon atoms, preferably containing from three to twelve carbon atoms, and which is a stable, saturated or unsaturated and attached to the remainder of the molecule through a simple single bond, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, etc. If the description does not specifically stated otherwise, it is understood that the term "cycloalkyl includes cycloalkyl group, is the quiet optionally substituted by one or more substituents, selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic group, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, cyano, halogen atom, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, Silla, trihalomethane, -R NR'r" (R' and R" represent alkyl groups that are specified in this application) or amino, including monosubstituted and disubstituted an amino group and a protected derivative.

"C3-C6-cycloalkyl" refers to cycloalkyl group as defined above containing three to six carbon atoms. C3-C6-cycloalkyl group optionally can be substituted as described for cycloalkyl.

"C3-C10-cycloalkyl" refers to cycloalkyl group as defined above containing three to ten carbon atoms. C3-C10-cycloalkyl group optionally can be substituted as described for cycloalkyl.

"C3-C12-cycloalkyl" refers to cycloalkyl group as defined above containing three to twelve carbon atoms. C3-C12-cycloalkyl group may not necessarily be semistatic, as indicated for cycloalkyl.

Used here, the term "heterocyclyl" refers to a stable 3 to 12-membered nonaromatic cyclic group, which consists of carbon atoms and contains from one to five heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur. Examples of such heterocyclyl groups include, but are not limited to, DIOXOLANYL, decahydroquinoline, imidazolines, imidazolidinyl, isothiazolinones, isoxazolidine, morpholine, octahedrally, activitiesunder, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, oxazolidinyl, piperidinyl, piperazinil, 4-piperidinyl, pyrrolidinyl, pyrazolidine, thiazolidine, tetrahydrofuryl, tritional, tetrahydropyranyl, thiomorpholine, thiomorpholine, 1-oxathiolanes and 1,1-dioxothiazolidine. If the description does not specifically stated otherwise, it is understood that the term "heteroseksualci includes heterocyclyl groups listed above, which are optionally substituted by one or more substituents selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic group, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aaltio, cyano, halogen atom, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-the Mido, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, Silla, trihalomethane, -NR'r R" (R' and R" represent alkyl groups that are specified in this application) or amino, including monosubstituted and disubstituted an amino group and a protected derivative.

It is implied that the term "prodrug" denotes a compound which under physiological conditions or by solvolysis can turn into a biologically active compound according to the present application. Therefore, the term "prodrug" refers to a metabolic precursor compounds according to the present application, which is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need of treatment, but becomesin vivothe active compound according to the present application. Prodrugs are typically rapidly transformedin vivogiving the original connection according to the present application, for example, by hydrolysis in blood. Connection-prodrug often has the advantages of solubility, tissue compatibility or delayed release in the body of a mammal (see publication Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

A discussion of prodrugs is provided in the publication Higuchi T.and other "Pro-drugs as Novel Delivery System" A. C. S. Symposium Series, so 14 and in the publication Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein in full by reference.

This also implies that the term "prodrug" includes any covalently associated media, which release the active compound according to the present application isin vivowhen such prodrug is administered to a mammal. Prodrugs of the compounds according to the present application can be obtained by modifying functional groups present in the compound of the present application, so that modifications were split either in the regular conversion, orinvivobefore starting compound according to the present application. Prodrugs include compounds according to the present application, in which the hydroxy-group, amino group or mercaptopropyl associated with any group that, when the prodrug of the compounds according to the present application is administered to a mammal, split with the formation of free hydroxy-group, the free amino or free mercaptopropyl, respectively. Examples of prodrugs include, but are not limited to, acetate, formiate and benzoate derivatives of alcohol or amidofunctional groups in the compounds according to the present application, etc.

p> "Optional" or "optionally" means that the following event in circumstances may occur or may not occur, and that the description includes instances when the said event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means aryl group can be substituted or may be unsubstituted, and the description includes both substituted aryl groups, and aryl groups without replacement.

"Pharmaceutically acceptable carrier" includes without limitation any ancillary medicinal substance, carrier, excipient, a substance promoting sliding, sweetener, diluent, preservative, dye/coloring agent, a flavor enhancer and smell, surfactant, moisturizer, dispersant, suspendisse agent, stabilizer, isoosmotic medium, solvent, or emulsifier, etc. that are approved by Management under the control over food and drugs U.S. as acceptable for use for humans and animals and do not have side effects on obtaining pharmaceutical compositions.

"Pharmaceutically acceptable salts" include both "pharmaceutically acceptable additive, acid salts, and the pharmaceutical is Eski acceptable salt additive bases."

"Pharmaceutically acceptable additive salt of the acid" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise unacceptable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and so on; and with organic acids, such as, but not limited to, acetic acid, 2,2-dichloracetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzolsulfonat acid, benzoic acid, 4-acetamidobenzoic acid, Campanula acid, camphor-10-sulfonic acid, capric acid, Caproic acid, Caprylic acid, carbonic acid, cinnamic acid, citric acid, reklamowa acid, modellerna acid, ethane-1,2-disulfonate acid, econsultancy acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactosemia acid, gentisic acid, glucoheptonate acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid is the somalina acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonate acid, mucus acid, naphthalene-1,5-disulfonate acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamula acid, propionic acid, pyroglutamyl acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sabotinova acid, stearic acid, succinic acid, tartaric acid, titanova acid,p-toluensulfonate acid, triperoxonane acid, undecenoate acid, etc.,

"Pharmaceutically acceptable additive salt base" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise unacceptable. Such salts are produced by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., the Preferred inorganic salts are the salts and mania, sodium, potassium, calcium and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including substituted amines of natural origin, salts of cyclic amines and basic ion exchange resins, such as ammonium salts, Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-Diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, benethamine, benzathine, Ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, trometamol, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. are Particularly preferred organic bases are Isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Often when crystallization formed MES compounds according to the present application. Used here, the term "MES" refers to the aggregated complex, which contains one or more molecules of the compounds according to the present application with one or more solvent molecules. The solvent may be a water, in which case the MES may be a hydrate. Al is ternative solvent may be an organic solvent. Therefore, the compounds according to the present application may exist as a hydrate, including the monohydrate, dihydrate, hemihydrate, Politologija, trihydrate, tetrahydrate, and so on, as well as the corresponding solvated forms. The connection according to the present application may be a true MES, while in other cases the connection according to the present application may simply store more water, or contain a mixture of water and any additional solvent.

The term "polymorphs" refers to a component having the same chemical formula, but with other structures.

The term "pharmaceutical composition" refers to the preparation of the compounds according to the present application and environment, typically used in this area for the delivery of biologically active compounds mammals, for example humans. This environment includes all pharmaceutically acceptable carriers, diluents or inert excipients for pharmaceutical compositions.

"Therapeutically effective amount" refers to that amount of the compound according to the present application, which, when administered to a mammal, preferably a human, is sufficient for effective treatment, as indicated below, mediated by the enzyme PDE4 disease or condition mlekopitayuschih is, preferably humans. The number of compounds according to the present application, which is "therapeutically effective amount" will vary depending on the connection state, its severity and the age of the mammal being treated, at the same time may be determined by an ordinary person skilled in the art that comes from their own knowledge and the description.

Used here, the term "treatment" or "treatment" cover the treatment of interest disease or condition of a mammal, preferably a human, having a disease or disorder of interest, and include:

(i) preventing the disease or condition in a mammal, in particular, when such mammal is predisposed to this condition, but its presence has not yet been diagnosed;

(ii) inhibiting the disease or condition,that is, the cessation of its development; or

(iii) facilitation of the severity of the disease or condition,i.e. the regression of the disease or condition.

Used here, the terms "disease" and "condition" may be used interchangeably or may differ from each other in the case where the causative agent of a particular disease or condition may be unknown (i.e., the etiology is still naratriptan) and therefore, the disease is not yet recognized as a disease but only as an undesirable condition or syndrome for which clinicians identified more or less specific set of symptoms.

Compounds according to this application or its pharmaceutically acceptable salt may contain one or more centers of asymmetry and may therefore lead to the formation of enantiomers, diastereoisomers and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R) - or (S)-, or (D)- or (L)- for amino acids. Assume that this application include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D) and (L)- isomers can be obtained using chiral synthons or chiral reagents, or to separate mixtures using conventional techniques, such as HPLC with chiral column. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is understood that the compounds include both E and Z geometric isomers. Similarly, it is understood that in a real application should include all tautomeric forms.

The term "stereoisomer" refers to the compound formed by those who s atoms, related in the same relationship, but with other three-dimensional structures which are not interchangeable. In this application discusses the various stereoisomers and mixtures thereof.

The term "tautomer" refers to the shift of a proton from one atom of a molecule to another atom of the same molecule. This application includes tautomers of any of the above mentioned connection.

Specific embodiments of the invention

In one aspect the present invention relates to the compound of formula (I), its stereoisomer, enantiomer or tautomer or a mixture of its stereoisomers, its pharmaceutically acceptable salts, its polymorphic modifications, MES, its prodrug or metabolite:

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

each of R4 5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

In some embodiments of the invention C1-C8is alkyl selected from the group consisting of C1-C4-alkyl and C1-C6-alkyl.

In some embodiments, is sushestvennee invention C 1-C8-alkoxy selected from the group consisting of C1-C4-alkoxy and C1-C6-alkoxy.

In some embodiments of the invention C1-C8-alkylthio selected from the group consisting of C1-C4-alkylthio and C1-C6-alkylthio.

In some embodiments of the invention C3-C10-cycloalkyl selected from C3-C6-cycloalkyl.

In some embodiments of the invention, each of R1and R2independently selected from the group consisting of hydrogen atom, methyl, ethyl, nitro, NH2, NHCH3CH3C(O)NH, CH3CH2C(O)NH, CH3SO2NH and ClCH2C(O)NH.

In some embodiments of the invention R3selected from the group consisting of C1-C8-alkyl and C1-C8-alkoxy.

In some embodiments of the invention R3selected from the group consisting of C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkyl(C1-C8-alkylen)hydroxy, C5-C12-aryl and C5-C12aryl(C1-C8-alkylen)hydroxy.

In some embodiments of the invention R3selected from the group consisting of methyl, ethyl and propyl.

In some embodiments of the invention, each of R4and R5independently selected from the group comprised the soup from a hydrogen atom, hydroxy, C1-C8-alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkylthio, cyano, C3-C10-cycloalkyl, (C1-C8-alkylen)C3-C10-cycloalkyl, C3-C10-cycloalkyl(C1-C8-alkylen)hydroxy, C3-C10-cycloalkane, C5-C12-aryl, C5-C12-aryloxy and C5-C12aryl(C1-C8-alkylen)hydroxy.

In some embodiments of the invention, each of R4and R5independently selected from the group consisting of C1-C8-alkoxy, halogen-substituted C1-C8-alkoxy and C5-C12-aryloxy.

In some embodiments of the invention, each of R4and R5independently selected from the group consisting of methoxy, deformedarse, triptoreline, ethoxy, propoxy and benzyloxy.

In some embodiments of the invention R8selected from the group consisting of a hydrogen atom, a C1-C8-alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkyl substituted amino), and C3-C12-heterocyclization C1-C8-alkyl.

In some embodiments of the invention R8selected from the group consisting of hydrogen atom, methyl, ethyl of dimethylaminomethyl, diethylaminomethyl, piperidinomethyl and morpholinylmethyl.

In some embodiments of the invention the compound of formula (I) selected from the group consisting of:

N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

(S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

(R)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

N-(5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

N-(5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

(S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

(R)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

(S)-5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

(S)-5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]Pirro is-4,6-diketone,

5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

N-(5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-methylamino-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

2-chloro-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)methanesulfonamide,

(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

(R)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone,

N-(5-(1-(3-ethoxy-4-debtor ethoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

N-(5-(1-(3-ethoxy-4-trifloromethyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

(S)-N-(5-(1-(3-ethoxy-4-deformational)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

(R)-N-(5-(1-(3-ethoxy-4-deformational)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

(S)-N-(5-(1-(3-ethoxy-4-trifloromethyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

(R)-N-(5-(1-(3-ethoxy-4-trifloromethyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

N-(5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)propionamide,

2-(dimethylamino)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

2-(diethylamino)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)acetamide", she

2-(piperidyl)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrole-1-ylacetamide and

2-(morpholinyl)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide.

In yet another aspect, the present application relates to a method for obtaining compounds of formula (I), enabling the mu in the interaction of the compounds of formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I):

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and n is necessarily substituted SO 2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

In some embodiments of the invention in the interaction of the compounds of formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I) as catalyst type tertiary amine.

Suitable examples of the catalyst which can be used in this application include, but are not limited to, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinedione and their mixture.

In some embodiments of the invention in the interaction of the compounds of formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I) optionally, you can add a dehydrating agent.

Suitable examples of dehydrating, which can be used in this application include, but are not limited to, DCC, EDC•HCl, CDI, DIC, complex diethyl ester of azodicarboxylic acid, complex diisopropyl ester of azodicarboxylic acid complex on the benzyl ester of azodicarboxylic acid and their mixture.

