New pyridine derivatives, method for making thereof and related pharmaceutical composition

FIELD: medicine.

SUBSTANCE: invention refers to new pyridine derivatives or to their pharmaceutically acceptable salts of general formula 1: wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from the group including hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino, C4-C9cycloalkylamino, C4-C9heterocycloalkylamino, C1-C10aralkylamino, arylamino, acylamino, saturated heterocyclyl, acyloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy; X represents oxygen or sulphur atom; Y represents oxygen atom or N-R8, wherein R8 is chosen from the group including hydrogen atom; aforesaid aryl group is chosen from phenyl, naphthyl and condensed phenyl group; aforesaid heteroaryl and saturated heterocyclic groups represent pentagonal or hexagonal heterocyclic ring containing 1 to 2 heteroatoms chosen from oxygen, nitrogen and sulphur atom; or condensed heterocyclic ring; and aforesaid aryl and heteroaryl groups are those that 1 to 4 assistants chosen from group including halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted. And specified compounds or their pharmaceutically acceptable salt of formula 1 are not compounds as follows 6-methyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 5-vinyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 6-methyl-8-furan-2-yl-3,4- dihydropyrano[3,4-c]pyridin-1-one, 3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-8-one and dimethyl ether (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthyridine-3,5-dicarboxylic acids.

EFFECT: compounds possess inhibitory action with respect to formation of cytokines involved in inflammatory reactions, can be used as a therapeutic agent for treatment of inflammatory diseases, immune diseases, chronic inflammations; it provides antiinflammatory and analgesic action.

21 cl, 7 tbl, 144 ex

 

The technical field of the invention

The present invention relates to new derivatives of pyridine, possessing inhibitory activity against the production of cytokines, which are known to be involved in the inflammatory response, and therefore, these derivatives can be used as therapeutic agents in the treatment of diseases associated with inflammation, immune, chronic inflammation, as well as funds that have anti-inflammatory and analgesic action. In addition, the present invention relates to a method for producing the above-mentioned derivatives and containing pharmaceutical compositions.

Background of the invention

Inflammatory reaction, the protective mechanism of the body consists of extremely complex transmission of biological signals that are run by immunological perception inflammations or lesions and caused by different cytokines inflammation. Usually the disease that destroys normal tissue as a result of disorders such inflammatory reactions, referred to as “inflammatory disease” and to clarify the details of this mechanism around the world have conducted extensive research. In addition, the increase in the number of inflammatory cytokines is associated with various autoimmune diseases.

The signal transmission system, is knitted with inflammation, is a series of chain reactions phosphorylation-dephosphorylation and mainly divided into three stages: 1) initial stage of transmission of the inflammatory signal in biomembrane with biomembrane receptor, starting thus a series of chain reactions signaling; 2) end-stage control of expression of genes encoding a protein associated with inflammation, with the help of transcription factors in the nucleus; and 3) the intermediate stage, which includes a series of chain reactions signaling, which is the link between the initial stage and terminal stage.

Examples of well-known inflammatory signalling factor in the initial stage are tumor necrosis factor (TNF; also known as TNF-α) and interleukin-1 (IL-1). Examples of well-known inflammatory signalling factor in the terminal stage are activating protein-1 (AP-1; activating protein-1), a transcription factor Kappa B to the nucleus (NFκB) and the factor of activated T-cells kernel (NFAT). Chain reaction at the intermediate stage is not adequately studied, but it is obvious that lipokortin, cyclooxygenase-1, 2 and PLA2 included in this stage.

With regard to factors of inflammation, TNF-α, produced, mainly by activated macrophages and T-cells, is the most effective cytokine and stimulates the production of other such vocal the tion of cytokines, as IL-1, IL-6 and IL-8, as well as products such transcription factors as NK-κB and C-jun/Ap-1. In fact, TNF-α is associated with the development of inflammatory diseases or immune diseases such as toxic shock syndrome, insulin dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis, Crohn's disease and ulcerative colitis. In particular, TNF-α is also associated with chronic inflammatory diseases such as psoriatic arthritis, psoriasis, ankylosing spondylitis, of still's disease in adults, polymyositis, dermatomyositis and vasculitis, such as Behcet's disease and granulomatous's granulomatosis. IL-1 is also a strong inflammatory cytokine, comparable with TNF-α and increases the expression of such genes as 2 PLA2, COX-2 and iNOS, and as a result, increases the production of PAF, PGE2 and NO, thus inducyruya inflammatory response. IL-1α and IL-1β both are associated with autoimmune diseases such as rheumatoid arthritis and insulin-dependent diabetes mellitus. IL-1β, like TNF-α is an important mediator of septic shock and cardio-respiratory failure, acute respiratory syndrome and multiple organ failure. IL-6 is a multifunctional cytokine produced by various cells, and is associated with diseases such as multiple myeloma, psoriasis, postmenopausal osteoporosis, trauma CNS viral and bacterial meningitis, disease Castleman, glomerulonephritis, dementia, AIDS, some nervous diseases, such as Alzheimer's disease, specific leukemia and systemic lupus erythematosus. IFN-γ originally is produced by T-cells and NK-cells and is associated with graft versus host disease, asthma and other inflammatory diseases such as atopic disease. In addition, IL-8 is associated with diseases such as stroke, myocardial infarction, acute respiratory distress syndrome, post-traumatic multiple organ lesions, acute glomerulonephritis, dermatitis, purulent meningitis or other Central nervous system, parahemophilia and necrotizing enterocolitis.

In addition, prostaglandins, known to play an important role in the inflammatory response. Inhibition of production of prostaglandins, mainly, PGG2, PGH2 and PGE2 plays a major role in the development of anti-inflammatory drugs. For example, the production of prostaglandins can be ingibirovany by inhibition of cyclooxygenase (COX), which is induced by inflammatory cytokines. Therefore, the production of prostaglandins can be ingibirovany by inhibiting cytokines.

Thus, as mentioned above, the decrease in the number of cytokines can be an effective method of treatment of inflammatory diseases and immune diseases.

Weeks the VNO to the authors of the present invention succeeded in synthesizing derivatives of pyridine with new structure, they also found that these new derivatives inhibit the production of cytokines involved in the inflammatory response, in particular, that they have excellent inhibitory activity against the production of TNF-α, IL-1, IL-6, IFN-γ and PGE2. Thus, the authors of the present invention have found that the new compounds synthesized by them have excellent therapeutic effect against diseases such as inflammatory diseases, immune diseases and chronic inflammatory diseases, and can also be used as a means possessing anti-inflammatory and analgesic action, and thus made the present invention.

Therefore, in a preferred embodiment, the present invention relates to new derivatives of pyridine.

In another preferred embodiment, the present invention relates to a method for producing the above-mentioned derivatives of pyridine.

In another preferred embodiment, the present invention relates to pharmaceutical compositions that can be used for the treatment of diseases caused by cytokines as inflammatory diseases, immune diseases, chronic inflammatory diseases, and can also be used as protivovospalitel inogo and analgesic tools.

Detailed description of the invention

The present invention relates to a derivative of pyridine, represented by the following formula 1 and their pharmaceutically acceptable salts

where R1, R2, R3, R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, halogen, cyano, nitro, acyl, hydroxy, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C6alkylthio, C1-C10alkylamino, C4-C9cyclooctylamino, C4-C9heterocyclochain, C1-C10aralkylamines, arylamino, acylamino, saturated heterocyclic group, acyloxy, C1-C6alkylsulfonyl, C1-C6alkylsulfonyl, C1-C6alkylsulfonamides, arylsulfonyl, arylsulfonyl, arylsulfonyl, aryl, heteroaryl, C1-C10aralkyl, C1-C10heteroalkyl, aryloxy, heteroaromatic group; or R1, R2, R3, R4, R5, R6and R7independently form a ring by linking with neighboring group Deputy;

X represents an oxygen atom or sulfur;

Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom, a C1-C6Nissi is alkyl, acyl, aryl, heteroaryl, C1-C10aralkyl and C1-C10heteroalkyl group; or forms a ring by linking with neighboring group of substituent R6or R7;

the above aryl group selected from phenyl, naphthyl and condensed phenyl group;

the above heteroaryl and saturated heterocyclic groups represent a heterocyclic ring pentagonal or hexagonal shape, containing from 1 to 3 heteroatoms selected from oxygen atom, nitrogen and sulfur; or a condensed heterocyclic ring; and

the above-mentioned aryl and heteroaryl groups are such that from 1 to 4 groups substituents selected from the group comprising halogen, hydroxy, C1-C6lower alkyl, lower C1-C6alkoxy, amino, cyano, nitro, carbonyl, and carboxyl group are substituted.

Derivatives of pyridine represented by the above formula (1) may form pharmaceutically acceptable salts by reacting with acid, such as hydrochloric acid, methyl acid, sulfuric acid, phosphoric acid, methanesulfonate acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid and tartaric acid.

In addition, derivatives of pyridine, presents seokatalog formula 1, can form pharmaceutically acceptable salts by reacting with ions of such alkali metal as sodium and potassium, or ammonium ion. Thus, the new compounds are obtained in accordance with the present invention also include pharmaceutically acceptable salts of pyridine derivatives represented by the above formula 1.

In a preferred embodiment of the present invention derivatives of pyridine represented by the above formula 1, are as follows:

thus, in the above formula 1, R1, R2and R3independently selected from the group comprising a hydrogen atom, halogen, hydroxy, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, aryloxy, amino, C1-C6alkylamino,

C1-C10aralkylamines, arylamino, acylamino, saturated heterocyclic group, aryl, heteroaryl and C1-C10heteroalkyl group; or adjacent R2and R3form a ring by linking with each other;

R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, a C1-C6the lower alkyl and aryl group; or R4, R5, R6and R7independently form a ring by linking with neighboring group will replace the La;

X represents an oxygen atom or sulfur;

Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom, a C1-C6lower alkyl, aryl and C1-C10aracelio group;

the aryl group is a phenyl group;

heteroaryl and saturated heterocyclic group selected from furan, thiophene, pyridine, piperidine, piperazine, research, pyrolidine and benzodioxole; and

aryl and heteroaryl groups are such that from 1 to 4 groups substituents selected from the group comprising halogen, hydroxy, C1-C6lower alkyl, C1-C6lower alkoxy, amino, cyano, nitro, carbonyl, and carboxyl group are substituted.

More specifically, derivatives of pyridine represented by the above formula 1, can be further defined as follows. That is, derivatives of pyridine represented by the above formula 1, are:

3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

5-vinyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6,8-dichloro-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6,8-dihydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

complex ever-methyl-1-oxo-3,4-dihydro-1H-pyrano-[3,4-c]pyridine-8-luxusni acid,

8-methoxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6,8-dimethyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-thiophene-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-pyridin-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-(4-forfinal)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-(4-chlorophenyl)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-morpholine-4-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-(4-methylpiperazin-1-yl)-3,4-dihydropyrido[3,4-c]pyridine-1-he,

6-methyl-8-(4-(pyrimidine-2-reparation-1-yl)-3,4-dihydropyrido[3,4-c]pyridine-1-he,

8-(4-forgenerating)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-(4-chlorpheniramine)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-(4-triptoreline)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-p-tolylamino-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-phenylamino-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-phenethylamine-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-[(benzo[1,3]dioxol-5-ylmethyl)amino]-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-8-phenoxy-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8 benzylamino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-(4-methoxybenzylamine)-6-methyl-3,4-dihydropyrano[,4-c]pyridine-1-he,

8-amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-acetamido-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8 benzamido-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-hydroxy-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-chloro-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-methyl-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

ester 1-oxo-6-phenyl-3,4-dihydro-1H-pyrano-[3,4-c]pyridine-8-luxusni acid,

8-methoxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-methylamino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-dimethylamino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-phenyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-morpholine-4-yl-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-phenyl-8-pyrrolidin-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-(4-forgenerating)-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-(4-methoxybenzylamine)-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-amino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-acetamido-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8 benzamido-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-hydroxy-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he

6-chloro-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-methyl-6-(thiophene-2-yl)-3,4-dihydropyrido[3,4-c]pyridine-1-he,

6-(furan-2-yl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-(benzo[d][1,3]dioxol-6-yl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-(4-(dimethylamino)phenyl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-hydroxy-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-chloro-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-propyl-6-chloro-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-morpholine-4-yl-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

ester 1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid

8-(4-methoxybenzylamine)-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-amino-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

N-(1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-yl)acetamide", she

3,4-dihydro-2-oxa-Aza-phenanthrene-1-he,

3,4-dihydropyrano[3,4-c]pyridine-1-tion,

2-(4-methoxybenzyl)-3,4-dihydro-2H-[2,7]naphthiridine-1-he,

3,4-dihydro-2H-[2,7]naphthiridine-1-he,

2-benzyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,

3-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

3-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,

8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,

2,8-dimethyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,

2-benzyl-8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,

6-cyclohexyl-8-hydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-he,

methyl is the first broadcast 6-cyclohexyl-1-oxo-3,4-dihydro-1H-pyrano-[3,4-c]pyridine-8-luxusni acid,

8-chloro-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-cyclohexyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-cyclohexyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-amino-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

8-hydroxy-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

methyl ester of 6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano-[3,4-c]pyridine-8-luxusni acid,

8-chloro-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-he,

6-isopropyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-c]pyridine-1-he; and

their pharmaceutically acceptable salts.

In another preferred embodiment, the present invention relates to a method for producing pyridine derivatives represented by the above formula 1.

Derivatives of pyridine according to the present invention represented by the above formula 1, where X and Y each individually represent an oxygen atom, can be obtained in 3 different ways in accordance with the following reaction schemes 1, 2 and 3.

In reaction scheme 1 briefly shows the first method of obtaining derivatives of pyridine according to the present invention represented by the above formula 1, where X and Y each individually represent an oxygen atom.

Scheme 1

In the above reactio the Noah scheme 1, R1, R2, R3, R4, R5, R6,

R7X and Y are as defined above, and M represents an alkali metal atom, and X1represents a halogen atom.

The connection represented by the above formula 2 used as starting product in the above method, can be easily obtained by a known method (J. Org. Chem., Vol. 41, No. 15,2542,1976; Pharmazie, 38(9), 591,1983)).

In accordance with the method shown in the above reaction scheme 1, the compound represented by the above formula 2, is first dissolved in an anhydrous inert aprotic solvent, after adding dropwise Foundation, is stirred at a temperature of from about -100°C to about -40°C, again added dropwise alkilany ether, preferably methyl ether (R6COOMe), and left to interact from about 2 to about 8 hours at a temperature of from -78°C to room and get the connection represented by the above formula 3.