In some embodiments of the invention in the interaction of the compounds of formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I) optionally, you can add an activating agent.

Suitable examples of the activating means, which can be used in this application include, but are not limited to, N-hydroxysuccinimide, HOBt, HOAt, BOP, Cl-HOBt, DEPBT, HATU, HBTU, HCTU, HOOBt, PyBOP, TATU, TBTU and their mixture.

In some embodiments of the invention the interaction of the compounds of formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I) is carried out in an organic solvent.

Suitable examples of the organic solvent which can be used in this application include, but are not limited to, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, simple diethyl ether, simple, isopropyl ether, ethyl acetate, easy dimethyl ether glycol, a simple diethyl ether glycol, benzene, toluene,nhexane, cyclohexane, DMF, DMSO, simple metaliteracy ether, simple methylpropyloxy ether, simple methyl-tbutyl ether, acetone, butanone, methylformate, ethyl formate, paperformat, bodyformat, methyl acetate, propyl, butyl acetate and a mixture thereof.

In some embodiments of the invention the reaction is connected to the I of the formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I) is carried out at -10°C-200°C.

In some embodiments of the invention the reaction of the compound of the formula (A-IV) with the compound of the formula (A-VII) with a compound of formula (I) is carried out at -10°C-150°C.

In some embodiments of the invention the dehydration of compounds of formula (A-III) is carried out with obtaining the compounds of formula (A-IV)

Suitable examples of dehydrating, which can be used in this application include, but are not limited to, acetic anhydride, triperoxonane anhydride and a mixture thereof.

In some embodiments of the invention the dehydration of compounds of formula (A-III) with a compound of the formula (A-IV) is carried out in an organic solvent.

Suitable examples of the organic solvent which can be used in this application include, but are not limited to, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, simple diethyl ether, simple isopropyl ether, cyclohexane,nhexane, ethyl acetate, easy dimethyl ether glycol, a simple diethyl ether glycol, benzene, toluene, DMF, DMSO, acetone, butanone, simple metaliteracy ether, simple methyl-tbutyl ether, simple methylpropyloxy ether, methylformate, ethyl formate, paperformat, bodyformat, methyl acetate, propyl, butylated is t, acetic acid, triperoxonane acid and their mixture.

In some embodiments of the invention the compound of formula (A-III) are obtained from the compounds of formula (A-II) in the presence of acid or base

Suitable examples of bases that can be used in this application include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide and a mixture thereof.

Suitable examples of acids which can be used in this application include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonate acid, econsultancy acid and their mixture.

In some embodiments of the invention the compound of formula (A-III) are obtained from the compounds of formula (A-II) in a solvent in the presence of acid or base.

Suitable examples of the solvent which can be used in this application include, but are not limited to, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, simple diethyl ether, simple isopropyl ether, cyclohexane,nhexane, ethyl acetate, easy dimethyl ether glycol, a simple diethyl ether glycol, benzene, toluene, DMF, DMSO, acetone, butanone, simple metaliteracy ether, simple methyl-tbutyl is the ether, simple methylpropyloxy ether, methylformate, ethyl formate, paperformat, bodyformat, methyl acetate, propyl, butyl acetate, acetic acid, triperoxonane acid, water and their mixture.

In some embodiments of the invention the compound of formula (A-III) are obtained from the compounds of formula (A-II) at 0°C-200°C in the presence of acid or base.

In some embodiments of the invention the compound of formula (A-III) are obtained from the compounds of formula (A-II) at 50°C-200°C in the presence of acid or base.

In some embodiments of the invention the compound of formula (A-III) are obtained from the compounds of formula (A-II) at 80°C-180°C in the presence of acid or base.

In some embodiments of the invention the reaction of the compound of the formula (A-I) cyanide is carried out with obtaining the compounds of formula (A-II)

Suitable examples of cyanide, which can be used in this application include, but are not limited to, copper cyanide (I), sodium cyanide, potassium cyanide and cyanide of mercury.

In some embodiments of the invention the reaction of the compound of the formula (A-I) cyanide is carried out in an organic solvent to obtain compounds of formula (A-II).

Suitable examples of the organic solvent which can be used in this application, on the require, but not limited to, DMF, DMSO, ndimethylacetamide, N-organic, simple, dimethyl ether of diethylene glycol, simple, diethyl ether of diethylene glycol and a mixture thereof.

In some embodiments of the invention the reaction of the compound of the formula (A-I) cyanide is carried out at 50°C-250°C to obtain the compounds of formula (A-II).

In some embodiments of the invention the reaction of the compound of the formula (A-I) cyanide is carried out at 100°C-250°C to obtain the compounds of formula (A-II).

In some embodiments of the invention the compound of formula (A-VII) are obtained by reacting compounds of the formula (A-VI) in the presence of means for removing protection,

Suitable examples of means for removing the protection that can be used in this application include, but are not limited to, tetrabutylammonium fluoride, fluoride of tetraethylammonium, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, triperoxonane acid, formic acid, methanesulfonate acid, econsultancy acid, benzosulfimide acid,p-toluensulfonate acid and their mixture.

In some embodiments of the invention the compound of formula (A-VII) are obtained by reacting compounds of the formula (A-VI) in the presence of media is tion to remove the protection in the solvent.

Suitable examples of the solvent which can be used in this application include, but are not limited to, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, simple diethyl ether, simple, isopropyl ether, ethyl acetate, ethanol, methanol, propyl alcohol, butyl alcohol, ethylene glycol, simple dimethyl ether glycol, a simple onomatology ether of ethylene glycol, simple monotropy ether of ethylene glycol, simple diethyl ether glycol, benzene, toluene,nhexane, cyclohexane, DMF, DMSO, acetic acid, triperoxonane acid, simple metaliteracy ether, simple methylpropyloxy ether, simple methyl-tbutyl ether, acetone, butanone, methylformate, ethyl formate, paperformat, bodyformat, methyl acetate, propyl, butyl acetate, water and their mixture.

In some embodiments of the invention the compound of formula (A-VII) are obtained by reacting compounds of the formula (A-VI) in the presence of means for removing protection at -20°C-200°C.

In some embodiments of the invention the compound of formula (A-VII) are obtained by reacting compounds of the formula (A-VI) in the presence of means for removing protection at 0°C-200°C.

In some embodiments of the invention the reaction of the compound of the formula (A-V) CH3S(O)2R3and (R14R15R16i) 2NM carried out in the presence of a strong base to obtain the compounds of formula (A-VII),

in which the group represented by R3in CH3S(O)2R3is identical to the group represented by R3in the compound of formula (I), and where each of R14, R15or R16in (R14Rl5R16Si)2NM independently selected from the group consisting of alkyl and phenyl, and M is selected from the group consisting of sodium, potassium and lithium.

Suitable examples of strong bases that can be used in this application include, but are not limited to, alkylate, alkylate, alkiline, sodium alcoholate, potassium alcoholate, the lithium alcoholate, alkylamide sodium, alkylamide lithium and alkylamide potassium.

In some embodiments of the invention suitable examples of strong bases that can be used in this application include, but are not limited to,nutility,tutility, motility, utility, sodium methylate, potassium methylate, lithium methylate, dimethylamide lithium, diethylamid lithium, DIPROPYLENE lithium, diisopropylamide lithium and their mixture.

Suitable examples of (R14R15R16Si)2NM, which can be used in this application include, but are not limited which are listed, bis(trimethylsilyl)amide and lithium bis(triethylsilyl)amide and lithium bis(Tripropylene)amide and lithium bis(triisopropylsilyl)amide and lithium bis(dimethylarsine)amide and lithium bis(dimethylpropyl)amide and lithium bis(dimethylazobenzene)amide and lithium bis(dimethylphenylsilane)amide and lithium bis(dimethylbenzylidene)amide and lithium bis(diethylethylene)amide and lithium bis(diethylproprion)amide and lithium bis(diethylenediamine)amide and lithium bis(diethyleneglycol)amide and lithium bis(diethylaniline)lithium amide, bis(diisopropylaminoethyl)amide and lithium bis(diisopropylaminoethyl)amide and lithium bis(diisopropylphenyl)amide and lithium bis(diisopropylaniline)amide and lithium bis(trimethylsilyl)amide and sodium bis(triethylsilyl)amide and sodium bis(Tripropylene)amide and sodium bis(triisopropylsilyl)amide and sodium bis(dimethylarsine)amide and sodium bis(dimethylpropyl)amide and sodium bis(dimethylazobenzene)amide and sodium bis(dimethylphenylsilane) amide and sodium bis(dimethylbenzylidene)amide and sodium bis(diethylethylene)sodium amide, bis(diethylproprion)amide and sodium bis(diethylenediamine)amide and sodium bis(diethyleneglycol)amide and sodium bis(diethylaniline)amide and sodium bis(diisopropylaminoethyl)amide and sodium bis(diisopropylaminoethyl)amide and sodium bis(diisopropylphenyl)amide and sodium bis(diisopropylaniline)amide and sodium bis(trimethylsilyl)amide and potassium, the IP(triethylsilyl)potassium amide, bis(Tripropylene)amide and potassium bis(triisopropylsilyl)amide and potassium bis(dimethylarsine)amide and potassium bis(dimethylpropyl)amide and potassium bis(dimethylazobenzene)amide and potassium bis(dimethylphenylsilane)amide and potassium bis(dimethylbenzylidene)amide and potassium bis(diethylethylene)amide and potassium bis(diethylproprion)amide and potassium bis(diethylenediamine)amide and potassium bis(diethyleneglycol)amide and potassium bis(diethylaniline)amide and potassium bis(diisopropylaminoethyl)amide and potassium bis(diisopropylaminoethyl)potassium amide, bis(diisopropylphenyl)amide and potassium bis(diisopropylaniline)amide potassium.

In some embodiments of the invention the reaction of the compound of the formula (A-V) CH3S(O)2R3and (R14R15R16Si)2NM with obtaining the compounds of formula (A-VII) is carried out with the catalyst in the presence of a strong base.

Suitable examples of the catalyst which can be used in this application include, but are not limited to, the fluorinating agent.

Suitable examples of the fluorinating agent that can be used in this application include, but are not limited to, boron TRIFLUORIDE.

In some embodiments of the invention the reaction of the compound of the formula (A-V) CH3S(O)2R3and (Rl4R15R16Si)2NM with receipt is m the compounds of formula (A-VII) is carried out in the presence of a strong base at -100°C-100°C.

In some embodiments of the invention the reaction of the compound of the formula (A-V) CH3S(O)2R3and (R14R15R16Si)2NM with obtaining the compounds of formula (A-VII) is carried out in the presence of a strong base at -100°C-50°C.

In yet another aspect, the present application relates to a method for obtaining compounds of formula (B-III), which includes the interaction of the compounds of formula (B-II) with the compound of the formula R11-Y, (R12)2Y or Y-R13-Z with obtaining the compounds of formula (B-III)

in which

R1selected from the group consisting of hydrogen atom, halogen atom, a C1-C8-alkyl, C1-C8-alkoxy, hydroxy, cyano, nitro and NR6R7;

R3selected from the group consisting of hydroxy, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkyl(C1-C8-alkylen)hydroxy, C5-C12-aryl, C5-C12aryl(C1-C8-alkylen)hydroxy, and NR6R7;

each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkylthio, cyano, C3-C10-cycloalkyl, (C1-C8-alkylen)C3-C10-cycloalkyl, C3-C10-cycloalkyl(C1-C8-alkylen)ACS is, C3-C10-cycloalkane, C5-C12-aryl, C5-C12-aryloxy and C5-C12aryl(C1-C8-alkylen)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, aryl, C(O)R8and SO2R8or R6and R7together represent a 1,4-butylidene, 1,5-pentylidene, 1,6-hexylidene or CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of hydrogen atom and halogen-substituted C1-C8-alkyl;

R11in R11-Y is selected from the group consisting of C1-C8-alkyl, C5-C12-aryl, C(O)R8and S(O)2R8; Y is selected from the group consisting of a halogen atom, OMs and OTs;

R12in (R12)2Y is selected from C(O)R8; and Y is O;

R13in the Y-R13Z is selected from the group consisting of 1,4-butylidene, 1,5-pentylidene, 1,6-hexylidene and CH2CH2CCI2CH2; each Y and Z is independently selected from the group consisting of a halogen atom, OMs and OTs, X represents O, S or NR8.

In some embodiments of the invention to the reaction mixture used for the reaction of compounds of formula (B-II) with the compound of the formula R11-Y, (R12)2Y or Y-R13-Z with the floor is the group of the compounds of formula (B-II), add alkaline reagent.

Suitable examples of alkaline reagent, which can be used in this application include, but are not limited to, triethylamine, trimethylamine, Tripropylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, N-methylpyrrolidine, N-ethylpyrrolidin, 4-dimethylaminopyridine, 4-pyrrolidinone, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, alumoweld lithium, sodium methylate, potassium methylate, lithium methylate, sodium ethylate, potassium ethylate, lithium ethylate, isopropylate sodium, isopropyl potassium, isopropyl lithium (R14R15R16Si)2NM, sodium amide, lithium amide, potassium amide, and a mixture thereof, where each of R14, R15and R16in (R14R15R16Si)2NM independently selected from the group consisting of C1-C8-alkyl and phenyl, M is selected from the group consisting of sodium, potassium and lithium.

Suitable examples of (R14R15R16Si)2NM, which can be used in this application include, but are not limited to, bis(trimethylsilyl)amide and lithium bis(triethylsilyl)AMI is lithium bis(Tripropylene)amide and lithium bis(triisopropylsilyl)amide and lithium bis(dimethylarsine)amide and lithium bis(dimethylpropyl)amide and lithium bis(dimethylazobenzene)amide and lithium bis(dimethylphenylsilane)amide and lithium bis(dimethylbenzylidene)amide and lithium bis(diethylethylene)amide and lithium bis(diethylproprion)amide and lithium bis(diethylenediamine)amide and lithium bis(diethyleneglycol)amide and lithium bis(diethylaniline)amide and lithium bis(diisopropylaminoethyl)amide and lithium bis(diisopropylaminoethyl)lithium amide, bis(diisopropylphenyl)amide and lithium bis(diisopropylaniline)amide and lithium bis(trimethylsilyl)amide and sodium bis(triethylsilyl)amide and sodium bis(Tripropylene)amide and sodium bis(triisopropylsilyl)amide and sodium bis(dimethylarsine)amide and sodium bis(dimethylpropyl)amide and sodium bis(dimethylazobenzene)amide and sodium bis(dimethylphenylsilane)amide and sodium bis(dimethylbenzylidene)amide and sodium bis(diethylethylene)amide and sodium bis(diethylproprion)amide and sodium bis(diethylenediamine)sodium amide, bis(diethyleneglycol)amide and sodium bis(diethylaniline)amide and sodium bis(diisopropylaminoethyl)amide and sodium bis(diisopropylaminoethyl)amide and sodium bis(diisopropylphenyl) amide and sodium bis(diisopropylaniline)amide and sodium bis(trimethylsilyl)amide and potassium bis(triethylsilyl)amide and potassium bis(Tripropylene)amide and potassium bis(triisopropylsilyl)potassium amide, bis(dimethylarsine)amide and potassium bis(dimethylpropyl)amide and potassium bis(dimethylazobenzene)amide and potassium bis(dimethylphenylsilane)amide and potassium bis(dimethylbenzylidene)amide and potassium bis(diethylethylene)amide and potassium bis(diethylproprion)amide and potassium bis(diethylenediamine)amide and potassium bis(diethyleneglycol)amide and potassium bis(diethylaniline)amide and potassium bis(diisopropylaminoethyl)amide and potassium bis(diisopropylaminoethyl)amide and potassium bis(diisopropylphenyl)amide and potassium bis(diisopropylaniline)amide potassium.

In some embodiments of the invention the reaction of the compound of the formula (B-II) with the compound of the formula R11-Y, (R12)2Y or Y-R13-Z is carried out in a solvent to obtain compounds of formula (B-II).

Suitable examples of the solvent which can be used in this application include, but are not limited to, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, acetone, butanone, methyl acetate, propyl, butyl acetate, isopropylacetate, methylformate, ethyl formate, paperformat, bodyformat, isopropylpalmitate, methylpropionate, ethylpropane, propylphosphonate, butylphosphonate, Isopropylamine, simple methyl ether, simple diethyl ether, simple methyldiethylamine ether, simple methyl-tbutyl ether, simple ethyl-tbutyl ether, simple IU Isopropylamine ether, simple ethylisopropylamine ether, simple, isopropyl ether, ethyl acetate, ethanol, methanol, propyl alcohol, butyl alcohol, ethylene glycol, simple dimethyl ether glycol, a simple onomatology ether of ethylene glycol, simple monotropy ether of ethylene glycol, simple diethyl ether glycol, benzene, toluene,nhexane, cyclohexane, DMF, DMSO, petroleum ether, water and their mixture.

In some embodiments of the invention the reaction of the compound of the formula (B-II) with the compound of the formula R11-Y, (R12)2Y or Y-R13-Z with obtaining the compounds of formula (B-II) is carried out at -20°C-200°C.

In some embodiments of the invention the reaction of the compound of the formula (B-II) with the compound of the formula R11-Y, (R12)2Y or Y-R13-Z with obtaining the compounds of formula (B-II) is carried out at -10°C-100°C.

In some embodiments of the invention the compound of formula (B-II) is produced from compound of formula (B-I),

in which

R1selected from the group consisting of hydrogen atom, halogen atom, a C1-C8-alkyl, C1-C8-alkoxy, hydroxy, cyano, nitro and NR6R7;

R3selected from the group consisting of hydroxy, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkyl(C1-C8-alkylen)hydroxy, C5-C12-Ari is a, C5-C12aryl(C1-C8-alkylen)hydroxy, and NR6R7;

each of R4and R5individually selected from the group consisting of a hydrogen atom, hydroxy, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkylthio, cyano, C3-C10-cycloalkyl, (C1-C8-alkylen)C3-C10-cycloalkyl, C3-C10-cycloalkyl(C1-C8-alkylen)hydroxy, C3-C10-cycloalkane, C5-C12-aryl, C5-C12-aryloxy and C5-C12aryl(C1-C8-alkylen)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, aryl, C(O)R8or SO2R8or R6and R7together represent a 1,4-butylidene, 1,5-pentylidene, 1,6-hexylidene and CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of hydrogen atom and halogen-substituted C1-C8-alkyl.

In some embodiments of the invention the reaction for obtaining compounds of formula (B-II) with the compound of the formula (B-I) is conducted in the presence of a reducing agent.

Suitable examples of the reducing agent that can be used in this application include, but are not limited to, powder is elesa, powder hydrosulfite sodium, powder of zinc and hydrogen.

In some embodiments of the invention the reaction for obtaining compounds of formula (B-II) with the compound of the formula (B-I) is carried out in the presence of a catalyst.

Suitable examples of the catalyst which can be used in this application include, but are not limited to, heavy metals, such as palladium, platinum, rhodium, Nickel, ruthenium, iridium, etc., and their oxides or salts such as hydrochloride; sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, methanesulfonate acid, econsultancy acid, benzosulfimide acid andp-toluensulfonate acid.

In some embodiments of the invention the reaction for obtaining compounds of formula (B-II) with the compound of the formula (B-I) is conducted in the presence of the following catalysts: hydrochloride, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid,p-toluensulfonate acid, palladium on carbon, platinum on carbon, platinum dioxide, palladium chloride, platinum chloride, Raney-Nickel or a mixture.

In some embodiments of the invention the reaction for obtaining compounds of formula (B-II) with compound f is rmula (B-I) is conducted in a solvent.

Suitable examples of the solvent which can be used in this application include, but are not limited to, methanol, ethanol, propyl alcohol, butyl alcohol, isopropyl alcohol, chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, simple dimethyl ether glycol, a simple diethyl ether glycol, a simple diethyl ether, simple metaliteracy ether, simple methylpropyloxy ether, simple methylbutanoyl ether, simple ethylpropyl ether, simple methyl-tbutyl ether, tetrahydrofuran, ethyl acetate, methyl acetate, propyl, butyl acetate, methylpropionate, ethylpropane, methylformate, ethyl formate, paperformat, isopropylacetate, acetone, butanone, pyridine, DMF, DMSO, acetonitrile, propionitrile, benzene, toluene, water and their mixture.

In some embodiments of the invention the compound of formula (B-II) is produced from compound of formula (B-I) at -20°C-250°C.

In some embodiments of the invention the compound of formula (B-II) is produced from compound of formula (B-I) at 0°C-150°C.

In some embodiments of the invention the compound of formula (B-II) is produced from compound of formula (B-I) at 1 ATM to 100 ATM.

In some embodiments of the invention the compound of formula (B-II) is produced from compound of formula (B-I) at 1 ATM 20 ATM.

In another aspect of nastoyasheva relates to pharmaceutical compositions, containing a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds of formula (I), its stereoisomer, enantiomer or tautomer or a mixture of its stereoisomers, its pharmaceutically acceptable salts, its polymorphic modifications, MES, its prodrugs or its metabolite,

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, neobythites is but substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

Examples of pharmaceutically acceptable carrier, diluent or inert filler, which can be used in pharmaceutical compositions according to the present application include, but are not limited to, any ancillary medicinal substance, carrier, excipient, a substance promoting sliding, sweetener, diluent, preservative, dye/coloring agent, a flavor enhancer and smell, surfactant, moisturizer, dispersant, suspendisse agent, stabilizer, isoosmotic tool, dissolve the ü or emulsifier, approved by Management under the control over food and drugs U.S. as acceptable for use for humans and animals.

In some embodiments of the invention the pharmaceutical composition according to the present application further comprises at least one active ingredient.

Suitable examples of active ingredients that can be used in this application include, but are not limited to, chlormethine (nitrogen mustard), aziridine, methylmelamine, alkylsulfonate, nitrosamine, Triesen, folacin, a pyrimidine analog, a purine analog, a Vinca alkaloid, epidophyllotoxin, an antibiotic, a topoisomerase inhibitor, an anticancer vaccine, acivicin, aclarubicin, acetasol hydrochloride, Cronin, adozelesin, aldesleukin, ambomycin, Metatron acetate, aminoglutetimid, amsacrine, anastrozole, astromicin, asparaginase, azithromycin, azacytidine, drug asettaa, azotomycin, batimastat, drug benzodepa, bikalutamid, bisantrene hydrochloride, benefit mesilate, bizelesin, bleomycin sulfate, busulfan, actinomycin C, calusterone, caracemide, carbetimer, carboplatin, carmustin, karubitsin hydrochloride, chlorambucil, cirolemycin, cladribine, krishnalal mesilate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin hydrochloride, deci the Abin, docetaxel, doxorubicin, raloxifene hydrochloride, epirubicin hydrochloride, asirobicon hydrochloride, estramustin, etanidazole, etoposide, floxuridine, fluorouracil, fluorocytosine, gemcitabine, idarubitsin hydrochloride, ifosfamide, interleukin II, interferon α-2a, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, Getropin, mitomycin, mitoxantrone, paclitaxel, procarbazine, drug thiotepa, vinblastine, vincristine, angiogenesis inhibitor, camptothecin, hexadecanol, aspirin, acetaminophen, indomethacin, ibuprofen, Ketoprofen, meloxicam, corticosteroid and adrenal corticosteroid.

In some embodiments of the invention the pharmaceutical composition according to the present application is receive in the form of tablets, solution, pellets, patches, ointments, capsules, aerosol or suppository, administered via parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral method of administration.

In yet another aspect, the present application relates to a method for decreasing the activity of PDE4 enzyme comprising contacting the enzyme PDE4 with a therapeutically effective amount of the compounds of formula (I), its enantiomer or tautomer or a mixture of its stereoisomers, its pharmaceutically acceptable salt, its polymorphic modification, its MES is m, its prodrug or metabolite

in which

each of R1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, obazatelno substituted C(O)R 8and optionally substituted SO2R8or R6and R7together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

In some embodiments of the invention the contacting of the PDE4 enzyme with a therapeutically effective amount of the compounds of formula (I), its enantiomers or tautomer or a mixture of its stereoisomers, its pharmaceutically acceptable salts, its polymorphic modifications, MES, its prodrugs or its metabolite performin vitro.

In another aspect of the present application additionally relates to a method of treatment of diseases or conditions mediated by the PDE4 enzyme, comprising the administration to a subject in need of treatment a therapeutically effective amount of the compounds of formula (I), its stereoisomer, enantiomer or tautomer or a mixture of its stereoisomers, its pharmaceutically acceptable salts, its polymorphic modifications, MES, its prodrugs or its metabolite,

in which

each of R 1and R2independently selected from the group consisting of hydrogen atom, halogen atom, optionally substituted alkyl, optionally substituted alkoxy, hydroxy, cyano, nitro, and optionally substituted NR6R7;

R3selected from the group consisting of hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl(alkylene)hydroxy, optionally substituted aryl, optionally substituted aryl(alkylene)hydroxy, and optionally substituted NR6R7;

each of R4and R5independently selected from the group consisting of a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted, alkylthio, cyano, optionally substituted cycloalkyl, optionally substituted (alkylen)cycloalkyl, optionally substituted cycloalkyl(alkylene)hydroxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy and optionally substituted aryl(alkylene)hydroxy;

each of R6and R7independently selected from the group consisting of a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted C(O)R8and optionally substituted SO2R8or R6and R7/sup> together represent an optionally substituted 1,4-butylidene, optionally substituted 1,5-pentylidene, optionally substituted 1,6-hexylidene or optionally substituted CH2CH2CCI2CH2in which X is selected from the group consisting of O, S and NR8;

R8selected from the group consisting of a hydrogen atom and optionally substituted alkyl.