In the above reaction used aprotic solvent includes tetrahydrofuran (THF), diethyl ether, dioxane and preferably THF. Examples of the base include: bis(trimethylsilyl)lithium amide (LHMDS), bis(trimethylsilyl)amide and potassium (KHMDS), diisopropylamide lithium (LDA), sodium hydride (NaH), potassium hydride (KH) and lithium hydride (LiH), and pre is respectfully, LHMDS.

Further, the compound of the above formula 3 add the reducing agent or metal reagent containing R7, and left to interact at a temperature from 0°C to room under stirring for 6 to 12 hours and receive a combination of alcohol represented by the above formula 4.

Examples of reducing agents include sodium borohydride (NaBH4) or lithium borohydride (LiB4).

Examples of the metal reagent containing R7include the alkali metal reagent represented by the formula, R7M, or a Grignard reagent represented by the formula, R7MgX1where R7is the same as defined above, M represents an alkaline metal such as lithium, sodium and potassium, X1represents a halogen atom.

Next, an alcohol compound represented by the above formula 4, is subjected to cyclization by heating under reflux for 6 to 12 hours in the presence of concentrated HCl, and finally get the connection represented by the above formula 1, where X and Y each individually represent an oxygen atom.

The following reaction scheme 2 briefly shows a second method of obtaining the compound represented by the above formula 1, where X and Y each individually represent an oxygen atom.

Scheme 2

In the above reaction scheme 2, R1, R2, R3, R4, R5, R6, R7X and Y are as defined above.

In accordance with the method shown in the above reaction scheme 2, the compound represented by the above formula 2, is first subjected to interaction with alkylcarboxylic compound represented by R6COR7(R6and R7are as defined above), together with a base in the presence of an anhydrous inert aprotic solvent, and get the connection represented by the above formula 4.

In the above reaction, examples of the aprotic solvent include tetrahydrofuran (THF), diethyl ether and dioxane, preferably THF.

Examples of the base include: bis(trimethylsilyl)lithium amide (LHMDS), bis(trimethylsilyl)amide and potassium (KHMDS), diisopropylamide lithium (LDA), sodium hydride (NaH), potassium hydride (KH) and lithium hydride (LiH), and, preferably, LHMDS.

Next, an alcohol compound represented by the above formula 4, is subjected to cyclization in a similar manner as shown above in reaction scheme 1, and finally get the connection represented by the above formula 1, where X and Y each independently represents an oxygen atom.

In the following reaction scheme 3 briefly shows the third method of obtaining compounds represented by the above formula 1, where X and Y each individually represent an oxygen atom.

Scheme 3

In the above reaction scheme 3, R1, R2, R3, R4, R5X and Y are as defined above, and X1represents a halogen atom.

In accordance with the method shown in the above reaction scheme 3, the compound represented by the above formula 2, is first subjected to interaction with alkoxymethyl compound represented by ROCH2X1(R represents a C1-C6lower alkyl, aryl or aracelio group, preferably methyl, ethyl or benzyl group, X1represents a halogen atom), with base in the presence of an anhydrous inert aprotic solvent, and get the connection represented by the above formula 7.

In the above reaction, examples of the aprotic solvent include tetrahydrofuran (THF), diethyl ether and dioxane, preferably THF.

Examples of the base include: bis(trimethylsilyl)lithium amide (LHMDS), bis(trimethylsilyl)amide and potassium (KHMDS), diisopropylamide lithium (LDA), sodium hydride (NaH), potassium hydride (KH) and lithium hydride (LiH), and, preferably, LHMDS.

Further, the compound represented by the above-mentioned the formula 7, is subjected to cyclization in a similar manner as shown above in reaction scheme 1, and finally get the connection represented by the above formula 1, where X and Y each individually represent an oxygen atom.

The following reaction scheme 3 briefly shows the third method of obtaining the compound represented by the above formula 1, where R6and R7each individually represent a hydrogen atom, and X and Y each individually represent an oxygen atom.

Derivatives of pyridine according to the present invention represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8can be obtained 4 different ways in accordance with the following reaction schemes 4, 5, 6 and 7.

In reaction scheme 4 briefly shows the first method of obtaining derivatives of pyridine according to the present invention represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8.

Scheme 4

In the above reaction scheme 4, R1, R2, R3, R4, R5, R6, R7, R8X and Y are as defined above.

In accordance with the method shown in the above reaction scheme 4, compound, performance is undertaken by the above formula 4, first is subjected to interaction with methanesulfonanilide (MsCl) or p-toluensulfonate together with a base such as pyridine or triethylamine (Et3N), in the presence of an organic solvent, and get the connection represented by the above formula 5.

In the above reaction, preferred examples of the organic solvent are methylene chloride (CH2Cl2) or chloroform (CHCl3).

Further, the compound represented by the above formula 5, is subjected to the interaction with the amine compound represented by R8NH2where R8is the same as defined above, to obtain compounds represented by the above formula 6, which is then cyclist in an acidic medium, for example in an alcohol solution containing hydrochloric acid or sulfuric acid, and finally get the connection represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8.

The following reaction scheme 5 briefly shows a second method of obtaining the compound represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8.

Scheme 5

In the above reaction scheme 5, R1, R2, R3, R4, R5, R , R7, R8X and Y are as defined above.

In accordance with the method shown in the above reaction scheme 5, the compound represented by the above formula 1, where X and Y each independently represents an oxygen atom, is first subjected to interaction with the amine compound represented by R8NH2where R8is the same as defined above, to obtain compounds of the above formula 8, which is then cyclist, and finally get the connection represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8.

In the above reaction, the cyclization perform interaction with triphenylphosphine and diethylazodicarboxylate in the presence of an organic solvent, such as tetrahydrofuran.

The following reaction scheme 6 briefly shows the third method of obtaining the compound represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8.

In the above reaction scheme 6, R1, R2, R3, R4, R5, R6, R7, R8X and Y are as defined above, and R9represents benzyl or 4-methoxybenzyl group.

In accordance with the method shown in the above R is the promotional scheme 6, the connection represented by the above formula 1, where R9represents benzyl or 4-methoxybenzyloxy group, first subjected to repair using a catalyst based on palladium in the presence of an alcoholic solvent, or subjected to interaction with the acidic reagent, such as p-toluensulfonate acid or triptorelin, in the presence of an organic solvent, such as toluene or methylene chloride, to obtain the compound of the above formula 1, which is then cyclist and finally get the connection represented by the above formula 1, where X represents an oxygen atom and Y represents NH.

Further, the above compound of formula 1, where X represents an oxygen atom and Y represents NH, is subjected to the interaction with an alkylating agent represented by R8X (R8is the same as defined above and X represents a halogen atom), together with such ground, as sodium hydride, potassium hydride, lithium hydride, potassium carbonate and sodium carbonate, in the presence of an organic solvent such as tetrahydrofuran or dimethylformamide, and, finally, get the connection represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8.

The following reaction scheme 7 WRC is tze shows a fourth method of obtaining a derivative of pyridine, represented by the above formula 1, where X represents an oxygen atom and Y represents N-R8.

Scheme 7

In the above reaction scheme 7, R1, R2, R3, R4, R5, R8X and Y are as defined above, and X1represents a halogen atom.

In accordance with the method shown in the above reaction scheme 7, the compound represented by the above formula 1, where R5represents a hydrogen atom, first subjected to interaction with N,N-dimethylformamidine in the presence of an aprotic solvent, such as tetrahydrofuran or dimethylformamide, and get the connection represented by the above formula 9, which then cyclist in an acidic environment, such as sulfuric acid or acetic acid, and receive the connection represented by the above formula 10.

Further, the above compound represented by formula 10, is subjected to the interaction with the alkylating reagent represented by R8X1(R8is the same as defined above and X1represents a halogen atom), together with a base such as sodium hydride, potassium hydride, lithium hydride, potassium carbonate and sodium carbonate, in the presence of an organic solvent, takagaki tetrahydrofuran or dimethylformamide, and get the connection represented by the above formula 11.

Further, the above compound represented by formula 11, is subjected to the repair using a catalyst based on palladium and hydrogen gas in the presence of an alcoholic solvent and receive the connection represented by the above formula 1, where R5, R6and R7each individually represents a hydrogen atom, X represents an oxygen atom and Y represents N-R8.

Meanwhile, in accordance with the above reaction scheme 7, when the above compound represented by formula 1, is subjected to the repair using a catalyst based on palladium and hydrogen gas in the presence of an alcoholic solvent, also get a connection to the above formula 1, where R5, R6and R7each individually represents a hydrogen atom, X represents an oxygen atom and Y represents N-R8.

Further, the above compound represented by formula 1, where Y represents NH, is subjected to the interaction with an alkylating agent represented by R8X1(R8is the same as defined above and X1represents a halogen atom), together with such ground, as sodium hydride, potassium hydride, lithium hydride, a carbonate to the lia and sodium carbonate, in the presence of an organic solvent such as tetrahydrofuran or dimethylformamide, and get the connection represented by the above formula 1, where R5, R6and R7each individually represents a hydrogen atom, X represents an oxygen atom and Y represents N-R8.

The following reaction scheme 8 briefly shows how simultaneous receipt of pyridine derivatives represented by the above formula 1, where R5represents a hydrogen atom and X and Y each individually represent an oxygen atom, and pyridine derivatives represented by the above formula 1, where R5represents a hydrogen atom, X represents an oxygen atom, X represents an oxygen atom and Y represents NH.

Scheme 8

In the above reaction scheme 8, R1, R2, R3, R4, R6, R7X and Y are as defined above.

In accordance with the method shown in the above reaction scheme 8, the compound represented by the above formula 4, where R5represents a hydrogen atom, first subjected to interaction with such a base as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, in the presence of alcohols the first solvent and receive connection represented by the above formula 12.

Then the above compound represented by formula 12, is subjected to cyclization in an acid environment, such as phosphoric acid, and simultaneously receive the derivatives of pyridine represented by the above formula 1, where R5represents a hydrogen atom and X and Y each independently represents an oxygen atom, and derivatives of pyridine represented by the above formula 1, where R5represents a hydrogen atom, X represents an oxygen atom and Y represents NH.

The following reaction scheme 9 briefly shows how to obtain the pyridine derivatives represented by the above formula 1, where X represents a sulfur atom, Y represents an oxygen atom or N-R8.

Scheme 9

In the above reaction scheme 9, R1, R2, R3, R4, R6, R7, R8X and Y are as defined above.

In accordance with the method shown in the above reaction scheme 9, the compound represented by the above formula 1, where X represents the oxygen atom, is subjected to the interaction with sulfurous reagent, for example, the reagent Lawesson (Lawesson), at relatively high temperatures and can easily get a connection, not only the TES by the above formula 1, where X represents a sulfur atom.

Further, of the pyridine derivatives of the present invention, the compound represented by formula 1, where R1, R2or R3represent amino, C1-C10alkylamino, C4-C9cyclooctylamino, C4-C9heterocyclochain, arylamino, acylamino, C1-C6alkylsulfonamides, arylsulfonate group, can be obtained in the following way. Thus, the compound represented by formula 1, where R1,

R2or R3each individually represent a halogen atom, can be converted into the compound represented by formula 1, where R1, R2or R3represent amino, C1-C10alkylamino, C4-C9cyclooctylamino, C4-C9heterocyclochain, arylamino, acylamino, C1-C6alkylsulfonamides, arylsulfonate group, its interaction with the corresponding amine compound in the presence of an organic solvent. In the above reaction, amination as a catalyst for the reaction, it is preferable to use triethylamine as a reaction solvent is ethanol or acetonitrile.

In addition, of the pyridine derivatives of the present invention, the compound represented by formula 1, where R1, R2or R3 represent benzylamino or 4 methoxybenzylamine can be converted into the compound represented by formula 1, where R1, R2or R3are amines, recovery. The above recovery can be carried out using a catalyst based on palladium in the presence of an alcoholic solvent, or, alternatively, using acidic reagent, such as p-toluensulfonate acid or triperoxonane acid, in the presence of an organic solvent, such as toluene or methylene chloride.

Further, the compound represented by formula 1, where R1, R2or R3represent amino groups, can be preobrazavana in the compound represented by formula 1, where R1, R2or R3represent acylamino, C1-C6alkylsulfonate or arylsulfonate group. The above acylation reaction or sulfonylurea can be performed using Alliluyeva agent or sulphurouses agent, together with such ground as triethylamine, in the presence of an organic solvent. Examples of the above Alliluyeva agent are allalone and allanheld, and examples of the above sulphurouses agent are alkylsulfonate and arylsulfonate. Examples in showcasing organic solvent are methylene chloride, acetonitrile, dimethylformamide and tetrahydrofuran.

Further, of the pyridine derivatives of the present invention, the compound represented by formula 1, where R1, R2or R3represent a halogen atom,

With1-C6lower alkoxy, aryloxy or acyloxy group, can be obtained as follows.

Thus, the compound represented by formula 1, where R1, R2or R3each individually represent a hydroxyl group, can be converted into the compound represented by formula 1, where R1, R2or R3each individually represent a halogen atom, interaction with a halogenation reagent. Examples of the above-mentioned halogenation reagent are: phosphorus oxychloride, thionyl chloride, tribromide phosphorus, N-chlorosuccinimide and N-iodosuccinimide.

Further, the compound represented by formula 1, where R1, R2or R3represent a hydroxy-group, can be converted into the compound represented by formula 1, where R1, R2or R3represents a C1-C6lower alkoxy, aryloxy or alloctype by appropriate alkylation. The way the above alkylation represents the interaction of the above compounds such basis as sodium hydride, guide the ID of potassium, the lithium hydride, potassium carbonate and sodium carbonate, together with the corresponding alkylating agent in the presence of an organic solvent, such as tetrahydrofuran or dimethylformamide. In addition, the above alkylation reaction can be carried out by appropriate interaction Alliluyeva reagent such basis as triethylamine, in such an organic solvent as methylene chloride, chloroform, acetonitrile, dimethylformamide and tetrahydrofuran.

Examples of reagents used in the above alkylation reaction are: alkylhalogenide as alkylating agent; alkylhalogenide agent may be used together with an acid agent instead of the base; and as Alliluyeva reagent can be used allalone and allanheld.

Further, of the pyridine derivatives of the present invention, the compound represented by formula 1, where R1, R2or R3represents a C1-C6lower alkyl, C2-C6lower alkenyl, C4-C9cycloalkyl, C4-C9heteroseksualci, aryl, heteroaryl,1-C10aralkyl or C1-C10heteroalkyl, can be obtained from compounds represented by the following formula 1, where R1, R2or R3represent a halogen atom, in the following way. the AK, the compound represented by formula 1, where R1, R2or R3represents a C1-C6lower alkyl, C2-C6lower alkenyl, C4-C9cycloalkyl, C4-C9heteroseksualci, aryl, heteroaryl,1-C10aralkyl or C1-C10heteroalkyl group, can be obtained by the interaction of the compounds represented by formula 1, where R1, R2or R3represent a halogen atom, with a catalyst based on iron, such as Fe(acac)3and an alkylating agent or Alliluyeva agent in the presence of an organic solvent.