In some embodiments the invention, the disease or condition selected from the group consisting of inflammatory diseases or conditions, infectious diseases or conditions, immune diseases or conditions and malignant diseases or conditions.

In some embodiments of the invention examples of diseases or conditions include, but are not limited to, carcinoma of the head, thyroid carcinoma, malignant tumor of the throat, cancer of the eye, cancer of the skin, malignant tumor of the oral cavity, cancer of the larynx, cancer of the esophagus, cancer of the breast, malignant bone tumor, leukemia, myeloma, a malignant lung tumor, a malignant tumor of the colon, carcinoma of the sigmoid colon, malignant tumor of the rectum malignant tumor of the stomach malignant tumor of the prostate, malignant tumor of the breast, malignant ovarian tumor, a malignant tumor of the kidney malignant tumor of the liver, cancer of the pancreas, malignant brain tumor, malignant tumor of the intestine, cancer of the heart, adrenal carcinoma, malignant subcutaneous tissue, malignant tumor of lymph nodes, malignant melanoma, malignant glioma, HIV, hepatitis, syndrome of respiratory disorders of the adult type, a disease associated with bone demineralization, chronic obstructive pulmonary disease, chronic pneumonia, dermatitis, inflammatory skin disease, atopic dermatitis, cystic fibrosis, septic shock, pyemia, indexedby bacterial toxic shock, dynamic blood shock (a sudden drop in blood pressure), sepsis syndrome disease, ischemia-reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft rejection associated with graft versus host disease, autoimmune disease, rheumatoid spondylitis, arthritic symptom (such as rheumatoid arthritis or osteoarthritis, osteoporosis, Crohn's disease, ulcerative colitis, enteritis, multiple sclerosis, systemic lupus erythematosus, leprosy knotted Erie is him with leprosy (ENL), radiation damage, asthma, gipertoksicheskaya lung injury, infections caused by microorganisms and infectious syndrome caused by microorganisms.

In some embodiments of the invention examples of infections caused by microorganisms and infectious syndrome, caused by microorganisms, mediated by the PDE4 enzyme and subjected to treatment according to the present application include, but are not limited to, bacterial infections, fungal infections, malaria, mycobacterial infection and opportunistic infections, induced by HIV.

In some embodiments of the invention to a subject in need of treatment of diseases or conditions mediated by the PDE4 enzyme, injected with a single dose in an amount of 0.1 mg to 1000 mg of the compounds of formula (I).

In some embodiments of the invention to a subject in need of treatment of diseases or conditions mediated by the PDE4 enzyme, administered a single dose of 1 mg to 1000 mg of the compounds of formula (I).

In some embodiments of the invention a method of treating diseases or conditions mediated by the PDE4 enzyme, further comprises the administration to a subject in need of treatment at least one active ingredient.

Suitable examples of active Ingram is antov, which can be used in this application include, but are not limited to, chlormethine, aziridine, methylmelamine, alkylsulfonate, nitrosamine, Triesen, folacin, a pyrimidine analog, a purine analog, a Vinca alkaloid, epidophyllotoxin, an antibiotic, a topoisomerase inhibitor, an anticancer vaccine, acivicin, aclarubicin, acetasol hydrochloride, Cronin, adozelesin, aldesleukin, ambomycin, Metatron acetate, aminoglutetimid, amsacrine, anastrozole, astromicin, asparaginase, azithromycin, azacytidine, drug asettaa, azotomycin, batimastat, drug benzodepa, bikalutamid, bisantrene hydrochloride, benefit mesilate, bizelesin, bleomycin sulfate, busulfan, actinomycin C, calusterone, caracemide, carbetimer, carboplatin, carmustin, karubitsin hydrochloride, chlorambucil, cirolemycin, cladribine, krishnalal mesilate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, epirubicin hydrochloride, asirobicon hydrochloride, estramustin, etanidazole, etoposide, floxuridine, fluorouracil, fluorocytosine, gemcitabine, idarubitsin hydrochloride, ifosfamide, interleukin II, interferon α-2a, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, Getropin, mitomycin, mitoxantrone, paclitax the ate, procarbazine, drug thiotepa, vinblastine, vincristine, angiogenesis inhibitor, camptothecin, hexadecanol, aspirin, acetaminophen, indomethacin, ibuprofen, Ketoprofen, meloxicam, corticosteroid and adrenal corticosteroid.

In some embodiments of the invention to a subject in need this method of treatment of diseases or conditions mediated by the PDE4 enzyme, simultaneously, concurrently, separately or sequentially administered the compound of formula (I) and at least one active ingredient.

EXAMPLES

Despite the fact that any person skilled in the art is able to obtain compounds according to the present application in accordance with the above-described General methods, for convenience, in this place of this description offers more specific details of methods of synthesis of compounds according to the present application. And in this case, all the reagents and reaction conditions used in the synthesis, known to specialists in this field and available from public or commercial sources.

Reduction

CDI 1,1'-carbonyldiimidazole;

DCM: dichloromethane;

THF: tetrahydrofuran;

TFA: triperoxonane acid;

DMAP: 4-(N,N-dimethylamino)pyridine;

TEA: triethylamine;

DMF: N,N-dimethylformamide;

DMSO: dimethyl sulfoxide;

HOBt: 1-hydroxybenzotriazole;

DCC: N,N-dice logicalgroove;

TBFA: tetrabutylammonium fluoride;

EDC•HCl: hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

Fmoc: 9-fluorenylmethoxycarbonyl;

MOM: methoxymethyl;

MEM: methoxyethoxymethyl;

MTM: methylthiomethyl;

SEM: 2-(trimethylsilyl)ethoxymethyl;

TMSE: 2-(trimethylsilyl)ethyl;

DIC: N,N'-diisopropylcarbodiimide;

HOAt: 1-hydroxy-7-azobenzenes;

BOP: hexaflurophosphate (benzotriazol-1 iloxi three(dimethylamino)phosphonium;

Cl-HOBt: 6-chloro-1-hydroxybenzotriazole;

DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-Pancreatin-4-one;

HATU: hexaphosphate bis(dimethylamino)metalenclosed[4,5-B]pyridine-3-oxide;

HBTU: hexaphosphate benzotriazole-N,N,N',N'-tetramethylrhodamine;

HCTU: hexaphosphate 6-chlorobenzotriazol-1,1,3,3-tetramethylrhodamine;

HOOBt: 3-hydroxy-1,2,3-Pancreatin-4(3H)-he;

PyBOP: hexaphosphoric acid.benzotriazol-1-electroporation;

TATU: tetrafluoroborate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylrhodamine;

TBTU: tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylrhodamine;

OMS: ester methanesulfonate acids;

OTS: ester p-toluensulfonate acid.

Obtaining the compounds according to the present application is illustrated by, but is not limited to the following examples.

Compound 1a

4-methoxy-3-ethoxybenzaldehyde

In a 500 ml three-neck flask, oborudovaniyeniye stirrer and a tube for inert gas supply added 30.5 g of isovanillin, of 55.2 g of potassium carbonate, to 49.9 g of iodata and 140 ml of DMF. The mixture was stirred over night at room temperature. The mixture was poured into 1400 ml of water, and then the resulting mixture was extracted with ethyl acetate (600 ml × 2). An ethyl acetate layers were combined. The organic phase was washed with saturated solution of Na2CO3(200 ml × 3), 200 ml of water and 200 ml saturated NaCl solution, dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining a pale yellow solid product. The solid product was recrystallized from a mixture solvent: ethyl acetate and petroleum ether (1:4), while receiving the white needle crystals (32,9 g). MS(m/z):181 [M+1]+.

The following compounds 1b-1d was obtained in the same way as described above.

Compound 1b

4 ethoxy-3-methoxybenzaldehyde

Repeating the method for obtaining compounds of1a using vanilla instead of isovanillin, thus obtaining a solid product.

MS (m/z): 181 [M+1]+.

Compound 1c

3,4-dimethoxybenzaldehyde

Repeating the method for obtaining compounds offor example1a with the use of iodomethane instead of itatani, thus obtaining a solid product. MS(m/z): 167 [M+1]+.

Compound 1d

3 phenylmethoxy-4-methoxybenzaldehyde

Repeating the method for obtaining compounds offor approx the Roux 1a using benzylchloride instead of itatani, thus obtaining a solid product. MS(m/z): 243 [M+1]+.

Compound 2a

1-(3-ethoxy-4-methoxyphenyl-2-(methylsulphonyl)-N-(trimethylsilyl)ethylamine

In a 500 ml three-neck flask equipped with a magnetic stirrer and a tube for supplying an inert gas, was added 3.7 g of dimethyl sulfone and 160 ml of THF. The mixture was cooled to -78°C and was added dropwise to a mixture of 22 ml of n-utility (a 2.2 M solution of n-hexane). After the addition the mixture was maintained at -78°C and was stirred for 30 minutes, while receiving the connection A. In a 250 ml three-neck flask equipped with a magnetic stirrer and a tube for supplying an inert gas, was added to 7.1 g of compound 1A. The flask was cooled in a bath with a mixture of ice and salt. To the flask was added dropwise 43 ml of bis(trimethylsilyl)amide lithium (1,06 M solution in THF). After the addition the mixture was stirred for 15 minutes, and then to the mixture was added dropwise 10 ml of a solution of boron TRIFLUORIDE in a simple diethyl ether. The resulting mixture was stirred for 5 minutes, thus obtaining the compound B. the Compound B was subjected to transformation in A. the Mixture was slowly heated to room temperature (within about 1.5 hours). The reaction was suppressed by using 200 ml of a 1.6 n solution of K2CO3. The mixture was stirred for 30 minutes and then separated. The aqueous layer was extracted with er what ilaclama (200 ml × 3). All organic layers were combined. The organic phase is washed with 200 ml saturated NaCl solution, dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining 10 g of pale yellow solid product in the form of foam.

The following compounds 2b-2d was obtained in the same way as described above.

Compound 2b:

1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)-N-(trimethylsilyl)ethylamine

Compound 2c:

1-(3,4-acid)-2-(methylsulphonyl)-N-(trimethylsilyl)ethylamine

Compound 2d:

1-(3-phenylmethanesulfonyl)-2-(methylsulphonyl)-N-(trimethylsilyl)ethylamine

Compound 3a

1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethylamine

500 ml odnogolosy flask equipped with a magnetic stir bar, was added 10 g of compound 2a, 100 ml simple diethyl ether and 100 ml of 4 n HCl solution. The mixture was stirred for 30 minutes at room temperature and separated. The organic layer was extracted with 4 N. HCl solution (100 ml × 3). The aqueous layers were combined. the pH of the aqueous phase was brought to 12 with 4 n sodium hydroxide solution in a bath with ice. The resulting mixture was extracted with ethyl acetate (200 ml × 3). The organic layers were combined. The organic phase is washed with 200 ml saturated NaCl solution, dried over anhydrous MgSO4and filtered. The solvent is evaporated. After you clean the key column chromatography was obtained 1.5 g of solid product is white in color.

1H NMR (CDCl3): 8 6,93-6,84 (m, MN), 4,60 (d, 1H, J=8 Hz), 4,12 (square, 2H, J=4 Hz), a 3.87 (s, 3H), 3,37-is 3.21 (m, 2H), 2,92 (s, 3H), of 1.86 (s, 2H), 1,48 (t, 3H, J=4 Hz); MS(m/z): 274 [M+1]+; Chiral HPLC (isopropanol/n-hexane/diethylamine = 35/65/0,1, column chiralcel®OJ-H, 250×4.6 mm, 1.0 ml/min, @234 nm): 15.2 min (R-isomer, 49,8%), 17.3 min (S-isomer, 50,2%).

The following compounds 3b-3d was obtained in the same way as described above.

Compound 3b:

1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethylamine

MS (m/z): 274 [M+1]+

Compound 3c:

1-(3,4-acid)-2-(methylsulphonyl)ethylamine

MS (m/z): 260 [M+1]+

Compound 3d:

1-(3-phenylmethanesulfonyl)-2-(methylsulphonyl)ethylamine

MS(m/z): 336 [M+1]+

Compound 4a

Salt (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethylamine•N-acetyl-L-valine

In 100 ml odnogolosy flask, equipped with magnetic stirrer, reflux condenser and a tube for supplying an inert gas, was added 6,920 g connection3a, 2,418 g N-acetyl-L-valine and 50 ml of anhydrous methanol. The mixture was heated under reflux on an oil bath for 1 hour, stirred for 3 hours at room temperature and was filtered under vacuum, thus obtaining a solid white product. The solid white product was added to 25 ml of anhydrous methanol. The resulting mixture was heated with reverse Kholodilin the com within 1 hour was stirred at room temperature for 3 hours and filtered under vacuum, thus obtaining 6,752 g of solid product is white in color.

Compound 4b

(S)-1-(3-ethoxy-4-methoxyphenyl-2-(methylsulphonyl)ethylamine

In a 250 ml odnogolosy flask equipped with a magnetic stir bar, was added 6,752 g connection4a, 150 ml of dichloromethane and 150 ml of water. To the mixture in a bath with ice was added dropwise a 5% aqueous solution of sodium hydroxide, bringing at this pH to 11. The resulting mixture was divided. The aqueous layer was extracted with 150 ml of dichloromethane. Dichloromethane layers were combined. The organic phase is washed with 100 ml saturated NaCl solution, dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining 2,855 g of a solid white product (99,0% E. I.). MS (m/z): 274 [M+1]+; Chiral HPLC (isopropanol/n-hexane/diethylamine = 35/65/0,1, column chiralcel®OJ-H, 250 × 4.6 mm, 1.0 ml/min, @234 nm): 15.2 min (R-isomer, 0,5%), 17.3 min (S-isomer, 15 99,5%).

Compound 4c

Salt (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethylamine•N-acetyl-D-leucine

In 100 ml odnogolosy flask, equipped with magnetic stirrer, reflux condenser and a tube for supplying an inert gas, was added 1,365 g of compound 3a, 0,519 g N-acetyl-D-leucine, 10 ml of anhydrous methanol. The mixture was heated under reflux on an oil bath for 1 hour, the, was stirred for 3 hours at room temperature and was filtered under vacuum, thus obtaining 1,290 g of a solid white product. The solid white product was added to 10 ml of anhydrous methanol. The resulting mixture was boiled under reflux for 1 hour, stirred for 3 hours at room temperature and filtered byin vacuum, thus obtaining 1,042 g of solid product is white in color.

Compound 4d

(R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethylamine

In a 250 ml odnogolosy flask equipped with a magnetic stir bar was added compound4c, 50 ml dichloromethane and 50 ml of water. To the mixture was added dropwise a 5% aqueous sodium hydroxide solution in a bath with ice, bringing the value of the pH to 11. The resulting mixture was divided. The aqueous layer was extracted with 50 ml dichloromethane. Dichloromethane layers were combined. The organic phase is washed with 50 ml saturated NaCl solution, dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining 0,622 g of a solid white product (99,0% E. I.). MS (m/z):274 [M+1]+; Chiral HPLC (isopropanol/n-hexane/diethylamine = 35/65/0,1, column chiralcel®OJ-H, 250 × 4.6 mm, 1.0 ml/min, @234 nm): 15.2 min (R-isomer, 99,5%), 17.3 min (S-isomer, 0,5%).

Connection 5

3,4-dicyanamide

In a 2000 ml three-neck flask, equipped with m Gnanou stirrer, reflux condenser and a tube for supplying an inert gas, was added to 96.8 g of 3,4-dibromothiophene, 104 g of copper cyanide(I) and 100 ml of anhydrous DMF. The mixture was heated at the boil under reflux for 4 hours and cooled to room temperature. To the reaction mixture solution was added 400 g of FeCl3•6H2About 700 ml of 1.7 n hydrochloric acid. Within 30 minutes maintained the temperature of the reaction solution at 60°C-70°C. After sufficient cooling to the reaction solution was added 500 ml of DCM. The resulting mixture was divided into several portions. Each portion comprising 300 ml, was extracted with DCM (300 ml × 2). All DCM layers were combined. The extract was divided into several portions. Each portion comprising 600 ml, then washed 6 N. a solution of hydrochloric acid (50 ml × 2), water, saturated aqueous Na2CO3and saturated saline, dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining a solid yellow color. The solid yellow product was washed with a mixture of solvents (ethyl acetate and petroleum ether (1:1) and filtered, to thereby obtain 21 g of a solid white product.1H NMR (CDCl3): δ 8,07 (s, 2H).

Connection 6

Thiophene-3,4-dicarboxylic acid

In a 500 ml round bottom flask, equipped with electric the magnetic stirrer and reflux condenser, added 15,978 g connection5, 43,997 g of potassium hydroxide and 174 ml of ethylene glycol. The mixture was boiled under reflux for 4 hours. After cooling, to the reaction mixture was added 350 ml of water. The resulting mixture was extracted with simple diethyl ether (100 ml × 2). The layers obtained with a simple diethyl ether, was removed. To the water layer in a bath with ice was added excess amount of concentrated hydrochloric acid, thus obtaining a white precipitate. White precipitate was filtered, and the solid product was dissolved in simple diethyl ether (about 2000 ml). The filtrate was extracted with simple diethyl ether (300 ml × 3). All the layers obtained with a simple diethyl ether, were United. The organic phase was dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining 15 g of a solid white product. The solid white product was recrystallized from water.

1H NMR (DMSO-d6): δ 10,35 (ush. s, 2H), 8,17 (s, 2H); MS (m/z): 171 [M-1]+.

Connection 7

Thiophene[3,4-c]furan-1,3-diketone

In a 250 ml round bottom flask equipped with an electromagnetic stirrer, reflux condenser and drying tube, was added 15 g of compound 6 and 120 ml of acetic anhydride. The mixture was boiled under reflux for 3 hours. The solvent is evaporated, thus obtaining 13 g of solid n is oduct brown.

Compound 8

2-nitrothiophen-3,4-dicarboxylic acid

In a 250 ml round bottom flask equipped with an electromagnetic stirrer and a drying tube, was added 40 ml of fuming nitric acid (95%). The flask was cooled to 0°C-5°C in a bath with ice. Portions (1 g in each portion) was added 10 g of compound 7. After the addition the mixture was subjected to interact for 30 minutes at ordinary temperature (stood a solid yellow color). The reaction mixture was poured into 80 g of a mixture of water with ice. The resulting mixture was extracted with ethyl acetate (100 ml × 3). All an ethyl acetate layers were combined. The organic phase is then washed with 50 ml × 2 of water and saturated saline, dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining 10 g of solid product yellow. MS(m/z): 216 [M-1]+.

Connection 9

4-nitrothiophen [3,4-c]furan-1,3-diketone

In a 250 ml round bottom flask equipped with an electromagnetic stirrer, reflux condenser and drying tube, was added 10 g of compound 8 and 100 ml of acetic anhydride. The mixture was boiled under reflux for 3 hours. The solvent is evaporated, thus obtaining 9 g of solid product are brown.

EXAMPLE 1

5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]PI is the roll-4,6-diketone

In a 250 ml round bottom flask equipped with an electromagnetic stirrer and a drying tube, was added to 1.99 g of compound (9), 2,73 g of compound 3a and 100 ml of THF. The mixture was stirred over night at room temperature. Added 1,944 g CDI. The resulting mixture was boiled under reflux on an oil bath for 2 hours. The mixture was cooled to room temperature in the open air. Was added 200 ml of ethyl acetate and 150 ml of water. The mixture was extracted and separated. The organic layer was washed with 100 ml of 0.5 n HCl, 100 ml saturated NaCl solution, then dried over anhydrous MgSO4and filtered. The solvent is evaporated. After purification column chromatography got 3,541 g of the solid product is a light yellow color. MS(m/z): 453 [M-1]+.

EXAMPLE 2

5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone

In a 250 ml round bottom flask equipped with an electromagnetic stirrer, reflux condenser and drying tube, was added, and 2.27 g of 5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone and 100 ml of THF. The mixture was heated at the boil under reflux. Was added 1.4 g of recovered iron powder. The resulting mixture was boiled under reflux for 2 hours and filtered under vacuum. The filtrate is evaporated. D is balali 200 ml of ethyl acetate and 150 ml of water. The mixture was extracted and separated. The organic layer was washed with 100 ml water, 100 ml saturated NaCl solution, then dried over anhydrous MgSO4and filtered. The solvent is evaporated. After purification column chromatography was obtained 1.68 g of the solid product is yellowish-brown color. MS(m/z): 425 [M+1]+.

EXAMPLE 3

N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Method I: In a 50 ml round bottom flask equipped with an electromagnetic stirrer, reflux condenser and drying tube, was added 0.1 g of 5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone, 0.005 g DMAP and 10 ml of acetic anhydride. The mixture was heated to 60°C and was stirred for 6 hours. The solvent is evaporated. After purification column chromatography was received 0.02 g of a solid white product.

Method II: In a 50 ml round bottom flask equipped with an electromagnetic stirrer, reflux condenser and drying tube, was added 0.1 g of 5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone and 5 ml of pyridine. In a bath with ice was added dropwise 0.2 ml of acetylchloride and was stirred for 1 hour at room temperature. The solvent is evaporated. Added 50 ml of ethyl acetate and 20 ml of water. The mixture extras who believed and shared. The organic layer is washed with 20 ml of 2 n HCl solution, 20 ml saturated NaCl solution, then dried over anhydrous MgSO4and filtered. The solvent is evaporated. After purification column chromatography was obtained 0.08 g of a white solid product in the form of foam. MS(m/z): 465 [M-1]+.1H NMR (CDCl3): δ 9,12 (s, 1H), 7,33 (s, 1H), was 7.08 (s, 1H), 7,07 (s, 1H), 6,83 (d, 1H, J=6 Hz), of 5.82 (DD, 1H, J=3 Hz, J=7 Hz), 4,56 (DD, 1H, J=5 Hz, J=11 Hz), 4,12 (square, 2H, J=3 Hz), 3,86 (s, 3H), 3,76 (DD, 1H, J=5 Hz, J=11 Hz), is 2.88 (s, 3H), to 2.29 (s, 3H), of 1.47 (t, 3H, J=5 Hz).

EXAMPLE 4

5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

In a 50 ml round bottom flask equipped with an electromagnetic stirrer and a drying tube, was added 0,077 g of compound 7, 0,137 g of compound 3a and 10 ml THF. The mixture was stirred over night at room temperature. Added 0,122 g CDI. The mixture was boiled under reflux for 2 hours on an oil bath and cooled to room temperature in the open air. To the mixture was added 100 ml of ethyl acetate and 50 ml of water. The resulting mixture was extracted and separated. The organic layer was washed with 20 ml of 0.5 n HCl solution, 20 ml saturated NaCl solution, then dried over anhydrous MgSO4and filtered. The solvent is evaporated, thus obtaining 0,121 g of solid product is white in color.

MS (m/z): 410 [M+1]+.

EXAMPLE 5

(S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 4 compound 4b instead of compound 3a, thus obtaining a solid product.

MS(m/z): 410 [M+1]+.

EXAMPLE 6

(R)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 4 compound 4d instead of compound 3a, thus obtaining a solid product.

MS (m/z): 410 [M+1]+.

EXAMPLE 7

5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 4 compound 3b instead of compound 3a, thus obtaining a solid product.

MS(m/z): 410 [M+1]+.

EXAMPLE 8

5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 4 compound 3c instead of compound 3a, thus obtaining a solid product.

MS(m/z): 396 [M+1]+.

EXAMPLE 9

5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 4 compound 3d instead of compound 3a, thus obtaining a solid product.

MS (m/z): 472 [M+1]+.

EXAMPLE 10

5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 1 with the an Association of the 3d instead of compound 3a, while receiving a solid product.

MS(m/z): 515[M-1]+.

EXAMPLE 11

5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 2 from the compound indicated in the heading of example 10, instead of the connection specified in the header of the example 1, thus obtaining a solid product.

MS (m/z): 487 [M+1]+.

EXAMPLE 12

N-(5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeated the procedure for example 3 with the connection specified in the header of example 11, instead of the connection specified in the header of example 2, thus obtaining a solid product.

MS (m/z): 527 [M-1]+.

EXAMPLE 13

5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeating the receiving procedure of example 1 with compound 3c instead of compound 3a, thus obtaining a solid product.

MS(m/z): 439 [M-1]+.

EXAMPLE 14

5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 2 from the compound indicated in the heading of example 13, instead of the connection specified in the header of the example 1, thus obtaining a solid product.

MS(m/z): 411 [M+1]+.

EXAMPLE 15

5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeating the receiving procedure of example 1 with compound 3b instead of compound 3a, thus obtaining a solid product.

MS(m/z): 453 [M-1]+.

EXAMPLE 16

5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeated the procedure for example 2 from the compound indicated in the heading of example 15, instead of the connection specified in the header of the example 1, thus obtaining a solid product.

MS(m/z): 425 [M+1]+.

EXAMPLE 17

5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-methylamino-5H-thiophene[3,4-c]pyrrole-4,6-diketone

In 10 ml of acetone was dissolved of 0.085 g of compound indicated in the heading of example 2. To the mixture was added 0.5 ml of iodomethane. The resulting mixture was heated up to 80°C and were subjected to interaction within 6 hours. After cooling, was added 100 ml of water. The mixture was extracted with ethyl acetate (30 ml × 3). The organic layers were combined. The organic phase is successively washed with 30 ml of water and saturated saline aqueous solution, dried over anhydrous MgSO4and filtered. The solvent is evaporated. After separating column chromatography on silica gel received 0,033 g of solid product. MS(m/z): 439 [M+1]+.