The above alkylating agent or allerease agent are preferably a Grignard reagent represented by the formula RMgX1where R represents a C1-C6lower alkyl, C2-C6lower alkenyl, C4-C9cycloalkyl, C4-C9heteroseksualci, aryl, heteroaryl, C1-C10aralkyl or1-C10heteroalkyl group, X1 represents a halogen atom.

Further, the compound represented by formula 1, where R1, R2or R3represent a hydroxy-group, can be converted into the compound represented by formula 1, where R1, R2or R3represents a C2-C6lower alkene is, aryl or heteroaryl group, using a catalyst based on palladium,

as Pd(PPh3)4together with the appropriate alkylating reagent or alleroisk reagent in the presence of an organic solvent.

In the above reaction of the alkylating agent or allerease agent represent alkeneamine connection tin, aryl compound of tin or heteroaryl compound of tin represented by the formula RSnR'3where R represents a C2-C6lower alkenyl, aryl or heteroaryl group, R' represents a group C1-C6lower alkyl, preferably boutelou group.

Further, the compound represented by formula 1, where R1, R2or R3represent a hydroxy-group, can be converted into the compound represented by formula 1, where R1, R2or R3represent aryl or heteroaryl group, using a catalyst based on palladium such as Pd(PPh3)4together with such a Foundation, as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, and the appropriate alkylating agent or allerease agent in the presence of an organic solvent such as toluene and benzene. The above allerease reagent is preferably, and the ilen boron compound or heteroaryl boron compound, presents RB(OH)2where R represents an aryl or heteroaryl group.

In another embodiment, the present invention relates to a compound represented by the above formula 1 and its pharmaceutically acceptable salts as an effective therapeutic component.

The pharmaceutical composition of the present invention can be obtained in a dosage form suitable for oral and parenteral administration, by combining the compounds represented by the above formula 1, or its pharmaceutically acceptable salt together with a conventional carrier, adjuvant or diluent. In the case of a medicinal product for oral administration, the compound may be incorporated into tablets, capsules, solutions, syrups and suspensions. In the case of a medicinal product for parenteral administration, the compound may be represented in the form of drugs for intraperitoneal, subcutaneous, intramuscular and intradermal injection.

An effective daily dose of the pharmaceutical composition of the present invention as anti-inflammatory and analgesic for adults is from about 0.01 to 1,000 mg/day, and it can vary depending on age, body weight, sex, method of administration, state of health is the extent of any existing disease. The introduction may be appropriate aliquot once a day or several times a day, after consultation with your doctor or pharmacist.

In another embodiment, the present invention relates to the use of pharmaceutical compositions containing a compound represented by the above formula 1 or its pharmaceutically acceptable salts, for the treatment and prevention of diseases.

Thus, the present invention relates to a compound represented by the above formula 1, or its pharmaceutically acceptable salts for use as a therapeutic agent in the treatment of inflammatory diseases, immunopathological diseases, chronic inflammatory diseases, and for use as anti-inflammatory and analgesic agent, and to the medical use of pharmaceutical compositions containing the above compounds.

The pharmaceutical composition of the present invention is effective in the treatment of diseases caused by TNF-α, IL-1α, IL-1β and IFN-γ. More specifically, the composition is effective in the treatment of diseases such as (i) inflammatory diseases or immunopathological diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, infectious gastrointestinal disease, that is their as ulcerative colitis, graft versus host disease, systemic erythematous skin tuberculosis, toxic shock syndrome, osteoarthritis and insulin-dependent diabetes mellitus; (ii) such chronic inflammatory diseases, such as psoriatic arthritis, psoriatic, alkiliruushim spondylitis, appearing with age of still's disease, polymyositis, dermatomyositis, vasculitis, such as Behcet's disease and Wegener's granulomatosis; and is also effective as (iii) anti-inflammatory and analgesic agent. In addition, it is effective in the treatment of diseases such as glomerulonephritis, dermatitis, asthma, stroke, myocardial infarction, acute respiratory distress syndrome, post-traumatic multiple organ failure, purulent meningitis, necrotizing enterocolitis, paragenetically syndrome, septic shock and post-menopausal osteoporosis.

EXAMPLES

A better understanding of the present invention can be achieved in the light of the following examples, which are provided for illustration, but should not be construed as limiting the present invention.

Example 1

Synthesis of methyl ester (3-cyano-4-yl)acetic acid

In 15 ml of anhydrous THF was dissolved 2,52 g of 4-methylnicotinamide and dropwise added 45 ml of 1M LHMDS at -78°C and was stirred for about 1 hour. To SECIPRO above the temperature was added dropwise to 1.98 ml dimethylcarbonate, was stirred for about 1 hour. Then the mixture was heated to 0°C and was stirred for about 2 hours. To the above mixture was added 5 ml of a saturated solution of ammonium chloride, diluted with 300 ml of ethyl acetate. Then the layer of organic solvent was washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and perform the purification of the obtained residue by chromatography on a column of silica gel using a mixed eluent of ethyl acetate and hexane, where the ethyl acetate and hexane mixed in a volume ratio of 1:3, and received 3,21 g (85%) of methyl ester of (3-cyano-4-yl)acetic acid as colorless oil.

1H NMR (300 MHz, CDCl3) δ 8,87 (c, 1H), up 8.75 (d, 1H, J=5,1 Hz), 7,41 (d 1H, J=5,1 Hz), 3,89 (c, 2H), of 3.77 (c, 3H).

Example 2

Synthesis of 4-(2-hydroxyethyl)nicotinanilide

In 18 ml of ethanol was dissolved 1,58 g methyl ester (3-cyano-4-yl)acetic acid was slowly added at -0°C 682 mg of sodium borohydride and stirred for about 2 hours. To the above mixture was added 3 ml of saturated solution of ammonium chloride, diluted with 200 ml of ethyl acetate. Then the layer of organic solvent was washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and filtered. The filtrate conc is listed under reduced pressure and perform the purification of the obtained residue by chromatography on a column of silica gel, using a mixed eluent of methylene chloride and methanol, where methylene chloride and methanol are mixed in a volume ratio of 50:1, and received 1,02 g (74%) of 4-(2-hydroxyethyl)nicotinanilide in the form of a colorless oil.

1H NMR (300 MHz, CDCl3) δ 8,82 (c, 1H), 8,69 (d, 1H, J=5.4 Hz), 7,39 (d, 1H, J=5,4 Hz), 3,99 (t, 2H, J=6.3 Hz), 3,10 (t, 2H, J=6.3 Hz).

Example 3

Synthesis of 3,4-dihydropyrano[3,4-c]pyridine-1-it

To 765 mg of 4-(2-hydroxyethyl)nicotinanilide added to 13.6 ml of concentrated HCl and was stirred for about 12 hours while heating under reflux. Removal of the solvent the above mixture was concentrated under reduced pressure. The filtrate was dissolved in water, and the aqueous layer was podslushivaet a saturated solution of sodium bicarbonate, and then extracted using ethyl acetate. Then, the layer of organic solvent was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by column chromatography using a mixed eluent of ethyl acetate and hexane, where the ethyl acetate and hexane mixed in a volume ratio of 1:2, and got 760 mg (98%) of 3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 9,25 (c, 1H), 8,72 (d, 1H, J=4,8 Hz), 7,22 (d, 1H, J=5,1 Hz), 4,58(t, 2H, J=6,0 Hz), 08 (t, 2H, J=6,0 Hz).

Example 4

Synthesis of methyl ester (5-cyano-2-methylpyridin-4-yl)acetic acid

Using the same method as in example 1, was obtained 3.2 g (77%) of methyl ester of (5-cyano-2-methylpyridin-4-yl)acetic acid as a colourless oil, except that instead of 4-methylnicotinamide used 2,88 g of 4,6-dimethylpentanenitrile.

1H NMR (300 MHz, CDCl3) δ is 8.75 (s,1H), 7,25 (c, 1H), 3,83 (c, 2H), 3,76 (c, 3H), 2.63 in (c, 3H).

Example 5

Synthesis of 4-(2-hydroxyethyl)-6-methylnicotinamide

Using the same method as in example 2, was obtained 1.5 g (65%) of 4-(2-hydroxyethyl)-6-methylnicotinamide in the form of a colorless oil, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 2.7 g of methyl ester of (5-cyano-2-methylpyridin-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 8,71 (c, 1H), 7.23 percent (c, 1H), of 3.97 (t, 2H, J=6,3 Hz), 3.04 from (t, 2H, J=6,3 Hz), 2,61 (c, 3H).

Example 6

Synthesis of 6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-it

Using the same method as in example 3 was obtained 1.19 g (99,4%) 6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 981 mg of 4-(2-hydroxyethyl)-6-methylnicotinamide.

1H NMR (300 MHz, CDCl3) δ 9,01 (s,1H), 7,79 (c, 1H), 4,60(t, 2H, J=6.0 Hz), 3,26 (t, 2H, J=6,0 Hz), 2,70 (s, 3H)./p>

Example 7

Synthesis of methyl ester (3-cyano-5-vinylpyridin-4-yl)acetic acid

Using the same method as in example 1, was obtained 2.5 g (74%) of methyl ester of (3-cyano-5-vinylpyridin-4-yl)acetic acid as a colourless oil, except that instead of 4-methylnicotinamide used to 2.42 g of 4-methyl-5-finalnational.

1H NMR (300 MHz, CDCl3) δ 8,83 (c, 1H), 8,77 (c, 1H), for 6.81 (DD, 1H, J=17,4 Hz and 11.1 Hz), 5,78 (d, 1H, J=17,4 Hz), the ceiling of 5.60 (d, 1H, J=11,1 Hz), 3,95 (c, 2H), 3,74 (c, 3H).

Example 8

Synthesis of 4-(2-hydroxyethyl)-5-finalnational

Using the same method as in example 2, was obtained 1.04 g (60%) of 4-(2-hydroxyethyl)-5-finalnational in the form of a solid white product, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 2.0 g methyl ester (3-cyano-5-vinylpyridin-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 8,92 (c, 1H), 8,84 (c, 1H), 7,05 (DD, 1H, J=17,4 Hz and 11.1 Hz), 5,96 (d, 1H, J=17,4 Hz), of 5.55 (d, 1H, J=11,1 Hz), 3,61 (t, 1H, J=6.6 Hz), 3.04 from (t, 2H, J=6.6 Hz).

Example 9

Synthesis of 5-vinyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 3, was received 817 mg (85%) of 5-vinyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 780 mg of 4-(2-hydroxyethyl)-5-wininit is nonfree.

1H NMR (300 MHz, CDCl3) δ 9,17 (c, 1H), 8,84 (c, 1H), for 6.81 (DD, 1H, J=17.7 and Hz and 11.1 Hz), of 5.81 (d, 1H, J=17.7 and Hz), 5,59 (d, 1H, J=11,1 Hz), 4,56 (t, 2H, J=6.0 Hz), to 3.09 (t, 2H, J=6.0 Hz).

Example 10

Synthesis of methyl ester (2,6-dichloro-3-cyano-4-yl)acetic acid

Using the same method as in example 1 were obtained 1.8 g (54%) of methyl ester (2,6-dichloro-3-cyano-4-yl)acetic acid as a colourless oil, except that instead of 4-methylnicotinamide used to 2.57 g of 2,6-dichloro-4-methylnicotinamide.

1H NMR (300 MHz, CDCl3) δ 7,40 (c, 1H), 3,88 (c, 2H), 3,78 (c, 3H).

Example 11

Synthesis of 2,6-dichloro-4-(2-hydroxyethyl)nicotinanilide

Using the same method as in example 2, was obtained 600 mg (68%) of 2,6-dichloro-4-(2-hydroxyethyl)nicotinanilide in the form of a colorless oil, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 1.0 g of methyl ester of 2,6-dichloro-(3-cyano-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 7,40 (c, 1H), 3,88 (c, 2H), 3,78 (c, 3H).

1H NMR (300 MHz, CDCl3) δ 7,40 (c, 1H), 3,98 (t, 2H, J=6.0 Hz), to 3.09 (t, 2H, J=6.0 Hz).

Example 12

Synthesis of 6,8-dichloro-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 3 was obtained 270 mg (90%) of 6,8-dichloro-3,4-dihydropyrano[3,4-C]pyridine-1-it is in the form of a solid of light yellow color, except the instead of 4-(2-hydroxyethyl)nicotinanilide used 300 mg of 2,6-dichloro-4-(2-hydroxyethyl)nicotinanilide.

1H NMR (300 MHz, CDCl3) δ 7,40 (c, 1H), 4,60 (t, 2H, J=6.0 Hz), 3,10 (t, 2H, J=6.0 Hz).

Example 13

Synthesis of methyl ester (2,6-bis-benzyloxy-3-cyano-4-yl)acetic acid

Using the same method as in example 1 was received 840 mg (35%) methyl ester (2,6-bis-benzyloxy-3-cyano-4-yl)acetic acid as a colourless oil, except that instead of 4-methylnicotinamide used 2,05 g of 2,6-bis-benzyloxy-4-methylnicotinamide.

1H NMR (300 MHz, CDCl3) δ 7,45-7,31 (m, 10H), 6,41 (s, 1H), 5,46 (c, 2H), 5,35 (c, 2H), 3,78 (c, 2H), 3,74 (c, 3H).

Example 14

Synthesis of 2,6-bis-benzyloxy-4-(2-hydroxyethyl)nicotinanilide

Using the same method as in example 2, was received 285 mg (62%) of 2,6-bis-benzyloxy-4-(2-hydroxyethyl)nicotinanilide in the form of a colorless oil, except that instead of methyl ester (3-cyano-4-yl)acetic acid used 500 mg methyl ester (2,6-bis-benzyloxy-3-cyano-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 7,44-7,30 (m, 10H), 6,41 (c, 1H), 5,44 (c, 2H), 5,35 (c, 2H), of 3.97 (t, 2H, J=6.3 Hz), 3,10 (t, 2H, J=6.3 Hz).

Example 15

Synthesis of 6,8-dihydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 3,was received 98 mg (98%) of 6,8-dihydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a thick oil, except that instead of 4-(2-hydroxyethyl)nicotine is itril used 200 mg of 2,6-bis-benzyloxy-4-(2-hydroxyethyl)nicotinanilide.

1H NMR (300 MHz, CDCl3) δ 5,48 (c, 1H), of 4.44 (t, 2H, J=6.3 Hz), is 2.88 (t, 2H, J=6.3 Hz).