EXAMPLE 18

2-chloro-N-(5-(1-(3-ethoxy-4-methoxide who yl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene [3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeated the procedure for the method II of example 3 using chloroacetanilide instead of acetylchloride, thus obtaining a solid product.

MS (m/z): 499 [M-1]+.

EXAMPLE 19

N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)methanesulfonamide

Repeated the procedure for the method II of example 3 using methanesulfonamide instead of acetylchloride, thus obtaining a solid product.

MS(m/z): 501 [M-1]+.

EXAMPLE 20

(S)-1-nitro-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeating the method for example 1 using the compounds 4b and compound (9).

EXAMPLE 21

(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeating the method of receiving according to example 2 with the connection specified in the header of example 20. MS(m/z): 425 [M+1]+.

EXAMPLE 22

(R)-1-nitro-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeating the method for example 1 using the compounds 4d and compound (9).

EXAMPLE 23

(R)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

Repeating the method of receiving according to example 2 with the use of compounds of the decree is tion in the header of example 22. MS(m/z): 425 [M+1]+.

EXAMPLE 24

(S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeating the method for example 3 using the connection specified in the header of the example 21. MS(m/z): 465 [M-1]+; Chiral HPLC (anhydrous ethanol/n-hexane/diethylamine = 40/60/0,1; column chiralcel®OJ-H, 250×4.6 mm, 1.0 ml/min @230 nm): 9.8 min (R-isomer, 1,2%), 13.8 min (S-isomer, 98,8%).

1H NMR (CDCl3): δ 9,27 (s, 1H), 7,30 (s, 1H), 7,07 (s, 1H), 7,05 (s, 1H), for 6.81 (d, 1H, J=6 Hz), of 5.81 (DD, 1H, J=3 Hz, J=7 Hz), of 4.54 (DD, 1H, J=8 Hz, J=11 Hz), 4,08 (square, 2H, J=3 Hz), of 3.84 (s, 3H), of 3.73 (DD, 1H, J=8 Hz, J=11 Hz), of 2.86 (s, 3H), and 2.27 (s, 3H), of 1.45 (t, 3H, J=5 Hz).

EXAMPLE 25

(R)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeating the method for example 3 using the connection specified in the header of example 23. MS(m/z): 465 [M-1]+; Chiral HPLC (anhydrous ethanol/n-hexane/diethylamine = 40/60/0,1; column chiralcel®OJ-H, 250×4.6 mm, 1.0 ml/min @230 nm): 9.8 min (R-isomer, 99,5%), 13.8 min (S-isomer, 0,5%).

EXAMPLE 26

N-(5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeating the method of obtaining the connection specified in the header of example 3, using the connection specified in the header of the example 16. The(m/z): 465 [M-1] +.

EXAMPLE 27

N-(5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)propionamide

Repeated the procedure for example 3 using the connection specified in the header of the example 11, and propionitrile, thus obtaining a solid product. MS(m/z): 541 [M-1]+.

EXAMPLE 28

2-(dimethylamino)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

In 10 ml of tetrahydrofuran was dissolved 50 mg of the compound indicated in the heading of example 18. Was added 0.3 ml of 2 n solution of dimethylamine in tetrahydrofuran. The mixture was stirred over night at room temperature. After completion of the reaction was added 100 ml of water. The resulting mixture was extracted with ethyl acetate (40 ml × 3). The organic layers were combined. The organic phase is then washed with 40 ml of water and saturated saline aqueous solution, dried over anhydrous magnesium sulfate, was filtered. The solvent is evaporated. After separating column chromatography on silica gel received 40 mg of solid product. MS(m/z): 510 [M+1]+.

EXAMPLE 29

2-(diethylamino)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeating the method of receiving according to example 28 using on the ethylamine instead of dimethylamine, while receiving specified in the title compound from example 29. MS(m/z): 538 [M+1]+.

EXAMPLE 30

2-(piperidyl)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeating the method of receiving according to example 28 using piperidine instead of dimethylamine, while receiving specified in the title compound from example 30. MS(m/z): 550 [M+1]+.

EXAMPLE 31

2-(morpholinyl)-N-(5-(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-c]pyrrol-1-yl)ndimethylacetamide

Repeating the method of receiving according to example 28 using the research instead of dimethylamine, while receiving specified in the title compound from example 31. MS(m/z): 552 [M+1]+.

EXAMPLE 32

Pharmacological research

1. Effects mononuclear cells (PBMC) stimulated by LPS in respect of TNFα

Research concerning the release of the cytokine TNFα mononuclear cells of peripheral blood (PBMC) after stimulation by lipopolysaccharide (LPS) canconductin vitro. The research method of inhibiting the release of the cytokine TNFα cells PBMC after stimulation of LPS, pharmaceutical active ingredients according to the present application is described below.

Cells PBMC were obtained from blood treated with heparin, at least from Tr the x donor volunteers. To obtain cells PBMC blood treated with heparin, from at least three donors, volunteers were subjected to gradient separation of PBMC cells according to a known method. Cells PBMC were collected and three times washed in the 1640 medium (10% fetal bovine serum, 2 mm L-glutamine, 100 mm mercaptoethanol, 50 μg/ml streptomycin and 50 IU/ml penicillin). The PBMC cells were added to 24-well plate at a concentration of 1×106cells/ml of medium 1640. The test compound was dissolved in dimethyl sulfoxide and was received in the form of a solution of the test compound of the desired concentration. The solution was added to the cell culture. After incubation in CO2-incubator (5% CO2, humidity 90%) for 1 hour was added LPS (Sigma) at 0.1 ng/ml (except for the control sample).

After additional incubation medium for 20 hours was measured content of TNFα in the supernatant medium culturing PBMC using the standard method, using a commercial ELISA kit (U. S Genzyme Co.). The degree of inhibition of TNFα was calculated using the values measured for the control wells not treated with the active ingredients, and the values measured for the test wells containing test compound. The concentration causing 50% inhibition of TNFα release (the value of the IC50), was calculated using the method nelina the CSOs regression analysis. Each concentration simultaneously measured twice and the expected average value. Some test results are shown in table 1.

Table 1
Activity of compounds against inhibition of releaseTNFαmononuclear cells stimulated by LPS
ConnectionIC50
(µm)
ConnectionIC50
(µm)
ConnectionIC50
(µm)
Example 240,065Example 62,5Example 11>10
Example 251,19Example 20,524Example 12>10
Example 30,296Example 210,142Example 26>10
Example 40,886 Example 231,9Example 180,216
Example 50,376Example 97,5Example 19in 0.288

2. Inhibitory activity and selective inhibitory activity of compounds against the enzyme PDE

(1) the Inhibitory activity of the compounds against hydrolysis of camp by the enzyme PDE4 investigated by inhibiting the activity of the enzyme PDE4. Analysis procedures described below.

Humanized PDE4A1A, PDE4B1 and PDE4D2 acquired company BPS bioscience (catalog No.: 60040, 60041, and 60043, respectively). The enzymatic reaction was performed in buffer containing 10 mm Tris-HCl (pH of 7.4) and 1 mm MgCl2. The concentration camp was 5 μm. The reaction temperature was maintained at 37°C from 15 minutes to 30 minutes in order to control the conversion of the substrate to within 20%. The reaction extinguished equal volume of acetonitrile. Produced a number of substrate AMF was measured using HPLC-MS. Inhibitory activity of compounds against the enzyme PDE4 was obtained by comparing the produced quantities of AMF in the experimental groups containing compounds, with quantities AMP in the control groups that do not contain the response. The data are shown in table 2.

(2) Inhibitory activity against PDE2 (selectivity for the enzyme PDE):

Humanitarianly PDE2A acquired company BPS bioscience (catalogue number: 60020). The enzymatic reaction was performed in buffer containing 10 mm Tris-HCl (pH of 7.4) and 1 mm MgCl2. The concentration camp was 5 μm. The reaction temperature was maintained at 37°C for 30 minutes in order to control the conversion of the substrate to within 20%. The reaction extinguished equal volume of acetonitrile. Produced a number of substrate AMF was measured using HPLC-MS. Inhibitory activity of compounds against the enzyme PDE2 was obtained by comparing the produced quantities of AMF in the experimental groups containing compounds, with quantities AMP in the control group containing compounds. The data are shown in table 2.

Table 2
Inhibitory activity of compounds against the enzyme PDE4 and selective inhibitory activity of compounds against the enzyme PDE
ConnectionPDE4B1 IC50(µm)PDE4D2 IC50(µm)PDE4A1A IC50(µm)PDE2A IC50(µm)
Note the R 24 0,1780,1140.104 g>50
Example 30,2560,2240,20836
Example 41,20,3290,366
Example 50,368
Example 62,30,315
Example 20,2121,9
Example 200,026
Example 230,7180,055
Example 95,3,831
Example 111,0
Example 121,2
Example 180,618
Example 190,167

From the foregoing it will be understood that although specific embodiments of the present application described herein for illustrative purposes, without deviating from the essence and scope of the present application can be implemented with various modifications. Accordingly, the present application is not limited by anything except the attached claims.

1. The compound of formula (I), a stereoisomer or pharmaceutically acceptable salt:

in which
each of R1and R2independently selected from the group consisting of a hydrogen atom, nitro and NR6R7;
R3represents a C1-C8Ala is l;
each of R4and R5independently selected from the group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylen)hydroxy;
each of R6and R7independently selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, C(O)R8and SO2R8;
R8selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkyl substituted amino), C1-C8of alkyl, substituted piperidine, and C1-C8of alkyl, substituted morpholine.

2. The compound of formula (I) under item 1, in which each of R1and R2independently selected from the group consisting of a hydrogen atom, nitro, NH2, NHCH3CH3C(O)NH, CH3CH2C(O)NH, CH3SO2NH and ClCH2C(O)NH.

3. The compound of formula (I) under item 1, in which R3selected from the group consisting of methyl, ethyl and propyl.

4. The compound of formula (I) under item 1, in which each of R4and R5independently selected from the group consisting of methoxy, ethoxy, propoxy, phenoxy.

5. The compound of formula (I) under item 1, in which R8selected from the group consisting of methyl, ethyl, dimethylaminomethyl, diethylaminomethyl, piperidinomethyl and morpholinylmethyl.

6. The compound of formula (I) under item 1, which SEL is ANO from the group consisting of:
N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
(S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
(R)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
(S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
(R)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
N-(5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
5-(1-(3,4-DIMET xifei)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
5-(1-(3,4-acid)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-1-nitro-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
5-(1-(3-methoxy-4-ethoxyphenyl)-2-(methylsulphonyl)ethyl)-1-amino-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-1-methylamino-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
2-chloro-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)methanesulfonamide,
(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
(R)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-5H-thiophene[3,4-C]pyrrole-4,6-diketone,
(R)-N-(5-(1-(3-ethoxy-4-trifloromethyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
N-(5-(1-(3-phenylmethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)propionamide,
2-(dimethylamino)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
2-(diethylamino)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)acetamide", she
2-(piperidyl)-N-(5-(1-(3-ethoxy-4-methox is phenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)ndimethylacetamide and
2-(morpholinyl)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulphonyl)ethyl)-4,6-diketone-5,6-dihydro-4H-thiophene[3,4-C]pyrrol-1-yl)ndimethylacetamide.

7. The method of obtaining the compounds of formula (I), which includes the interaction of the compounds of formula (IV) with the compound of the formula (VII) with a compound of formula (I):

in which
each of R1and R2independently selected from the group consisting of a hydrogen atom, nitro and NR6R7;
R3represents a C1-C8alkyl;
each of R4and R5independently selected from the group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylen)hydroxy;
each of R6and R7independently selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, C(O)R8and SO2R8;
R8selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkyl substituted amino), C1-C8of alkyl, substituted piperidine, and C1-C8of alkyl, substituted morpholine.

8. The method according to p. 7, which in the interaction of the compounds of formula (IV) with the compound of the formula (A-VII) with a compound of formula (I) as catalyst type tertiary amine, and in which the tertiary s is N. preferably selected from the group consisting of pyridine, 4-dimethylaminopyridine, 4-pyrrolidinedione and mixtures thereof.

9. The method of obtaining the compounds of formula (B-III), which includes the interaction of the compounds of formula (II) with the compound of the formula R11-Y or R12)2Y obtaining the compounds of formula (B-III),
in which,
R1selected from the group consisting of a hydrogen atom, nitro and NR6R7;
R3represents a C1-C8alkyl;
each of R4and R5independently selected from the group consisting of C1-C8alkoxy, phenoxy and phenyl(C1-C8alkylen)hydroxy;
each of R6and R7independently selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, C(O)R8and SO2R8;
R8selected from the group consisting of a hydrogen atom, a C1-C8of alkyl, halogen-substituted C1-C8-alkyl, C1-C8-alkyl, substituted (C1-C8-alkyl substituted amino), C1-C8of alkyl, substituted piperidine, and C1-C8of alkyl, substituted morpholine;
R11in connection R11-Y is selected from the group consisting of C1-C8of alkyl, C5-C12aryl, C(O)R8and S(O)2R8Y is selected from the group consisting of halogen, OMs, and OTs;
R12in the compound (R12)2Y is selected from C(O)Rsup> 8and Y represents O; R17selected from the group consisting of NH(C1-C8the alkyl), NHC(O)R8and the NHS(O)2R8.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds on p. 1, its stereoisomer or pharmaceutically acceptable salt, to reduce the activity of the PDE4 enzyme or for the treatment of diseases or conditions mediated by the PDE4 enzyme.