Example 16

Synthesis of 2-methoxy-4,6-dimethylpentanenitrile

2-Chloro-4,6-diethylnicotinamide (2.5 g, 15,01 mmol) was dissolved in anhydrous methanol (70 ml), was added sodium methoxide (4,27 g, 75,03 mmol) at 0°C and was stirred for about 10 hours in nitrogen atmosphere. The above mixture was concentrated under reduced pressure and then neutralized with a saturated solution of ammonium chloride and then was extracted twice with 150 ml of methylene chloride. The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (20% EtOAc/hexane) and got to 2.41 g (99%) 2-methoxy-4,6-dimethylpentanenitrile in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 2,44 (c, 3H), 2,45 (c, 3H), 4,01 (s,3H), 6,68 (c, 1H).

Example 17

Synthesis of methyl ester (3-cyano-2-methoxy-6-methylpyridin-4-yl)acetic acid

Using the same method as in example 1 was received 3.03 g (97%) of methyl ester of (3-cyano-2-methoxy-6-methylpyridin-4-yl)acetic acid, except that instead of 4-methylnicotinamide used 2.3 g of 2-methoxy-4,6-dimethylpentanenitrile.

1H NMR (300 MHz, CDCl3) δ 2.49 USD (c, 3H), of 3.75 (s, 3H), 3,78 (c, 2H), 4,03 (c, 3H), 6,79 (c, 1H).

Example 18

With ntes 4-(2-hydroxyethyl)-2-methoxy-6-methylnicotinamide

Using the same method as in example 2, was received 2,04 g (88%) of 4-(2-hydroxyethyl)-2-methoxy-6-methylnicotinamide, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used to 2.65 g of methyl ester of (3-cyano-2-methoxy-6-methylpyridin-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 1.55V (shirt, 1H, J=5.4 Hz), 2,48 (c, 3H), of 3.00 (t, 2H, J=6.3 Hz), 3,92-of 3.97 (m, 2H), was 4.02 (c, 3H), 6,78 (c, 1H).

Example 19

Synthesis of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 3, was received 337 mg (84%) of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 430 mg of 4-(2-hydroxyethyl)-2-methoxy-6-methylnicotinamide.

1H NMR (300 MHz, DMSO-d6) δ 2,30 (c, 3H), 2.63 in (t, 2H, J=6.0 Hz), of 4.44 (t, 2H, J=6.0 Hz), 6,67 (c, 1H), of 12.26 (Sirs, 1H).

Example 20

Synthesis of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

In phosphorus oxychloride (POCl3, 2.5 ml) was dissolved 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (280 mg, 1,561 mmol) and was heated to boiling under reflux for about 15 hours under nitrogen atmosphere. The above mixture was added to 20 ml of distilled water and neutralized by slowly adding saturated sodium carbonate solution, stirring at 0°C, and then was extracted twice, using the 100 ml of methylene chloride (MC). The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (2% MeOH/MC) and received 273 mg (89%) of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 2,59 (c, 3H), 3,03 (t, 2H, J=6.0 Hz), 4,48 (t, 2H, J=6.0 Hz), 7,03 (s, 1H).

Example 21

Synthesis of ester 6-methyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid

In anhydrous dimethylformamide (DMF, 6 ml) suspended 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (280 mg, 1,561 mmol) and then dropwise added triethylamine (0,65 ml, 4,683 mmol) and acetic anhydride (of 0.44 ml, 4,683 mmol), in this order, and was stirred for approximately 24 hours at 70°C in nitrogen atmosphere. The mixture was concentrated under reduced pressure, was added 20 ml of distilled water and then was extracted with twice 30 ml of methylene chloride. The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (2% MeOH/MC) and received 224 mg (65%) of ester 6-methyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 2.40 a (c, 3H), 2,58 (c, 3H), 3,05 (t, 2H, J=6.0 Hz), 4,51 (t, 2H, J=6.0 Hz), 7,05 (c, 1H).

Example 22

Synthesis of 8-methoxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

In anhydrous dimethylformamide (DMF, 10 ml) suspended 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (324 mg, is 1,809 mmol) and anhydrous potassium carbonate and then was added dropwise itmean (1.13 ml, 18,09 mmol) and was stirred for about 4 hours at 70°C in nitrogen atmosphere. The mixture was concentrated under reduced pressure, was added 50 ml of distilled water and then was extracted six times with 40 ml of 10% MeOH/MC. The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (10% MeOH/MC) and obtained 215 mg (62%) of 8-methoxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid of light yellow color.

1H NMR (300 MHz, DMSO-d6) δ is 2.41 (s, 3H), 2,82 (t, 2H, J=6.0 Hz), 3,42 (c, 3H), 4,29 (t, 2H, J=6.0 Hz), 6,20 (c, 1H).

Example 23

Synthesis of 2,4,6-trimethylaminoethyl

In 20 ml of anhydrous THF was dissolved 2-chloro-4,6-diethylnicotinamide (700 mg, 4,201 mmol) and Pd(PPh3)4(243 mg, 0,210 mmol)was added chloride medicine (2M CH3ZnCl/THF, and 12.6 ml, 25,21 mmol), was heated under reflux for about 40 hours in nitrogen atmosphere. The mixture was added to saturated EDTA solution (50 ml) and was neutralized with potassium carbonate under stirring at 0°C, and the ATEM was extracted with twice 150 ml of methylene chloride. The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (25% EtOAc/hexane) and received 535 mg (87%) 2,4,6-trimethylaminoethyl in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 2,48 (c, 3H), 2,54 (c, 3H), 2,72 (c, 3H), 6,95 (c, 1H).

Example 24

Synthesis of methyl ester (3-cyano-2,6-dimethylpyridin-4-yl)acetic acid

Using the same method as in example 1 was received 592 mg (80%) of the methyl ester (3-cyano-2,6-dimethylpyridin-4-yl)acetic acid in the form of oil is light yellow in color, except that instead of 4-methylnicotinamide used 2,4,6-trimethylaminoethyl (530 mg, 3,625 mmol).

1H NMR (300 MHz, CDCl3) δ 2.57 m (c, 3H), 2,74 (c, 3H), 3.75 to (c, 3H), 3,80 (c, 2 H), 7,06 (s, 1H).

Example 25

Synthesis of 4-(2-hydroxyethyl)-2,6-dimethylpentanenitrile

Using the same method as in example 2, was received 433 mg (87%) of 4-(2-hydroxyethyl)-2,6-dimethylpentanenitrile in the form of a solid white product, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used methyl ether (3-cyano-2,6-dimethylpyridin-4-yl)acetic acid (580 mg, 2,840 mmol).

1H NMR (300 MHz, CDCl3) δ 1,70 (t, 1H, J=5.7 Hz), 2,56 (c, 3H), 2,73 (c, 3H), 3,03 (t, 2H, J=6.3 Hz), of 3.97 (q, 2H, J=6.0 Hz), 7,05 (c, 1H).

The use of the 26

Synthesis of 6,8-dimethyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 3,was received 274 mg (97%) of 6,8-dimethyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 4-(2-hydroxyethyl)-2,6-diethylnicotinamide (280 mg, 1,589 mmol).

1H NMR (300 MHz, CDCl3) δ 2,56 (c, 3H), 2,87 (c, 3H), of 2.97 (t, 2H, J=6.0 Hz), of 4.45 (t, 2H, J=6.0 Hz), 6,92 (c, 1H).

Example 27

Synthesis of 6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it

In 12 ml of anhydrous toluene was dissolved 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (250 mg, the 1.265 mmol) and Pd(PPh3)4(146 mg, to 0.127 mmol)was added dropwise 2-(tributylstannyl)furan (0,80 ml, 2,530 mmol) and then heated to the boil under reflux for about 15 hours under nitrogen atmosphere. Under stirring at 0°C. to the mixture was added 15 ml of 2%aqueous KF solution and 20 ml of distilled water and then was extracted with twice 50 ml of methylene chloride. The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (5% EtOAc/MC) and received 225 mg (78%) of 6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 2.63 in (c, 3H), 3,01 (t, 2H, J=5.7 G is), to 4.52 (t, 2H, J=5.7 Hz), is 6.54 (DD, 1H, J=3,6, 1.8 Hz), 6,97 (c, 1H), 7,12 (DD, 1H, J=3,6, 0.6 Hz), EUR 7.57 (DD, 1H, J=1,8, 0.6 Hz).

Example 28

Synthesis of 6-methyl-8-thiophene-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 27, was received 247 mg (80%) of 6-methyl-8-thiophene-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 2-(tributylstannyl)furan was used 2-(tributylstannyl)thiophene.

1H NMR (300 MHz, CDCl3) δ 2,59 (c, 3H), of 3.00 (t, 2H, J=5.7 Hz), 4,51 (t, 2H, J=5.7 Hz), 6,92 (c, 1H), 7,07 (DD, 1H, J=5,1, 3,9 Hz), was 7.45 (DD, 1H, J=5,1, 1.2 Hz), of 7.70 (DD, 1H, J=3,9, 1.2 Hz).

Example 29

Synthesis of 6-methyl-8-pyridin-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 27, was received 228 mg (75%) of 6-methyl-8-pyridin-2-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 2-(tributylstannyl)furan was used 2-(tributylstannyl)pyridine.

1H NMR (300 MHz, CDCl3) δ 2,66 (c, 3H), 3,05 (t, 2H, J=5.7 Hz), 4,58 (t, 2H, J=5.7 Hz), 7,12 (s,1H), 7,31-7,35 (m, 1H), to 7.67-of 7.70 (m, 1H), 7,80-a 7.85 (m, 1H), 8,62-8,64 (m, 1H).

Example 30

Synthesis of 8-(4-forfinal)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

In 10 ml of anhydrous toluene suspended 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (250 mg, the 1.265 mmol), 4-ftorhinolony acid (265 mg, 1,898 mmol), Pd(PPh3)4(146 mg, to 0.127 mmol) and anhydrous to rbonate potassium (350 mg, 2,530 mmol) and then heated under reflux for about 15 hours under nitrogen atmosphere. Under stirring at 0°C. to the mixture was added 20 ml of a saturated solution of ammonium chloride and 10 ml of distilled water and then was extracted twice with 60 ml of methylene chloride. The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was subjected to chromatography on a column of silica gel (5% EtOAc/MC) and received 135 mg (42%) of 8-(4-forfinal)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid of light yellow color.

1H NMR (300 MHz, CDCl3) δ 2,64 (c, 3H), 3.04 from (t, 2H, J=6.0 Hz), 4,56 (t, 2H, J=6.0 Hz), 7,05 (s,1H), 7,08-7,14 (m, 2H), 7,51-of 7.55 (m, 2H).

Example 31

Synthesis of 8-(4-chlorophenyl)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 30, was received 95 mg (27%) of 8-(4-chlorophenyl)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid of light yellow color, except that instead of 4-forfinal Bronevoy acid used 4-chlorophenyl Bronevoy acid.

1H NMR (300 MHz, CDCl3) δ 2,64 (c, 3H), 3,05 (t, 2 H, J=5.7 Hz), 4,56 (t, 2H, J=5.7 Hz), 7,06 (s,1H), 7,38-7,41 (m, 2H), 7,46 is 7.50 (m, 2H).

Example 32

Synthesis of 6-methyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it

In 8 ml of anhydrous acetonitrile suspended 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]feast the DIN-1-he (250 mg, the 1.265 mmol) and then was added dropwise 1.0 ml of triethylamine and piperidine (0,19 ml, 1,898 mmol), in that order, and heated to boiling under reflux for about 3 hours in nitrogen atmosphere. The mixture was concentrated under reduced pressure, was added 10 ml of a saturated solution of ammonium chloride and 10 ml of distilled water and then was extracted with twice 30 ml of methylene chloride. The obtained organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (10% EtOAc/MC) and received 296 mg (95%) of 6-methyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 1,66 (Sirs, 6H), 2,37 (c, 3H), of 2.86 (t, 2H, J=5.7 Hz), 3,48 (Sirs, 4H), 4,39 (t, 2H, J=5.7 Hz), 6,32 (c, 1H).

Example 33

Synthesis of 6-methyl-8-morpholine-4-yl-3,4-dihydropyrano[3,4-C]pyridine-1-it

Using the same method as in example 32 was received 284 mg (90%) of 6-methyl-8-morpholine-4-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product except that 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-ONU was added morpholine instead of piperidine.

1H NMR (300 MHz, CDCl3) δ 2,39 (c, 3H), 2,90 (t, 2H, J=5.7 Hz), 3,53 (DD, 4H, J=5,1, 4,2 Hz), 3,82 (DD, 4H, 1=5,1, 4,2 Hz)to 4.41 (t, 2H, J=5.7 Hz), 6.42 per (c, 1H).

Example 34

Synthesis of 6-methyl-8-(4-methylpiperazin--yl)-3,4-dihydropyrido[3,4-c]pyridine-1-it

Using the same method as in example 32, received 323 mg (98%) of 6-methyl-8-(4-methylpiperazin-1-yl)-3,4-dihydropyrido[3,4-C] pyridine-1-it is in the form of a solid white product, except that instead of piperidine to 8-chloro-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-ONU was added 1-methylpiperazine.

1H NMR (300 MHz, CDCl3) δ 2,35 (c, 3H), 2,38 (c, 3H), of 2.54 (DD, 4H, J=5,1, 4,8 Hz), is 2.88 (t, 2H, J=5.7 Hz), 3,57 (DD, 4H, J=5,1, 4,8 Hz), and 4.40 (t, 2H, J=5.7 Hz), 6,38 (c, 1H).

Example 35

Synthesis of 8-(4-forgenerating)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

In 5 ml of ethanol was dissolved 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (200 mg, 1,012 mmol) and then were added 4-ftoranila (224,9 mg, 2,024 mmol), and stirred at 80°C during the night. The mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (20% EtOAc/Hexane) and received 250 mg (90%) of 8-(4-forgenerating)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid of light yellow color.

1H NMR (300 MHz, CDCl3) δ 10,37 (c, 1H), 7,73-to 7.68 (m, 2H),? 7.04 baby mortality-6,98 (m, 2H), 6.42 per (c, 1H), 4,50 (t, J=6.0 Hz, 2H), 2,93 (t, J=6.0 Hz, 2H), 2,42 (s, 3H).

Example 36

Synthesis of 6-methyl-8-(4-(pyrimidine-2-yl-piperazin-1-yl)-3,4-dihydropyrido[3,4-c]pyridine-1-it

Using the same method as in example 35 was obtained 170 mg (70%) of 6-methyl-8-(4-(pyrimidine-2-yl-piperazin-1-yl)-3,4-dihydropyrido[3,4-c]pyridine-1-it is in the form of terdag the product is white, except that instead of 4-foranyone to 150 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it was added 1-(2-pyrimidyl)piperazine·2HCl.