11. The pharmaceutical composition according to p. 10, further containing at least one active ingredient.

12. The pharmaceutical composition according to p. 11, in which the active ingredient is selected from the group consisting of chlormethine, aziridine, methylmelamine, alkylsulfonate, nitrosamine, triazine, folacin, a pyrimidine analog, purine analog, a Vinca alkaloid, epidemiologia, antibiotics, topoisomerase inhibitor, an anti-cancer vaccine, acivicin, aclarubicin, Hakodate hydrochloride, acronine, adozelesin, aldesleukin, ambomycin, Metatron acetate, aminoglutethimide, amsacrine, anastrozole, astromicin, asparaginase, azithromycin, azacitidine, drug asettaa, azotomycin, batimastat, preparation of benzodepa, bikalutamida, bisantrene hydrochloride, bisnafide nelfinavir, bizelesin, bleomycin sulfate, busulfan, actinomycin C, clusterin is, caracemide, carbetimer, carboplatin, carmustine, karubitina hydrochloride, hlorambuzila, caroliniana, cladribine, krishnalila nelfinavir, cyclophosphamide, tsitarabina, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, epirubicin hydrochloride, asirobicon hydrochloride, estramustine, etanidazole, etoposide, floxuridine, fluorouracil, fluorocytosine, gemcitabine, idarubitsina hydrochloride, ifosfamide, interleukin-II, interferon α-2A, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, metropia, mitomycin, mitoxantrone, paclitaxel, procarbazine, drug thiotepa, vinblastine, vincristine, inhibitor of angiogenesis, camptothecin, hexadecanol, aspirin, acetaminophen, indomethacin, ibuprofen, Ketoprofen, meloxicam, steroid and adrenal corticosteroid.

13. The pharmaceutical composition according to p. 10, obtained in the form of tablets, solution, pellets, patches, ointments, capsules, aerosol or suppository, administered via parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral method of administration.

14. The use of compounds on p. 1, its stereoisomer or its pharmaceutically acceptable salt to obtain drugs the military means to reduce the activity of the enzyme PDE4.

15. The use of compounds on p. 1, its stereoisomer or its pharmaceutically acceptable salt for a medicinal product for the treatment of diseases or conditions mediated by the PDE4 enzyme.

16. Application under item 15, wherein the disease or condition selected from the group consisting of inflammatory diseases or conditions, infectious diseases or conditions, immune diseases or conditions and malignant diseases or conditions.

17. Application under item 16, wherein the disease or condition selected from the group consisting of carcinoma of the head organs, cancer of the thyroid gland, malignant tumor of the throat, malignant neoplasm of eye malignant neoplasm of skin malignant tumors of the oral cavity, cancer of larynx, malignant tumors of the esophagus, malignant breast tumors, malignant bone tumors, leukemia, myeloma, malignant tumors of the lung, malignant tumors of the colon, carcinoma of the sigmoid colon malignant tumor of the rectum malignant tumor of the stomach malignant tumors of the prostate, malignant breast tumors, malignant tumors of the ovaries, malignant tumors of the kidney, malignant liver tumors, malignant tumors of pojulu the internal gland, malignant brain tumors, malignant tumors of the intestine, malignant tumors of the heart, adrenal carcinoma, a malignant tumor subcutaneous tissue, malignant tumors of the lymph nodes, malignant melanoma, malignant glioma, HIV, hepatitis, syndrome of respiratory disorders of the adult-type disease associated with bone demineralization, chronic obstructive pulmonary disease, chronic pneumonia, dermatitis, inflammatory skin diseases, atopic dermatitis, cystic fibrosis, septic shock, pyemia, endokrinologa bacterial-toxic shock, dynamic blood shock (sudden fall in blood pressure), septic syndrome disease, ischemia-reperfusion damage, meningitis, psoriasis, fibrotic diseases, cachexia, transplant rejection associated with graft versus host disease, autoimmune diseases, rheumatoid spondylitis, arthritic symptoms (such as rheumatoid arthritis or osteoarthritis, osteoporosis, Crohn's disease, ulcerative colitis, enteritis, multiple sclerosis, systemic lupus erythematosus, leprosy erythema with leprosy (ENL), radiation damage, asthma, giperatsidnogo lung damage, infections caused by microorganisms, and infectional the syndrome, caused by microorganisms.

18. Application under item 15, wherein the drug contains a single dose in an amount of 0.1 mg to 1000 mg of the compounds of formula (I).

19. Application under item 15, in which the medicinal product further comprises at least one active ingredient.

20. Application under item 19, wherein the active ingredient is selected from the group consisting of chlormethine, aziridine, methylmelamine, alkylsulfonate, nitrosamine, triazine, folacin, a pyrimidine analog, purine analog, a Vinca alkaloid, epidemiologia, antibiotics, topoisomerase inhibitor, an anti-cancer vaccine, acivicin, aclarubicin, Hakodate hydrochloride, acronine, adozelesin, aldesleukin, ambomycin, Metatron acetate, aminoglutethimide, amsacrine, anastrozole, astromicin, asparaginase, azithromycin, azacitidine, drug asettaa, azotomycin, batimastat, preparation of benzodepa, bikalutamida, bisantrene hydrochloride, bisnafide nelfinavir, bizelesin, bleomycin sulfate, busulfan, actinomycin C, calusterone, caracemide, carbetimer, carboplatin, carmustine, karubitina hydrochloride, hlorambuzila, caroliniana, cladribine, krishnalila nelfinavir, cyclophosphamide, tsitarabina, dacarbazine, actinomycin D, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin is hydrochloride, droloxifene, epirubicin hydrochloride, asirobicon hydrochloride, estramustine, etanidazole, etoposide, floxuridine, fluorouracil, fluorocytosine, gemcitabine, idarubitsina hydrochloride, ifosfamide, interleukin-II, interferon α-2A, interferon α-2b, irinotecan hydrochloride, letrozole, mercaptopurine, methotrexate, metropia, mitomycin, mitoxantrone, paclitaxel, procarbazine, drug thiotepa, vinblastine, vincristine, inhibitor of angiogenesis, camptothecin, hexadecanol, aspirin, acetaminophen, indomethacin, ibuprofen, Ketoprofen, meloxicam, steroid and adrenal corticosteroid.

21. Application under item 20, wherein the compound of formula (I) and at least one active ingredient is administered simultaneously, concurrently, separately or sequentially.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a compound of formula and to its pharmaceutically acceptable salt and its enantiomers, wherein D means pyridyl, which is substituted by 1-2 independently specified groups R38; M means , wherein * means an attachment position to D; and † means an attachment position to Z; Z means -O-; Ar means phenyl, which is optionally substituted by 0-4 groups R2; and G means ; wherein each R38 means -C0-C6-alkyl-(substituted by one group containing heterocyclyl, which means a monocyclic structure, and contains 5 to 7 atoms, wherein 1 or 2 atoms are independently specified in a group containing N, O and S optionally substituted by one or more oxo groups); in each specific case R2 is independently specified in -H and halogen; each R13 means -H; Q means cyclopropyl. The invention also refers to a pharmaceutical composition based on the composition of formula (I), a method for inhibiting the activity of protein kinase of the growth factor receptors and a method of treating choroidal neovascularisation.

EFFECT: there are prepared new compounds possessing the activity on protein kinase inhibitors.

7 cl, 8 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining compounds of formula . The compounds of formula 6 are intermediate products for obtaining dihydrothieno[3,2-d]pyrimidines, which produce an impact on the cardiovascular system, possess sedative action, or can be applied in treatment of inflammatory diseases of joints, skin, eyes or diseases of the peripheral or central nervous system, respiratory or gastrointestinal disorders. The method includes the following stages: a) interaction of reagents of formulas HS-CH2-CO2Ra and CHR5=CR4-CO2Ra with obtaining an intermediate product of formula ; and b) cyclisation of the intermediate product of formula 7 in a solvent in the presence of TiCl2(O-iPr)2, TiCl(O-iPr)3, TiCl3(O-iPr) and in the presence of a base-amine, with obtaining a product of formula 6. Ra stands for alkyl, R4 and R5 are independently selected from a group, including H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkylene, C5-C10-heteroaryl-C1-C6-alkylene, C3-C10-heterocycle and C5-C10-heteroaryl, -O-C1-C6-alkyl, -O-C6-C10-aryl, -O-C3-C10-heterocycle and -O-C5-C10-heteroaryl, -NR'R", fluorine, C1-C6-fluoroalkyl and C1-C6-fluoroalkoxygroup, where R' and R" are independently selected from a group, including H and C1-C6-alkyl, and where in each case the group can be optionally substituted with one or more groups, selected from a group, including OH, oxogroup, halogen, C1-C6-alkyl and O-C1-C6-alkyl. The method makes it possible to obtain the intermediate products 6, which do not require carrying out distillation and chromatographic purification between stages in realisation of processes suitable for wide-scale synthesis of dihydrothieno[3,2-d]pyrimidines.

EFFECT: invention results in higher total output of the final products as compared to that in realisation of methods of preceding level of technology.

6 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compound with structural formula (I) or to its pharmaceutically acceptable salt, where R represents cyanogroup. Invention also relates to method of obtaining said compound and to pharmaceutical composition against platelet aggregation based on the compound.

EFFECT: obtained is novel compound and based on its pharmaceutical composition, which can be applied in medicine for production of medication for prevention or treatment of diseases of cardiac and cerebral vessels, such as coronary syndromes, myocardial infarction and myocardial ischemia, caused by aggregation of platelets.

13 cl, 3 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to thieno[3,2-d]pyrimidine derivative of formula (I) or to its pharmaceutically acceptable salt: (I), where Y stands for -CH=CR1-, -C≡C- or -C(=O)NR1-; L stands for -C(=O)NR2-, -NR2C(=O)- or -NR2C(=O)NR2-; R1 and R2, each independently stands for H; R stands for H, a halogen atom, methyl or methoxy; E stands for phenyl or C3-10heteroaryl, which is non-substituted or substituted with 1-2 substituents, consisting of a group, which includes a halogen atom, -CF3, C1-6alkyl, hydroxy-C1-6alkyl, C3-8cycloalkyl, -(CH2)n-C1-6alkylamino, -(CH2)n-diC1-6alkylamino, -(CH2)nC1-6alkoxy, -(CH2)n-OS(=O)2-C1-6-alkyl, -(CH2)n-phenyl, -(CH2)n-C2-5heteroaryl and -(CH2)n-C4-6heterocycloalkyl, where C3-10heteroaryl represents pyridine, isoquinoline, indole or isoxazole, C2-5heteroaryl of radical -(CH2)n-C2-5heteroaryl represents imidazole or pyrrol, C4-6heterocycloalkyl of radical -(CH2)n-C4-6heterocycloalkyl represents piperazine, morpholine, diazepam, pyrrolidine or piperidine, and phenyl, heteroaryl and heterocycloalkyl each independently, is non-substituted or substituted with substituent selected from a group, which consists of C1-6alkyl, hydroxy-C1-6alkyl, a halogen atom and diC1-6alkylamino, n is equal to 0 or 1; and Z stands for H, -C(=O)R3, C1-6alkyl, hydroxyC1-6alkyl, C3-8cycloalkyl, piperidine, phenyl or pyridine, where piperidine, phenyl and pyridine, each independently, is non-substituted or substituted with C1-6alkyl, C1-6alkoxy or R3-piperazinyl and R3 represents C1-6alkyl or phenyl. The invention also relates to an intermediate compound for obtaining the claimed final compound of formula (I).

EFFECT: novel compound, which can be applied in medicine for the prevention or treatment of diseases, characterised by an anomalous growth of cells as a result of an excessive expression of proteinkinase, is obtained.

8 cl, 2 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I , which represents agent of in vivo visualisation of peripheral benzodiazepine receptor (PBR), where Q represents hydrogen or fluorine; X represents hydrogen or C1-4alkoxy; Y represents S; and R represents C1-6fluoroalkyl; and where, at least, one atom of said agent of in vivo visualisation of formula I represents radioisotope, suitable for in vivo visualisation and representing either gamma-emitting radioactive halogen or positron-emitting radioactive non-metal; and where if said radioisotope is a carbon radioisotope, it is carbonyl carbon.

EFFECT: obtaining novel derivatives.