1H NMR (300 MHz, CDCl3) δ 8,31 (s, 1H), 8.30 to (c, 1H), 7,02 (d, J=7.2 Hz, 1H), 6.48 in (t, J=4,8 Hz, 1H), 6,41 (s,1H), of 4.44 (t, J=6.0 Hz, 2H), 3,95 (m, 4H), 3,63 (m, 4H), 2.57 m (c, 3H), 3,01 (t, J=6.0 Hz, 2H).

Example 37

Synthesis of 8-(4-chlorpheniramine)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 35, received 342 mg (94%) of 8-(4-chlorpheniramine)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 4-foranyone to 200 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it was added 4-Chloroaniline.

1H NMR (300 MHz, CDCl3) δ 10,45 (s, 1H), 7,74-of 7.70 (m, 2H), 7,28-7,24 (m, 2H), 4,50 (t, J=6.0 Hz, 2H), equal to 2.94 (t, J=6.0 Hz, 2H), 2,46 (c, 3H).

Example 38

Synthesis of 8-(4-triptoreline)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 35 was obtained 130 mg (67%) of 8-(4-triptoreline)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 4-foranyone to 120 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it was added 4-triptorelin.

1H NMR (300 MHz, CDCl3) δ 10,67 (c, 1H), to $ 7.91 (d, J=8.5 Hz, 2H), EUR 7.57 (d, J=8.5 Hz, 2H), 6,51 (c, 1H), 4,51 (t, J=6.3 Hz, 2H), 2,96 (t, J=6.3 Hz, 2H), 2.49 USD (c, 3H).

Example 39

Synthesis of 6-methyl-8-p-tolylamino-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 35, received 188 mg (92%) of 6-methyl-8-p-tolylamino-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid of light yellow color, except that instead of 4-foranyone to 150 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it was added 4-methylaniline.

1H NMR (300 MHz, CDCl3) δ 10,34 (c, 1H), to 7.64 (d, J=8.7 Hz, 2H), 7,13 (d, J=8.7 Hz, 2H), 6,38 (c, 1H), 4,49 (t, J=6.3 Hz, 2H), 2,92 (t, J=6.3 Hz, 2H), 2,44 (c, 3H), 2,32 (c, 3H).

Example 40

Synthesis of 6-methyl-8-phenylamino-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 35, received 145 mg (87%) of 6-methyl-8-phenylamino-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid of light yellow color, except that instead of 4-foranyone to 130 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it was added aniline.

1H NMR (300 MHz, CDCl3) δ 10,44 (s, 1H), 7,79-7,76 (m, 2H), 7,35-7,30 (m, 2H), 7,07-7,01 (m, 1H), 6,41 (c, 1H), 4,49 (t, J=6.0 Hz, 2H), 2,93 (t, J=6.0 Hz, 2H), 2,46 (c, 3H).

Example 41

Synthesis of 6-methyl-8-phenethylamine-3,4-dihydropyrano[3,4-c]pyridine-1-it

Using the same method as in example 35, received 175 mg (61%) of 6-methyl-8-phenethylamine-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, except that instead of 4-foranyone to 200 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it was added phenethylamine.

1H NMR (300 MHz, CDCl3

Example 42

Synthesis of 8-[(benzo[1,3]dioxol-5-ylmethyl)amino]-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 139 mg (74%) of 8-[(benzo[1,3]dioxol-5-ylmethyl)amino]-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 35, except that instead of 4-foronline together with piperidylamine was added 120 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) of 8.47 δ (c, 1H), 6.87 in-6,72 (m, 3H), 6,23 (c, 1H), 5,91 (c, 2H), of 4.66 (d, J=6.0 Hz, 2H), 4,42 (t, J=6.0 Hz, 2H), 2,85 (t, J=6.0 Hz, 2H), 2,38 (c, 3H).

Example 43

Synthesis of 4,6-dimethyl-2-fenilcetonuria

Received 752 mg (100%) of 4,6-dimethyl-2-familycommunity in the form of a yellow oil, using the same method as in example 30, except that instead of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 600 mg of 2-chloro-4,6-diethylnicotinamide and instead of 4-ftorpolimernoj acid used phenylboric acid.

1H NMR (300 MHz, CDCl3) δ 7,87-7,83 (m, 2H), 7,50-of 7.48 (m, 3H), 7,10 (c, 1H), 2.63 in (c, 3H), 2,58 (c, 3H).

Example 44

Synthesis of methyl ester (3-cyano-6-methyl-2-phenylpyridine-4-yl)acetic acid

Received 705 mg (90%) of methyl ester of (3-cyano-6-methyl-2-phenylpyridine-4-yl)acetic acid in the form of a solid about the ukta yellow using the same method as in example 1, except that instead of 4-methylnicotinamide used 618 mg of 4,6-dimethyl-2-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 7,88-a 7.85 (m, 2H), 7,51-7,49 (m, 3H), 7,20 (c, 1H), 3,93 (c, 2H), 3,78 (c, 3H), 2,67 (c, 3H).

Example 45

Synthesis of 4-(2-hydroxyethyl)-6-methyl-2-fenilcetonuria

Received 542 mg (100%) 4-(2-hydroxyethyl)-6-methyl-2-fenilcetonuria in the form of a colorless oil, using the same method as in example 2, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 606 mg methyl ester (3-cyano-6-methyl-2-phenylpyridine-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ a 7.85-of 7.82 (m, 2H), 7,50-of 7.48 (m, 3H), 7,18 (c, 1H), 3,95 (t, J=6.3 Hz, 2H), to 3.09 (t, J=6.3 Hz, 2H), 2,64 (c, 3H).

Example 46

Synthesis of 6-methyl-8-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 380 mg (83%) of 6-methyl-8-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 405 mg of 4-(2-hydroxyethyl)-6-methyl-2-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 7,54-7,52 (m, 2H), 7,42-7,40 (m, 3H),? 7.04 baby mortality (s, 1H), 4,55 (t, J=6.0 Hz, 2H), 3,03 (J=6.0 Hz, 2H), 2.63 in (c, 3H).

Example 47

Synthesis of 4,6-dimethyl-2-Phenoxyethanol

4,6-Dimethyl-2-chloronicotinamide (600 mg, 3.6 mmol) was dissolved in 30 ml of anhydrous THF and then added the trihydrate of peroxide sodium (a 3.06 g, 18,00 mmol), and stirred at 80°C during the night. The mixture was extracted with methylene chloride, dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (10% EtOAc/hexane), and got 730 mg (90%) of 4,6-dimethyl-2-Phenoxyethanol in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 7,39 was 7.36 (m, 2H), 7,22-to 7.15 (m, 3H), 6,80 (c, 1H), 2,52 (c, 3H), 2,35 (c, 3H).

Example 48

Synthesis of methyl ester (3-cyano-6-methyl-2-phenoxypyridine-4-yl)acetic acid

Received 580 mg (83%) of methyl ester of (3-cyano-6-methyl-2-phenoxypyridine-4-yl)acetic acid as a solid yellow product, using the same method as in example 1, except that instead of 4-methylnicotinamide used 556 mg of 4,6-dimethyl-2-Phenoxyethanol.

1H NMR (300 MHz, CDCl3) δ 7,43-7,37 (m, 2H), 7,25-7,16 (m, 3H), 6.90 to (s, 1H), 3,85 (c, 2H), 3,78 (c, 3H), 2,38 (c, 3H).

Example 49

Synthesis of 4-(2-hydroxyethyl)-6-methyl-2-Phenoxyethanol

Received 380 mg (90%) of 4-(2-hydroxyethyl)-6-methyl-2-Phenoxyethanol in the form of a colorless oil, using the same method as in example 2, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 467 mg of methyl ester of (3-cyano-6-methyl-2-phenoxypyridine-4-yl)who kusnoy acid.

1H NMR (300 MHz, CDCl3) δ 7,42-7,37 (m, 2H), 7,25-to 7.15 (m, 3H), 6.89 in (c, 1H), 3,98 (t, J=6.3 Hz, 2H), 3,06 (t, J=6.3 Hz, 2H), 2,37 (c, 3H).

Example 50

Synthesis of 6-methyl-8-phenoxy-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 280 mg (86%) of 6-methyl-8-phenoxy-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 326 mg of 4-(2-hydroxyethyl)-6-methyl-2-Phenoxyethanol.

1H NMR (300 MHz, CDCl3) δ 7,38-7,33 (m, 2H), 7,20-7,14 (m, 3H), 6,74 (c, 1H), 4,47 (t, J=6.0 Hz, 2H), 2,98 (t, J=6.0 Hz, 2H), 2,33 (c, 3H).

Example 51

Synthesis of 8-benzylamino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 313 mg (51%) 8 benzylamino-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-it is in the form of a solid white product, using the same method as in example 32, except that instead of piperidine was added 460 mg of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-she, along with benzylamine.

1H NMR (300 MHz, CDCl3) δ 2,38 (c, 3H), 2,87 (t, 2H, J=6.0 Hz), of 4.44 (t, 2H, J=6.0 Hz), 4,78 (d, 2H, J=5.7 Hz), 6,24 (s, 1H), 7,21-7,39 (m, 5H), 8,55 (Sirs, 1H).

Example 52

Synthesis of 8-(4-methoxybenzylamine)-6-methyl-3,4-dihydropyrano[3,4c]pyridine-1-it

Received of 2.97 g (98%) of 8-(4-methoxybenzylamine)-6-methyl-3,4-dihydropyrano[3,4c]pyridine-1-it is in the form of a solid white product, using the same the manual, as in example 32, except that instead of piperidine was added 2.0 g of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-she, along with 4-methoxybenzylamine.

1H NMR (300 MHz, CDCl3) δ 2,39 (c, 3H), of 2.86 (t, 2H, J=6.0 Hz), 3,79 (c, 3H), 4,43 (t, 2H, J=6.0 Hz), 4,69 (d, 2H, J=5.7 Hz), 6,23 (s, 1H), 6,83-to 6.88 (m, 2H), 7,28-7,33 (m, 2H), 8,48 (Sirs, 1H).

Example 53

Synthesis of 8-amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

8-(4-Methoxybenzylamine)-6-methyl-3,4-dihydropyrano[3,4c]pyridine-1-he (2.7 g, 9,05 mmol) was dissolved in 30 ml of anhydrous methylene chloride and then dropwise added anisole (1.97 ml, 18,10 mmol) and triperoxonane acid (30 ml), in this order, and then was heated to boiling under reflux for about 15 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure, was added 50 ml of distilled water and neutralized by addition of a saturated solution of sodium carbonate, and then extracted with twice 150 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate and filtered. The obtained residue was purified by chromatography on a column of silica gel (5% MeOH/MC) and received 1,53 g (95%) of 8-amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, DMSO-d6) δ 2,28 (c, 3H), 2,87 (t, 2H, J=6.0 Hz), 4,39 (t, 2H, J=6.0 Hz), 6,39 (c, 1H), 7,26 (Sirs, 2H).

Example 54

Synthesis of N-(1-ox is-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-8-yl)ndimethylacetamide

8-Amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (200 g, 1,122 mmol) was dissolved in 6 ml of anhydrous acetonitrile and then dropwise added triethylamine (0.63 ml, 4,490 mmol) and acetic anhydride (0,42 ml, 4,490 mmol), in this order, and then was heated to boiling under reflux for about 20 hours in nitrogen atmosphere. The mixture was concentrated under reduced pressure, was added 15 ml of a saturated solution of sodium carbonate and 15 ml of distilled water and then was extracted twice with 40 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate and filtered. The obtained residue was purified by chromatography on a column of silica gel (5%MeOH/MC) and received 219 mg (89%) of N-(1-oxo-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-8-yl)ndimethylacetamide in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ of 2.46 (s, 3H), 2,54 (c, 3H), of 3.00 (t, 2H, J=6.0 Hz), to 4.52 (t, 2H, J=6.0 Hz), 6.75 in (c, 1H), 10,89 (Sirs, 1H).

Example 55

Synthesis of N-(1-oxo-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-8-yl)benzamide

220 mg (69%) of N-(1-oxo-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-8-yl)benzamide was obtained in the form of a solid white product, using the same method as in example 54, except that instead of acetic anhydride was added together with the anhydride of benzoic acid 200 mg, 8-amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MG IS, CDCl3) δ 2,65 (c, 3H), 3,05 (t, 2H, J=6.0 Hz), of 4.57 (t, 2H, J=6.0 Hz), 6,82 (c, 1H), 7,47-to 7.59 (m, 3H), 8,06-8,10 (m, 2H), 11,98 (Sirs, 1H).

Example 56

Synthesis of 5-iodine-2-methoxy-4,6-dimethylpentanenitrile

2-Methoxy-4,6-diethylnicotinamide (1.0 g, 6,166 mmol) was dissolved in 30 ml of anhydrous methylene chloride and then added 6 ml triperoxonane acid and N-iodosuccinimide (2.2 g, 9,248 mmol), in that order, with stirring at 0°C under nitrogen atmosphere, and then stirred at room temperature for about 4 hours. To the mixture was added 60 ml of a saturated solution of sodium carbonate and 60 ml of a saturated solution of Na2S2O3and then was extracted twice with 80 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate and filtered. The obtained residue was purified by chromatography on a column of silica gel (5% EtOAc/hexane) and got a rate of 1.67 g (94%) 5-iodine-2-methoxy-4,6-dimethylpentanenitrile in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ of 2.64 (s, 3H), 2,75 (c, 3H), 4,01 (s, 3H).

Example 57

Synthesis of 2-methoxy-4,6-dimethyl-5-fenilcetonuria

5-iodine-2-methoxy-4,6-diethylnicotinamide (1.6 g, 5,554 mmol), Pd(PPh3)4(642 mg, 0,555 mmol), phenylboric acid (1,05 g 8,331 mmol) and anhydrous potassium carbonate (1.54 g, is 11.11 mmol) suspended in a mixed solution of 60 ml of anhydrous toluene and 3 ml bezvodno the ethanol and then heated to the boil under reflux for about 72 hours in an atmosphere of nitrogen. The mixture was filtered, added to 100 ml of a saturated solution of ammonium chloride and then extracted with twice 100 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate and then concentrated. The obtained residue was purified by chromatography on a column of silica gel (5% EtOAc/hexane) and was obtained 1.04 g (78%) of 2-methoxy-4,6-dimethyl-5-fenilcetonuria in the form of a solid of light yellow color.

1H NMR (300 MHz, CDCl3) δ 2,18 (c, 3H), 2,22 (c, 3H), 4,06 (c, 3H), 7,08 for 7.12 (m, 2H), 7,37-7,49 (m, 3H).

Example 58

Synthesis of methyl ester (3-cyano-2-methoxy-6-methyl-5-vinylpyridin-4-yl)acetic acid

851 mg (86%) of Methyl ester of (3-cyano-2-methoxy-6-methyl-5-vinylpyridin-4-yl)acetic acid was obtained in the form of a solid of light yellow color, using the same method as in example 1, except that instead of 4-methylnicotinamide used 800 mg of 2-methoxy-4,6-dimethylpentanenitrile.

1H NMR (300 MHz, CDCl3) δ 2,24 (c, 3H), 3,57 (c, 2H), 3,61 (c, 3H), 4,08 (c, 3H), 7,07-7,11 (m, 2H), 7,38-7,46 (m, 3H).

Example 59

Synthesis of 4-(2-hydroxyethyl)-2-methoxy-6-methyl-5-fenilcetonuria

Received 429 mg (68%) of 4-(2-hydroxyethyl)-2-methoxy-6-methyl-5-fenilcetonuria in the form of a solid white product, using the same method as in example 2, except that instead of methyl ester (3-cyano-4-and the)acetic acid was used 700 mg of methyl ester of (3-cyano-2-methoxy-6-methyl-5-vinylpyridin-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 1,36 (shirt, 1H, J=6.3 Hz), 2,20 (c, 3H), and 2.83 (t, 2H, J=6.9 Hz), 3,68 (square, 2H, J=6.9 Hz), 4,06 (c, 3H), 7,12-to 7.15 (m, 2H), 7,40-7,49 (m, 3H).

Example 60

Synthesis of 8-hydroxy-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 442 mg (94%) of 8-hydroxy-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 492 mg of 4-(2-hydroxyethyl)-2-methoxy-6-methyl-5-fenilcetonuria.

1H NMR (300 MHz, DMSO-d6) δ 2,02 (c, 3H), 2,46 (t, 2H, J=6.0 Hz), 4,19 (t, 2H, J=6.0 Hz), 7.24 to 7,27 (m, 2H), 7,37-7,49 (m, 3H), 12,15 (Sirs, 1H).

Example 61

Synthesis of 8-chloro-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 267 mg (89%) of 8-chloro-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 20, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 280 mg 8-hydroxy-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 2,37 (c, 3H), 2,71 (t, 2H, J=5.7 Hz), 4,36 (t, 2H, J=5.7 Hz), 7,13-7,17 (m,2H), 7,43-rate of 7.54 (m, 3H).

Example 62

Synthesis of 6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

8-Chloro-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he (120 mg, 0,438 mmol), palladium acetate (5.0 mg, 0,022 IMO the ü) and sodium acetate (72 mg, 0,877 mmol) suspended in 5 ml of anhydrous methanol and then stirred at room temperature for about 2 hours in hydrogen atmosphere. The mixture was filtered and then concentrated under reduced pressure, was added 15 ml of saturated sodium hydrogen carbonate solution and then was extracted with twice 20 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. The obtained residue was purified by chromatography on a column of silica gel (2% MeOH/MC) and received 101 mg (96%) of 6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 2,41 (c, 3H), 2,71 (t, 2H, J=6.0 Hz), 4,43 (t, 2H, J=6.0 Hz), 7,14-7,20 (m, 2H), 7,41-7,53 (m, 3H), 9,18 (c, 1H).

Example 63

Synthesis of 2-hydroxy-4-methyl-6-fenilcetonuria

1-Benzoyl-acetone (5 g, 30,52 mmol) and cyanoacetamide (2,56 g, 30,52 mmol) was dissolved in 100 ml of anhydrous ethanol was added piperidine (2,598 g, 30,52 mmol)and then stirred for 2 days at 80°C. the Mixture was evaporated under reduced pressure to remove solvent. The obtained solid product was filtered and washed with methanol and water, and then dried with receipt of 4.75 g (73%) of 2-hydroxy-4-methyl-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 7,81-to 7.77 (m, 2H), 7,54-7,51 (m, 3H), 6.73 x (c, 1H), 2,41 (c, 3H).

Example 64

Synthesis of 2-chloro-4-ethyl-6-fenilcetonuria

Received 2.17 g (92%) of 2-chloro-4-methyl-6-fenilcetonuria in the form of a solid brown color, using the same method as in example 20, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 2 g of 2-hydroxy-4-methyl-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 8,04 shed 8.01 (m, 2H), 7.62mm (c, 1H), 7,51-of 7.48 (m, 3H), 2,65 (s, 3H).

Example 65

Synthesis of 4-methyl-6-fenilcetonuria

Received 390 mg (92%) of 4-methyl-6-fenilcetonuria, using the same method as in example 62, except that instead of 8-chloro-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 500 mg of 2-chloro-4-methyl-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ cent to 8.85 (c, 1H), 8,04 shed 8.01 (m, 2H), 7,69 (c, 1H), 7,53-of 7.48 (m, 3H), 2,62 (c, 3H).

Example 66

Synthesis of methyl ester (5-cyano-2-phenylpyridine-4-yl)acetic acid

Received 600 mg (92%) of methyl ester of (5-cyano-2-phenylpyridine-4-yl)acetic acid as a colourless oil, using the same method as in example 1, except that instead of 4-methylnicotinamide used 500 mg of 4-methyl-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 8,92 (c, 1H), 8,06-8,03 (m, 2H), 7,82 (c, 1H), 7,52-to 7.50 (m, 3H), 3,94 (c, 2H), 3,79 (c, 3H).

Example 67

Synthesis of 4-(2-hydroxyethyl)-6-fenilcetonuria

Received 400 mg (90%) of 4-(2-hydroxyethyl)-6-phenyldiamine the Rila in the form of a solid white product using the same method as in example 2, except that instead of methyl ester (3-cyano-4-yl)acetic acid used 500 mg of methyl ester of (5-cyano-2-phenylpyridine-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 8,87 (c, 1H), 8,05-8,02 (m, 2H), to 7.77 (c, 1H), 7,51-7,49 (m, 3H), 3,74 (t, J=6.3 Hz, 2H), 3.15 in (t, J=6.3 Hz, 2H).

Example 68

Synthesis of 6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 286 mg (95%) 6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 300 mg of 4-(2-hydroxyethyl)-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 9,31 (c, 1H), 8.07-a of 8.04 (m, 2H), 7,63 (c, 1H), 7,52-7,49 (m, 3H), 4,60 (t, J=5.7 Hz, 2H), 3,13 (t, J=5.6 Hz, 2H).

Example 69

Synthesis of 2-methoxy-4-methyl-6-fenilcetonuria

2-Chloro-4-methyl-6-familycommunity (455 mg, 1,99 mmol) was dissolved in 20 ml of DME was added 95%sodium methoxide (1.13 g, 19,90 mmol) and then stirred at room temperature for about 1 hour. The mixture was poured into cold water and set pH from about 6 to 7 with 10%HCl and then was extracted with ethyl acetate. The obtained residue was purified by chromatography on a column of silica gel (10% EtOAc/hexane) and received 370 mg (83%) of 2-methoxy-4-methyl-6-fenilcetonuria in the form of a solid product b is the logo color.

1H NMR (300 MHz, CDCl3) δ 8,06-8,03 (m, 2H), of 7.48-7,46 (m, 3H), 7,30 (c, 1H), 4,14 (c, 3H), 2,65 (s, 3H).

Example 70

Synthesis of methyl ester (3-cyano-2-methoxy-6-phenylpyridine-4-yl)acetic acid

Received 770 mg (90%) of methyl ester of (3-cyano-2-methoxy-6-phenylpyridine-4-yl)acetic acid as a colourless oil, using the same method as in example 1, except that instead of 4-methylnicotinamide used 680 mg of 2-methoxy-4-methyl-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 8,06-8,03 (m, 2H), 7,49-7,40 (m, 3H), 7,40 (c, 1H), 4,16 (c, 3H), 3,89 (c, 2H), 3,76 (c, 3H).

Example 71

Synthesis of 4-(2-hydroxyethyl)-2-methoxy-6-fenilcetonuria

Received 414 mg (95%) of 4-(2-hydroxyethyl)-2-methoxy-6-fenilcetonuria in the form of a solid white product, using the same method as in example 2, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 550 mg methyl ether (3-cyano-2-methoxy-6-phenylpyridine-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 8,06-8,03 (m, 2H), of 7.48-7,46 (m, 3H), 7,39 (c, 1H), 4,14 (c, 3H), 4.00 points (t, J=6.0 Hz, 2H), to 3.09 (t, J=6.0 Hz, 2H).

Example 72

Synthesis of 8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 360 mg (95%) of 8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nor is aminonitriles used 400 mg of 4-(2-hydroxyethyl)-2-methoxy-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 7,88-to 7.84 (m, 2H), 7,54-7,51 (m, 3H), 7,17 (c, 1H), 4,39 (t, J=6.0 Hz, 2H), 2,97 (t, J=6.0 Hz, 2H).

Example 73

Synthesis of 8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 230 mg (82%) of 8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 20, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 300 mg of HCl salt of 8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 8,05-8,02 (m, 2H), 7,56 (c, 1H), 7,50-7,47 (m, 3H), 4,50 (t, J=6.0 Hz, 2H), 3,12 (t, J=6.0 Hz, 2H).

Example 74

Synthesis of 2,4-dimethyl-6-fenilcetonuria

The copper bromide (2,56 g, 17,49 mmol) suspended in 20 ml of anhydrous THF was added dropwise to the magnesium bromide (3,0M ether, 11,66 ml, 34,99 mmol) at -78°C and was stirred for about 20 minutes. To a solution in which was dissolved 2-chloro-6-phenyl-4-methylnicotinamide was added dropwise 10 ml of anhydrous THF under the above temperature and then was stirred for about 1 hour at room temperature. To the mixture was added a saturated solution of ammonium hydroxide and set the pH of the solution equal to 10 using 1N. NaOH. Then the solution was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue behaviour is whether chromatography on a column of silica gel (5% EtOAc/hexane) and received 550 mg (55%) of 2,4-dimethyl-6-fenilcetonuria in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 8,03-of 8.00 (m, 2H), 7,50-7,47 (m, 3H), 2,82 (c, 3H), 2,59 (c, 3H).

Example 75

Synthesis of methyl ester (3-cyano-2-methyl-6-phenylpyridine-4-yl)acetic acid

Using the same method as in example 1 was received 610 mg (95%) methyl ether (3-cyano-2-methyl-6-phenylpyridine-4-yl)acetic acid in the form of a solid white product, except that instead of 4-methylnicotinamide used 500 mg of 2,4-dimethyl-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 8,04 shed 8.01 (m, 2H), to 7.61 (c, 1H), 7,50-7,47 (m, 3H), 3,91 (c, 2H), of 3.77 (c, 3H), 2,85 (c, 3H).

Example 76

Synthesis of 4-(2-hydroxyethyl)-2-methyl-6-fenilcetonuria

Using the same method as in example 2, was received 465 mg (95%) of 4-(2-hydroxyethyl)-2-methyl-6-fenilcetonuria in the form of a solid white product, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 550 mg methyl ester (3-cyano-2-methyl-6-phenylpyridine-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 8,04 shed 8.01 (m, 2H), 7,60 (s, 1H), 7,49-7,47 (m, 3H), 3,99 (t, J=6.0 Hz, 2H), 3,12 (t, J=6.0 Hz, 2H), 2,83 (c, 3H).

Example 77

Synthesis of 8-methyl-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 440 mg (99%) 8-methyl-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 3, except that instead of the 4-(2-hydroxyethyl)nicotinanilide used 444 mg of 4-(2-hydroxyethyl)-2-methyl-6-fenilcetonuria.

1H NMR (300 MHz, CDCl3) δ 8.07-a of 8.04 (m, 2H), 7,49-7,47 (m, 3H), 4,50 (t, J=5.7 Hz, 2H), is 3.08 (t, J=5.7 Hz, 2H), 2,97 (c, 3H).

Example 78

Synthesis of 1-oxo-6-phenyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-yl acatalog ether

Received 255 mg (84%) of 1-oxo-6-phenyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-yl acatalog ether in the form of a solid white product, using the same method as in example 21, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 300 mg of 8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she.

1H NMR (300 MHz, CDCl3) δ 8,03-of 8.00 (m, 2H), EUR 7.57 (c, 1H), 7,49-7,46 (m, 3H), 4,53 (t, J=6.0 Hz, 2H), 3,12 (t, J=6.0 Hz, 2H), 2,43 (c, 3H).

Example 79

Synthesis of 8-methoxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

HCl salt of 8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she (300 mg, 1,080 mmol), itmean (3,68 g, 25,92 mmol), silver oxide (936 mg, 4.04 mmol) and calcium sulfate (239,7 mg of 1.76 mmol) was dissolved in 20 ml of anhydrous obretenova solvent and then stirred overnight at room temperature. The mixture was evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (30% EtOAc/hexane) and received 193 mg (70%) of 8-methoxy-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 8,05-8,02 (m, 2H), 7,45-the 7.43 (m, 3H), 7,21 (c, 1H), of 4.44 (t, J=6.0 Hz, 2H), 4,15 (c, 3H), 3,01(t, J=6.0 Hz, 2H).

Example 80

Synthesis of 8-methylamino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 101 mg (45%) 8-methylamino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 35, except that instead of 4-foronline was added 230 mg of 8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she, along with methylamine.

1H NMR (300 MHz, CDCl3) δ 8.17 and (c, 1H), 8,11-of 8.06 (m, 2H), 7,51-7,44 (m, 3H), 6,83 (c, 1H), 4,50 (t, J=6.0 Hz, 2H), 3,18 (d, J=4,8 Hz, 3H), 2,98 (t, J=6.0 Hz, 2H).

Example 81

Synthesis of 8-dimethylamino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 140 mg (99%) 8-dimethylamino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 35, except that instead of 4-foronline added 137 mg of 8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she, along with dimethylamine.

1H NMR (300 MHz, CDCl3) δ 8.07-a with 8.05 (m, 2H), 7,46-7,44 (m, 3H), 6,95 (c, 1H), 4,47 (t, J=6.0 Hz, 2H), 3,18 (s, 6H), 3,01 (t, J=6.0 Hz, 2H).

Example 82

Synthesis of 6-phenyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 127 mg (98%) of 6-phenyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 35, except that instead of 4-foronline was added 110 mg of 8-chloro-6-phenyl-3,4-di is itaperuna[3,4-c]pyridine-1-she, along with piperidine.