15 cl, 2 dwg, 1 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I, including stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof: where Z1 is CR1; Z2 is CR2; Z3 is CR3 or N; Z4 is CR4 or N; where (i) X1 is N and X2 is S or (iv) X1 is S and X2 is CR7; R1, R2, R3, R4 and R7 are independently selected from H, F, Cl, Br, I, -CN, -CH2OR10, -(C1-C12 alkylene)NR10R11, -(C1-C12 alkylene)NR12C(=O)R10, -CO2R10, -C(=O)N(R10)OR11, -NR10R11, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)OR11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)R11, -C(=O)NR10(C1-C12 alkylene)R11, -C(=O)NR10(C1-C12 alkylene)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(-O)NR10R11, -NR12C(=O)(C1-C12 alkylene)NR10R11, NR12(C=O)C1-C12 alkylene)NR11(C=O)R12, -C≡CR10, C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-6 ring atoms, where 1-4 ring atoms are nitrogen atoms, and phenyl, where the heteroaryl and phenyl are optionally substituted with one or two groups selected from -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -CO2H, -CH2CO2CH3, -NH2 and -S(O)2CH3; A is selected from -C(=O)NR5R6, -C(=S)NR5R6, phenyl and C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-10 ring atoms, 1-4 of which are heteroatoms selected from nitrogen, oxygen or sulphur, C1-C20 heteroaryl and phenyl are optionally substituted with one or three groups independently selected from C1-C12 alkyl, -(C1-C12 alkylene)NR10R11, -CH3, oxo, -CO2CH3, -NH2, 1-methylpiperid-4-yl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, benzoimidazolyl, benzyl and phenyl, where the alkyl, benzoimidazolyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CF3, -CH2OH, -CH3, -C(=O)NHCH3, -NH2, -OH, -OCH3, -CH2OCH3, -C(=O)N(CH3)2, -N(CH3)2, -C(CH3)2OH, -CH(CH3)2, -CH2(1H-1,2,4-triazol-5-yl) and C(=O)4-methylpiperazin-1-yl; R5 is selected from C1-C12 alkyl, optionally substituted with one group independently selected -NH2, -NHCOCH3 and -OH; R6 is selected from pyridinyl and phenyl, each optionally substituted with one or two groups independently selected from F, Cl, Br, I, -CN, -CF3, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11 and -C(=O)NR10R11; R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-phenyl, cyclopentyl, pyridinyl and imidazolyl, where C1-C12 alkyl, cyclopentyl are optionally substituted with one or two groups independently selected from -CH2OH, -N(CH3)2, -NHCOCH3, -OH and -S(O)2CH3; or R10 and R11 together with a nitrogen atom to which they are bonded form a C5-C6 heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, or pyrazolyl, optionally substituted with one or two groups independently selected -CH3, -NH2, -N(CH3)2; -OH and oxo. The invention also relates to a pharmaceutical composition having PI3K inhibiting activity based on said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for treating cancer.

25 cl, 5 dwg, 2 tbl, 331 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to compounds of formula I:

, where X means S or CR5;Y means S or CR7; where one of X or Y means S; each of R2, R5, R6 and R7 has been independently chosen from a group including the following: a) halogen; b) R8, -O-R8, -(C1-C6)alkylene-R8, -(C1-C6)alkylene-O-R8; where in each case R8 has been independently chosen from a group containing H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl and aryl; R3 means -W-R31 and bond is an ordinary bond; where W means O and R31 means (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-; R4 means aryl or Het, where each aryl and Het optionally contains 1 to 5 substitutes, each of which has been independently chosen from a group containing halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -OH, -O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl and -N((C1-C6)alkyl)2, which can be used for treatment of HIV infection.

EFFECT: improving compound application efficiency.

15 cl, 4 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to dihydrothienopyrimidinesulphoxides of formula 1, and pharmaceutically acceptable salts thereof , where X denotes SO, R1 denotes H, R2 denotes H or a residue selected from C1-C10alkyl, which is optionally substituted with one or more residues selected from OR2.1, where R2.1 denotes H or C1-C6alkyl, R2.2 and R2.3 independently denote H or C1-C6alkyl, where Het is a 6-member monocyclic, saturated heterocycle containing 1 heteroatom selected from N or O, and where the hetaryl is a 5-11-member mono- or bicyclic, optionally anellated heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, S or O, and where the cycloalkyl can be saturated, or R2 denotes a monocyclic C3-cycloalkyl, which is optionally substituted with a residue selected from a branched or linear C1-C6alkanol, C1-C3alkylene-OR2.1, or R2 denotes phenyl which is optionally substituted with a halogen, or R2 denotes a residue selected from Het and hetaryl, each optionally substituted with one or more residues selected from halogen, OH, oxo group and OR2.1, C1-C6alkyl, and where R3 denotes a bicyclic 9-11-member unsaturated or partially saturated heterocycle which is optionally substituted with one or more residues selected from a group comprising F, O, Br, CF3, CN, OH, methyl, ethyl, propyl, isopropyl, -O-methyl, -O-ethyl, phenyl, NR2.2R2.3, where the phenyl is optionally substituted with F, Cl or Br. The invention also relates to pharmaceutical compositions based on said compounds, having phosphodiesterase 4 (PDE4) inhibiting activity.

EFFECT: obtaining novel compounds and pharmaceutical compositions based thereon, which can be used in medicine to treat respiratory or gastrointestinal complaints or diseases, inflammatory diseases of joints, skin or eyes, diseases of the peripheral or central nervous system or cancers.

20 cl, 1 tbl, 156 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of the following formulae . The invention also relates to a pharmaceutical composition based on said compositions, having protein tyrosine kinase inhibiting activity.

EFFECT: novel compounds which can be used in medicine to treat ophthalmic diseases, disorders and pathological conditions.

11 cl, 7 tbl, 223 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

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

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

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. What is presented is a polypeptide containing two binding fragments presented by antibodies; the first of them binds to CD3e(epsilon) chain epitope of a human or a primate, other than a chimpanzee, particularly Callithrix jacchus, Saguinus oedipus and Saimiri sciureus; the second one - to EGFR, Her2/neu or IgE of a human or a primate, other than a chimpanzee, with the above CD3e epitope containing the amino acid sequence Gln-Asp-Gly-Asn-Glu. There are also disclosed a coding sequence of the nucleic acid, a vector, a host cell and a method for preparing the above peptide, as well as a pharmaceutical composition and using the polypeptide in preventing, treating or relieving a proliferative disease, a malignant disease or an immunological disorder.

EFFECT: invention provides the clinical improvement of T-cell redistribution and the enhanced safety profile.

17 cl, 8 tbl, 26 dwg, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to lactic-acid bacteria strain used as a therapeutic agent for treating allergy, as well as to using the above strains for preparing a composition for treating allergy. There are presented the lactic-acid bacteria strain Lactobacillus plantarum CBS120663, the lactic-acid bacteria strain Lactobacillus plantarum CBS120664 and the lactic-acid bacteria strain Lactobacillus fermentum CBS120661. The strains possess an ability to elicit the Th1 and/or Th3 responses, and/or inhibit the Th2 responses, which can be defined by cytokine profiles induced in human peripheral blood mononuclear cells if incubated together with the above strains. What is also presented is using the above strains for preparing the composition for treating allergy.

EFFECT: group of inventions can be effectively used for relieving allergy in the patient.

11 cl, 9 tbl, 3 ex

FIELD: agriculture.

SUBSTANCE: method of application of feed additive for pigs, comprising lactic ferment based on consortium of live lactic acid and propionic acid bacteria of three complexes: the 1st of strains of lactic acid bacteria S. salivarius-LT-1, S. Thermophilus-LT9, LT10, LT11 and strain of propionic acid bacteria Propionibacterium freidenreichii-LT8 in the ratio of 1:3; 2nd of strains of lactic acid bacteria L. Plantarum-LT7, L. Acidophilus-LT12 and strain of propionic acid bacteria Propionibacterium freidenreichii-LT8 in the ratio of 2:1; 3rd of the strains of propionic acid bacteria Propionibacterium freidenreichii-LT8 and lactic acid bacteria S. salivarius-LT-1, L. Plantarum-LT7, S. Thermophilus-LT9, LT10, LT11, L. Acidophilus-LT12 in a ratio of 7:2, which is then used for fermenting pasteurized milk with fat content of 1.5-2.5% and a ratio of 1:30, and the additive is daily fed together with the combined feed, in addition the minerals are periodically added to the composition of the feed additive: potassium iodide - KI and sodium selenite - Na2SeO3, adding is carried out after every day of omission, alternating with potassium iodide and sodium selenite weekly during the fattening period, starting with the four months of age of the piglets, and potassium iodide is added in an amount of 0.46 mg and sodium selenite - in an amount of 0.44 mg, i.e. 0.2 mg of pure selenium, per 1 kg of dry matter of diet.

EFFECT: increase in live body weight due to increase in muscle tissue, improving the quality of meat by reducing the layer of subcutaneous fat, increase in total body resistance to diseases of pigs.

8 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to immunology and biotechnology. There are presented variants of antagonist antibodies binding to the interleukin-7 receptor (IL-7R). There are described: variants of nucleic acids coding the antibodies; a host cell recombinant producing the antibody; a pharmaceutical composition inhibiting the human IL-7R function, and methods of treating and/or preventing: an autoimmune disease specified in the group of type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis; type 2 diabetes or graft-versus-host disease based on using the antibody.

EFFECT: invention provides the antagonist anti-IL-7R antibodies that can find application in medicine.

17 cl, 15 dwg, 8 tbl, 13 ex

FIELD: biotechnology.

SUBSTANCE: humanised antibody against human IFN-α is proposed, obtained based on the murine antibodies ASO-1. Also the therapeutic composition and method of prevention, treatment or diminution of intensity of the symptoms of an autoimmune or inflammatory disease or disorder is considered.

EFFECT: invention may find further application in treatment of IFN-α-related diseases.

13 cl, 13 dwg, 18 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: what is presented is a fused protein that is a Notch1 antagonist, which consists of a human Fc region fused with the EGF-like repeat 1-13 of Notch1 or the EGF-like repeat 1-24 of Notch1. Fc-portion is localised on a carboxy-terminal portion of the EGF-repeat. There are described a pharmaceutical composition for the protein-based Notch signal transmission inhibition and using it for preparing the pharmaceutical composition for treating an individual suffering from: tumour; ovarian cancer; metabolic disorder; vascular proliferative retinopathy. What is presented is using the fused protein for producing the pharmaceutical composition for inhibition: angiogenesis in the individual; physiological lymphangiogenesis or pathological lymphangiogenesis in the individual; tumour deposits in the individual.

EFFECT: using the invention provides the proteins expressed in a supernatant at a level by several times more than the fused protein containing the EGF-like repeats 1-36 of Notch1; they penetrate into the tumour better, maintain a ligand-binding ability with the fused protein containing the repeats 1-24, binds to DLL4 and JAG1, whereas the fused protein containing the repeats 1-13 only binds to DLL4, but not to JAG1 that can find application in therapy of various diseases related to the Notch1 activity.

18 cl, 124 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a polymer conjugate of an indolocarbazole compound of formula (I), where R1, R2, R3, W1 and W2 represent hydrogen, X represents methoxy-polyethyleneglycol. The method includes the interaction of a polymer compound of formula (II) with an indolocarbazole compound of formula (III), where Y stands for a methoxygroup. The nvention also relates to a polymer conjugate of formula (I), a pharmaceutical composition, containing the conjugate of formula (I) as an active ingredient, and to the application of the polymer conjugate of formula (I).

EFFECT: obtaining the polymer conjugate of the formula with a high output, the polymer conjugate of the formula for treatment of skin pathologies and HMGB1-associated pathologies.

48 cl, 7 dwg, 7 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with application of mutein of human interleukin-2(mutein hIL-2), which has amino acid substitution of asparagine in position 88 for arginine or glycine or for isoleucine and/or substitution of aspartic acid in position 20 for histidine or isoleucine, or for tyrosine and/or substitution of glutamine in position 126 for leucine to prepare medication, intended for treatment and/or prevention of autoimmune disease and for formation of regulatory T-cells in living organism.

EFFECT: group of inventions provides good tolerability and low toxicity of medication.

12 cl, 10 tbl, 10 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to immunology and biotechnology. There are presented version recombinant human VEGF antibodies containing variable regions of heavy and light chains containing complementarity-determining regions (CDR) of rabbit antibodies. There are also presented: recovered molecules of nucleic acids coding the above antibodies; an expression vector containing the above molecule of nucleic acid; and a host cell for expression of the antibody according to the invention, containing the above expression vector. What is disclosed is a pharmaceutical composition containing a therapeutically effective amount of the above antibody and a pharmaceutically acceptable carrier.

EFFECT: invention enables extending the range of human VEGF antibodies recovered from a rabbit.

24 cl, 15 dwg, 12 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole derivatives of general formula (I) as cytostatic preparations for fighting oncologic process in form of bases or pharmacologically acceptable salts. In formula (I) R1, R2 can be similar or different and independently represent hydrogen, halogen, alkyl, R3 represents alkyl, aralkyl, heteroalkyl, cycloalkyl.

EFFECT: increased efficiency of composition application.

2 tbl

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