1H NMR (300 MHz, CDCl3) δ 8,05 shed 8.01 (m, 2H), 7,45-7,42 (m, 3H), 6,93 (c, 1H), 4,45 (t, J=6.0 Hz, 2H), to 3.58 (m, 4H), 2,98 (t, J=6.0 Hz, 2H), 1.70 to (s, 6H).

Example 83

Synthesis of 8-morpholine-4-yl-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 128 mg (98%) 8-morpholine-4-yl-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 35, except that instead of 4-foronline was added 110 mg of 8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-together with morpholine.

1H NMR (300 MHz, CDCl3) δ 8,03-of 8.00 (m, 2H), 7,46-the 7.43 (m, 3H), 7,02 (c, 1H), 4,45 (t, J=6.0 Hz, 2H), 3,85 (t, J=5.1 Hz, 4H), 3,63 (t, J=5.1 Hz, 4H), to 2.99 (t, J=6.0 Hz, 2H).

Example 84

Synthesis of 6-phenyl-8-pyrrolidin-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 120 mg (97%) of 6-phenyl-8-pyrrolidin-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 35, except that instead of 4-foronline was added 110 mg of 8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she, along with pyrolidine.

1H NMR (300 MHz, CDCl3) δ 8.07-a of 8.04 (m, 2H), 7,45-the 7.43 (m, 3H), 6,93 (c, 1H), 4,46 (t, J=6.0 Hz, 2H), 3,57 (c, 4H), of 3.00 (t, J=6.0 Hz, 2H), 1,99-of 1.95 (m, 4H).

Example 85

Synthesis of 8-(4-forgenerating)-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 134 mg (95%) of 8-(4-forgenerating)-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid product light W is logo color, using the same method as in example 35, except that instead of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she was using 110 mg of 8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 10,42 (c, 1H), 8,04 shed 8.01 (m, 2H), to 7.77-7,72 (m, 2H), 7,49-7,46 (m, 3H), 7,10-7,03 (m, 3H), of 4.57 (t, J=6.0 Hz, 2H), of 3.07 (t, J=6.0 Hz, 2H).

Example 86

Synthesis of 8-(4-methoxybenzylamine)-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 2,03 g (98%) of 8-(4-methoxybenzylamine)-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid product is light yellow in color, using the same method as in example 35, except that instead of 4-foronline was added 1.5 g of 8-chloro-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she, along with 4-methoxybenzylamine.

1H NMR (300 MHz, CDCl3) δ 2,98 (t, 2H, J=6.0 Hz), 3,79 (c, 3H), of 4.49 (t, 2H, J=6.0 Hz), 4,82 (d, 2H, J=5.4 Hz), at 6.84-6.89 in (m, 3H), 7,32-7,37 (m, 2H), 7,42-7,47 (m, 3H), 8,02-with 8.05 (m, 2H), 8,57 (Sirs, 1H).

Example 87

Synthesis of 8-amino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received of 1.30 g (96%) of 8-amino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 53, except that instead of 8-(4-methoxybenzylamine)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 2,03 g of 8-(4-methoxybenzylamine)-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ a 3.01 (t, 2H, J=6.0 Hz), to 4.52 (t, 2H, J=6.0 Hz), 6,91 (c, 1H), 7,44 is 7.50 (m, 3H), 7,95-to 7.99 (m, 2H).

Example 88

Synthesis of N-(1-oxo-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-8-yl)ndimethylacetamide

Received 212 mg (90%) of N-(1-oxo-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-8-yl)ndimethylacetamide in the form of a solid white product, using the same method as in example 54, except that instead of 8-amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 200 mg of 8-amino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 2,60 (c, 3H), of 3.12 (t, 2H, J=6.3 Hz), of 4.57 (t, 2H, J=6.3 Hz), 7,33 (c, 1H), 7,47-7,52 (m, 3H), 8,05-8,10 (m, 2H), 10,99 (Sirs, 1H).

Example 89

Synthesis of N-(1-oxo-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-8-yl)benzamide

Received 260 mg (83%) of N-(1-oxo-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-8-yl)benzamide in the form of a solid white product, using the same method as in example 55, except that instead of 8-amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she was using 220 mg of 8-amino-6-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ and 3.16 (t, 2H, J=6.0 Hz), to 4.62 (t, 2H, J=6.0 Hz), 7,41 (c, 1H), 7,47-to 7.61 (m, 6H), 8,08-to 8.12 (m, 2H), 8,21-of 8.25 (m,2H), 12,02 (Sirs, 1H).

Example 90

Synthesis of 2,6-dichloro-4-methylnicotinamide

To 2,6-dihydroxy-4-methylnicotinamide (6 g, 39,96 mmol) and benzyltriethylammonium chloride (18,20 g, 79,92 mmol) was added phosphorus oxychloride (30.63 per g, 199,8 mmol) and premesis is whether over night at 120°C. The mixture was slowly poured into cold water and the resulting solid product was filtered to obtain only 6.64 g (89%) of 2,6-dichloro-4-methylnicotinamide.

1H NMR (300 MHz, CDCl3) δ 7.29 trend (c, 1H), 2,59 (c, 3H).

Example 91

Synthesis of 2-chloro-6-methoxy-4-methylnicotinamide

2,6-Dichloro-4-methylnicotinamide (3,70 g, 19,83 mmol) was dissolved in 30 ml of methanol, was added to 4.28 ml of methanol containing 25% sodium methoxide, and then was stirred for about 3 hours at room temperature. The mixture was poured into cold water, set pH 6 to 7 with 10% HCl and was extracted using methylene chloride. The extract was dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Was carried out by chromatography on a column of silica gel (10% EtOAc/hexane) and was obtained 1.8 g (50%) of 2-chloro-6-methoxy-4-methylnicotinamide in the form of a solid of light yellow color.

1H NMR (300 MHz, CDCl3) δ 7,42 (c, 1H), 4,29 (c, 3H), 2,60 (c, 3H).

Example 92

Synthesis of 6-methoxy-2,4-dimethylpentanenitrile

Received 266 mg (60%) of 6-methoxy-2,4-dimethylpentanenitrile in the form of a solid white product, using the same method as in example 74, except that instead of 2-chloro-6-phenyl-4-methylnicotinamide used 500 mg of 2-chloro-6-methoxy-4-methylnicotinamide.

1H NMR (300 MHz, CDCl3) δ 6,47 (c, 1H), 3,94 (c, 3H), 2,64 (c, 3H), 2,4 (, 3H).

Example 93

Synthesis of methyl ester (3-cyano-6-methoxy-2-methylpyridin-4-yl)acetic acid

Received 1.0 g (93%) of methyl ester of (3-cyano-6-methoxy-2-methylpyridin-4-yl)acetic acid in the form of a solid white product, using the same method as in example 1, except that instead of 4-methylnicotinamide used 786 mg of 6-methoxy-2,4-dimethylpentanenitrile.

1H NMR (300 MHz, CDCl3) δ 6,58 (c, 1H), 3.96 points (c, 3H), 3,76 (c, 2H), 3.75 to (c, 3H), 2,67 (c, 3H).

Example 94

Synthesis of 4-(2-hydroxyethyl)-6-methoxy-2-methylnicotinamide

Received 862 mg (98%) of 4-(2-hydroxyethyl)-6-methoxy-2-methylnicotinamide in the form of a colorless oil, using the same method as in example 2, except that instead of methyl ester (3-cyano-4-yl)acetic acid used 1 g methyl ester (3-cyano-6-methoxy-2-methylpyridin-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 6,58 (c, 1H), 3,94 (c, 3H), of 3.97 (t, J=6.0 Hz, 2H), to 3.09 (t, J=6.0 Hz, 2H), 2,64 (c, 3H).

Example 95

Synthesis of the HCl salt of 6-hydroxy-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 1,17 g (100%) of the HCl salt of 6-hydroxy-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 860 mg of 4-(2-hydroxyethyl)-6-methoxy-2-methylnicotinamide.

1H the Mr (300 MHz, CDCl3) δ 7,14 (c, 1H), 4,50 (t, J=6.0 Hz, 2H), 3,00 (t, J=6.0 Hz, 2H), 2,87 (c, 3H).

Example 96

Synthesis of 6-chloro-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 196 mg (89%) of 6-chloro-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it, using the same method as in example 20, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 200 mg of 6-hydroxy-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 7,12 (c, 1H), 4,46 (t, J=6.0 Hz, 2H), 3,01 (t, J=6.0 Hz, 2H), 2,86 (c, 3H).

Example 97

Synthesis of 8-methyl-6-(thiophene-2-yl)-3,4-dihydropyrido[3,4-c]pyridine-1-it

2-(Tributylstannyl)thiophene (940 mg, 2,52 mmol) was added dropwise to the toluene solution of 6-chloro-8-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-she (250 mg, of 1.26 mmol) and Pd(PPh3)4(146 mg, 0.13 mmol) and then stirred overnight at 100°C. the Solution was cooled to room temperature, was added 15 ml of 0,4M solution of KF and then were extracted with methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (33% EtOAC/hexane) and received 298 mg (96%) of 8-methyl-6-(thiophene-2-yl)-3,4-dihydropyrido[3,4-c]pyridine-1-it is in the form of a solid yellow color.

1H NMR (300 MHz, CDCl3) δ to 7.68 (DD, J=1.1 Hz), 3.75 Hz, 1H), 7,49 DD, J=1.1 Hz, 3,75, 1H), was 7.36 (c, 1H), 7,14 (DD, J=3,9 Hz, 5.1 Hz, 1H), 4,48 (t, J=6.0 Hz, 2H), 3.04 from (t, J=5,9 Hz, 2H), 2.91 in (c, 3H).

Example 98

Synthesis of 6-(furan-2-yl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 251 mg (87%) 6-(furan-2-yl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid pink color, using the same method as in example 97 except that instead of 2-(tributylstannyl)of thiophene was added 6-chloro-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (250 mg, of 1.26 mmol) with 2-(tributylstannyl)furan.

1H NMR (300 MHz, CDCl3) δ 7,58 (d, J=0.9 Hz, 1H), 7,42 (c, 1H), 7.23 percent (d, J=3.3 Hz, 1H), 6,57 (kV, J=1.8 Hz, 1H), 4,48 (t, J=6.0 Hz, 2H), 3,05 (t, J=5,9 Hz, 2H), 2,92 (c, 1H).

Example 99

Synthesis of 6-(benzo[d][1,3]dioxol-6-yl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

To the orange solution of 6-chloro-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she (250 mg, of 1.26 mmol) and Fe(acac)3(22 mg, 0.06 mmol) in a mixture of THF/NMP (6 ml/0.6 ml) was slowly added 3,4-(methylendioxy)phenylboronic magnesium (1M solution in a mixture of toluene/THF = 1/1, 2.5 ml, 2.5 mmol) and then stirred at room temperature for 10 minutes. The above mixture was added dropwise 50 ml of a saturated solution of ammonium chloride was added 20 ml of water and then was extracted with 100 ml of ethyl acetate. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated under reduced Yes the tion. The obtained residue was purified by chromatography on a column of silica gel (33% EtOAC/hexane) and received 214 mg (59%) of 6-(benzo[d][1,3]dioxol-6-yl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it, and recrystallized from a mixture of MC/ether to obtain 116 mg of the same product in the form of white powder.

1H NMR (300 MHz, CDCl3) δ to 7.61 (s,1H), 7,58 (d, J=1.8 Hz, 1H), 6,91 (d, J=8.7 Hz, 1H), 6,04 (c, 2H), 4,49 (t, J=5.7 Hz, 2H), 3,36 (t, J=5.7 Hz, 2H), 2,94 (c, 3H).

Example 100: Synthesis of 6-(4-(dimethylamino)phenyl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

160 mg (45%) of 6-(4-(dimethylamino)phenyl)-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he was received in the form of a solid of light yellow color, using the same method as in example 99, except that instead of 3,4-(methylendioxy)panelbased magnesium was added 6-chloro-8-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-he (250 mg, of 1.26 mmol) with 4-(N,N-dimethyl)aniline magnesium bromide.

1H NMR (300 MHz, CDCl3) δ 8,00-8,03 (m, 2H), 7,34 (s, 1H), 6,76-6,79 (m, 2H), 4,47 (t, J=5.7 Hz, 2H), 3,01 was 3.05 (m, 8H), 2,93 (c, 3H).

Example 101

Synthesis of 2-methoxy-4-methyl-6-propylnitrosamine

In transparent red color solution of 6-chloro-2-methoxy-4-methylnicotinamide (2.00 g, 11.0 mmol) and Fe(acac)3(387 mg, 1.1 mmol) in a mixture of THF/NMP(50 ml/5 ml) was slowly added 11 ml of n-propyl bromide magnesium (2M solution in diethyl ether) and then was stirred for about 20 minutes. The mixture was then added 1 ml of 1M HCl solution and diluted with 300 ml of ethyl acetate. The obtained organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then filtered. Was carried out by chromatography on a column of silica gel (10% EtOAc/hexane), the filtrate obtained when the concentration of the above residue under reduced pressure, and received of 2.23 g (88%) 2-methoxy-4-methyl-6-propylnitrosamine in the form of a colorless oil.

1H NMR (300 MHz, CDCl3) δ 6,77 (s, 1H), 4,01 (s,3H), 2,77 (t, J=7.5 Hz, 2H), 2,46 (c, 3H), 1,80-of 1.73 (m, 2H), 0,99 (t, J=7.5 Hz, 3H).

Example 102

Synthesis of methyl ester (3-cyano-2-methoxy-6-propylpyridine-4-yl)acetic acid

Was obtained 2.2 g (89%) of methyl ester of (3-cyano-2-methoxy-6-propylpyridine-4-yl)acetic acid as a colourless oil, using the same method as in example 1, except that instead of 4-methylnicotinamide used to 1.9 g of 2-methoxy-4-methyl-6-propylnitrosamine.

1H NMR (300 MHz, CDCl3) δ 6,79 (c, 1H), 4,03 (c, 3H), 3,79 (s, 2H), 3,74 (c, 3H), 2,69 (t, J=7.5 Hz, 2H), 1.77 in-1,72 (m, 2H), of 0.96 (t, J=7.5 Hz, 3H).

Example 103

Synthesis of 4-(2-hydroxyethyl)-2-methoxy-6-propylnitrosamine

Received 1.8 g (94%) of 4-(2-hydroxyethyl)-2-methoxy-6-propylnitrosamine in the form of a colorless oil, using the same method as in example 2, except that instead of methyl ester (5-cyano-4-yl)acetic acid was used 2.15 g IU the silt ether (3-cyano-2-methoxy-6-propylpyridine-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 6.75 in (c, 1H), was 4.02 (c, 3H), of 3.95 (t, J=6.6 Hz, 2H), 3,00 (t, J=6.6 Hz, 2H), 2,68 (t, J=7.2 Hz, 2H), 1,78-1,71 (m, 2H), of 0.96 (t, J=7.2 Hz, 2H).

Example 104

Synthesis of the HCl salt of 8-hydroxy-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-she and HCl salt of 6-hydroxy-8-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received the HCl salt of 8-hydroxy-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-she and HCl salt of 6-hydroxy-8-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-she, 1.8 g (90%) and 1.7 g (85%), respectively, in the form of a solid white product, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide, respectively, used 1.8 g of 4-(2-hydroxyethyl)-2-methoxy-6-propylnitrosamine and 4-(2-hydroxyethyl)-6-methoxy-2-propenolatomethyl.

1H NMR (300 MHz, CDCl3) δ 7,01 (c, 1H), 4,48 (t, J=6.0 Hz, 2H), 3,03 (t, J=6.0 Hz, 2H), 2,77 (t, J=7.2 Hz, 2H), 1,81 to 1.76 (m, 2H), of 0.96 (t, J=7.2 Hz, 3H).

1H NMR (300 MHz, CDCl3) δ 7,08 (c, 1H), 4,46 (t, J=6.0 Hz, 2H), 3,20-3,14 (m, 2H), 3,01 (t,J=6.0 HzJ2H), 1.77 in was 1.69 (m, 2H), 0,99 (t, J=7.5 Hz, 3H).

Example 105

Synthesis of 8-chloro-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it 8-propyl-6-chloro-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 8-chloro-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-he and 8-propyl-6-chloro-3,4-dihydropyrano[3,4-c]pyridine-1-he, 450 mg (97%) and 400 mg (86%), respectively, in the form of a solid white product, using the same method as in the example except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-it, respectively, used 500 mg of HCl salt of 8-hydroxy-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-she and HCl salt of 6-hydroxy-8-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 7,00 (c, 1H), 4,48 (t, J=6.0 Hz, 2H), 3.04 from (t, J=6, 2H), 2,77 (t, J=7.2 Hz, 2H), 1,80-of 1.73 (m, 2H), and 0.98 (t, J=7.2 Hz, 3H).

1H NMR (300 MHz, CDCl3) δ to 7.09 (s,1H), of 4.44 (t, J=6.0 Hz, 2H), 3,17 (t, J=7.2 Hz, 2H), 3,00 (t, J=6.0 Hz, 2H), 1.77 in-1,72 (m, 2H), 0,99 (t, J=7.2 Hz, 3H).

Example 106

Synthesis of 8-morpholine-4-yl-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 367 mg (90%) 8-morpholine-4-yl-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 35, except that instead of 4-foronline was added 300 mg of 8-chloro-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-she, along with morpholine.

1H NMR (300 MHz, CDCl3) δ 7,02 (c, 1H), 4,49 (t, J=6.0 Hz, 2H), 3,88 (t, J=5.4 Hz, 4H), to 3.64 (t, J=5.4 Hz, 4H), 3,05 (t, J=6.2 Hz, 2H), 2,77 (t, J=7.2 Hz, 2H), 1,80-of 1.73 (m, 2H), and 0.98 (t, J=7.2 Hz, 3H).

Example 107

Synthesis of ester 1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid

Received 500 mg (87%) of the ester of 1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid in the form of a solid white product, using the same method as in example 21, except that instead of 4-ftoranila-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 564 mg of HCl salt of 8-hydroxy-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 7,02 (c, 1H), 4,51 (t, J=6.0 Hz, 2H), 3,05 (t, J=6.0 Hz, 2H), 2,77 (t, J=7.5 Hz, 2H), 2,74 (c, 3H), 1,80-of 1.73 (m, 2H), and 0.98 (t, J=7.5 Hz, 3H).

Example 108

Synthesis of 8-(4-methoxybenzylamine)-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 450 mg of 8-(4-methoxybenzylamine)-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a colorless oil, using the same method as in example 32, except that instead of piperidine was added 335 mg of 8-chloro-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-she, along with 4-methoxybenzylamine.

1H NMR (300 MHz, CDCl3) δ 8,50 (c, 1H), 7,33-7,28 (m, 2H), 6,88-6,83 (m, 2H), 7,01 (c, 1H), 4,69 (d, J=5.7 Hz, 2H), 4,50 (t, J=6.0 Hz, 2H), 3,05 (t, J=6.0 Hz, 2H), 2,77 (t, J=7.5 Hz, 2H), 1,80-of 1.73 (m, 2H), and 0.98 (t, J=7.5 Hz, 3H).

Example 109

Synthesis of 8-amino-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 200 mg (80%) of 8-amino-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 53, except that instead of 8-(4-methoxybenzylamine)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 400 mg of 8-(4-methoxybenzylamine)-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 7,02 (c, 1H), to 4.52 (t, J=6.0 Hz, 2H), 3,05 (t, J=6.0 Hz, 2H), 2,77 (t, J=7.5 Hz, 2H), 1,80-of 1.73 (m, 2H), 0,97 (t, J=7.5 Hz, 3H).

Example 110

Synthesis of N-(1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-yl)ndimethylacetamide

Was obtained 220 mg(92%) of N-(1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-yl)ndimethylacetamide in the form of a solid white product using the same method as in example 54, except that instead of 8-amino-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 200 mg of 8-amino-6-propyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 10,9 (c, 1H), 7,00 (c, 1H), 4,50 (t, J=6.0 Hz, 2H), 3.04 from (t, J=2 Hz, 2H), 2,77 (t, J=7.5 Hz, 2H), 2,60 (s, 3H), 1,81-of 1.74 (m, 2H), 0,99 (t, J=7.5 Hz, 3H).

Example 111

Synthesis of 4-(2-methoxyethyl)quinoline-3-carbonitrile

4-Methylinosine-3-carbonitrile (600 mg, 3,567 mmol) was dissolved in 10 ml of anhydrous THF, was added LHMDS (1M solution in THF, 3.9 ml, 3,924 mmol) at -78°C under nitrogen atmosphere and then was stirred for about 1 hour at the same temperature. To the mixture was added dropwise chloromethylation ether (0,30 ml, 3,924 mmol), and then was stirred for about 1 hour at -50°C, and then for about 1 hour at 0°C. To the above mixture under stirring at 0°C was added 5 ml of a saturated solution of ammonium chloride and 10 ml of distilled water and then was extracted twice with 50 ml EtOAc. The obtained organic layer was washed with a saturated solution of sodium chloride, dried on anhydrous sodium sulfate and filtered. Was carried out by chromatography on a column of silica gel (30% EtOAc/hexane), the filtrate obtained when the concentration of the above residue under reduced pressure, and got 305 mg (40%) of 4-(2-methoxyethyl)quinoline-3-carbonitrile in the form of a solid product is velo yellow color.

1H NMR (300 MHz, CDCl3) δ to 3.34 (s, 3H), 3,62 (t, 2H, J=6.6 Hz), of 3.78 (t, 2H, J=6.6 Hz), to 7.67-7,73 (m, 1H), 7,84-7,89 (m, 1H), 8,15-8,19 (m, 2H), 8,98 (c, 1H).

Example 112

Synthesis of 3,4-dihydro-2-oxa-9-Aza-phenanthrene-1-it

4-(2-Methoxyethyl)quinoline-3-carbonitrile (250 mg, 1,178 mmol) was dissolved in 10 ml of concentrated HCl and heated to boiling under reflux for about 15 hours. The mixture was concentrated under reduced pressure, was dissolved in 10 ml of distilled water, neutralized with a saturated solution of sodium bicarbonate and was extracted with twice 50 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. Was carried out by chromatography on a column of silica gel (3% MeOH/MC) of the filtrate obtained when the concentration of the above residue under reduced pressure, and received 216 mg (92%) of 3,4-dihydro-2-oxa-9-Aza-phenanthrene-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) δ 3,49 (t, 2H, J=6.3 Hz), to 4.73 (t, 2H, J=6.3 Hz), 7.68 per-7,74 (m, 1H), 7,86-a 7.92 (m, 1H), 8,03 (d, 1H, J=8.1 Hz), 8,21 (d, 1H, J=8.1 Hz), 9,48 (c, 1H).

Example 113

Synthesis of 3,4-dihydropyrano[3,4-c]pyridine-1-thione

3,4-Dihydropyrano[3,4-c]pyridine-1-he (250 mg, 1,676 mmol) was dissolved in anhydrous toluene, was added a reagent Lawesson (Lawesson) and was stirred over night at room temperature (420 mg, 1,005 mmol). The mixture was evaporated p. and reduced pressure, and the obtained residue was purified by chromatography on a column of silica gel (70% EtOAc/hexane) and received 200 mg (72%) of 3,4-dihydropyrano[3,4-c]pyridine-1-thione in the form of a solid yellow color.

1H NMR (300 MHz, CDCl3) δ 9,50 (s, 1H), 8,68 (d, J=4,8 Hz, 1H), 7,15 (d, J=4,8 Hz, 1H), 4,60 (t, J=6.3 Hz, 2H), is 3.08 (t, J=6.3 Hz, 2H).

Example 114

Synthesis of 4-(2-hydroxyethyl)-N-(4-methoxybenzyl)nicotinamide

3,4-Dihydropyrano[3,4-C]pyridine-1-he (1/5 g, 10,06 mmol) was dissolved in 40 ml of anhydrous THF was added dropwise 4-methoxybenzylamine (13 ml, 100,56 mmol) and then heated to the boil under reflux for about 45 hours in nitrogen atmosphere. The mixture, under stirring at 0 neutralized by addition of 1N. HCl and was extracted with three times 100 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (7% Meon/MS) and received 2.24 g (78%) of 4-(2-hydroxyethyl)-N-(4-methoxybenzyl) nicotinamide as a colorless oil.

1H NMR (300 MHz, DMSO-d6) δ 2,87 (t, 2H, J=6, 6 Hz), 3,62 (Shir. t, 2H, J=6.6 Hz), 3,74 (s, 3H), and 4.40 (d, 2H, J=5.7 Hz), 4,84 (Shir. s, 1H), 6,88-6,92 (m, 2H), 7.24 to 7,29 (m, 2H), 7,34 (d, 1H, J=5,l Hz)and 8.50 (d, 1H, J=5,l Hz), 8,51 (s, 1H), 9,03 (Shir. t, 1H, J=5.7 Hz).

Example 115

Synthesis of 2-(4-methoxybenzyl)-3,4-dihydro-2H-[2,7]naphthiridine-1-it 4-(2-Hydroxyethyl)-N-(4-methoxybenzyl)nicotinamide (2.2 g, ,683 mmol) and triphenylphosphine (4,03 g, shed 15.37 mmol) was dissolved in 50 ml of anhydrous THF. To the mixture, under stirring at 0 C in an atmosphere of nitrogen was added dropwise diethylazodicarboxylate (1,4 ml, 9,220 mmol) and was stirred for about 1 hour at room temperature. The mixture was then concentrated under reduced pressure, and the obtained residue was purified by chromatography on a column of silica gel (3% Meon/MS) and received 1.88 g (91%) of 2-(4-methoxybenzyl)-3,4-dihydro-2H-[2,7]naphthiridine-1-it is in the form of a solid white color.

1H NMR (300 MHz, CDCl3) δ of 2.92 (t, 2H, J=6, 6 Hz), 3,49 (t, 2H, J=6.6 Hz), 3,80 (s, 3H), 4.72 in (s, 2H), 6,85-of 6.90 (m, 2H), 7,10 (d, 1H, J=5,1 Hz), 7.24 to 7,29 (m, 2H), 8,61 (d, 1H, J=5,1 Hz), 9,27 (c, 1H).

Example 116

Synthesis of 3,4-dihydro-2H-[2,7]naphthiridine-1-it

2-(4-Methoxybenzyl)-3,4-dihydro-2H-[2,7]naphthiridine-1-he (1.63 g, 6,075 mmol) suspended in 30 ml of anhydrous toluene, was added monohydrate p-toluensulfonate acid (4,62 g, 24,30 mmol) and was heated to boiling under reflux for about 6 hours in nitrogen atmosphere. The mixture, under stirring at 0°C, neutralized by addition of a saturated solution of sodium carbonate and was extracted seven times with 150 ml of 15% MeOH/MC. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. The obtained residue was purified by chromatography on a column of silica gel (7% MeOH/MC) and received 550 mg (61%) of 3,4-dihydro-2H-[2,7]naphthiridine-one in a solid white color.

1H NMR (300 MHz, CDCl3) δ of 2.93 (t, 2H, J=6.6 Hz), 3,38-of 3.43 (m, 2H), 7,35 (d, 1H, J=5,1 Hz), 8,08 (Sirs, 1H), 8,59 (d, 1H, J=5,1 Hz), 8,90 (c, 1H).

Example 117

Synthesis of 2-benzyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it

193 mg (52%) of 2-benzyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it has received in the form of a colorless oil, using the same method as in example 2, except that instead of 2H-[2,7]naphthiridine-1-she used 3,4-dihydro-2H-[2,7]naphthiridine-1-he (230 mg, 1,552 mmol).

1H NMR (300 MHz, CDCl3) δ equal to 2.94 (t, 2H, J=6.6 Hz), 3,52 (t, 2H, J=6.6 Hz), 4,79 (c, 2H), 7,11 (d, 1H, J=5,1 Hz), 7,27 was 7.36 (m, 5H), to 8.62 (d, 1H, J=5,1 Hz), 9.28 are (c, 1H).

Example 118

Synthesis of 4-(2-hydroxy-2-phenylethyl)nicotinanilide

4-Methylnicotinamide (2.0 g, 16,93 mmol) was dissolved in 20 ml of anhydrous THF (20 ml)was added LHMDS (1M solution in THF, 34 ml, 33,86 mmol) at -78°C under nitrogen atmosphere and then was stirred for about 1 hour at the same temperature. To the mixture was added dropwise benzaldehyde (2.1 ml, 20,32 mmol) and stirred at -50°C for about 1 hour. To the mixture, under stirring at 0°C, was added 30 ml of a saturated solution of ammonium chloride and 50 ml of distilled water and then was extracted twice with 100 ml of EtOAc. The obtained organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column with what likehell (2% MeOH/MC), and received of 3.46 g (91%) of 4-(2-hydroxy-2-phenylethyl)nicotinanilide in the form of a solid of light yellow color.

1H NMR (300 MHz, CDCl3) δ of 2.16 (d, 1H, J=3.3 Hz), 3,22-3,24 (m, 2H), 5,03-5,08 (m, 1H), 7,29 (d, 1H, J=5.4 Hz), 7,32-7,38 (m, 5H), 8,64 (d, 1H, J=5.4 Hz), 8,80 (c, 1H).

Example 119

Synthesis of 4-styrylnicotinic

4-(2-Hydroxy-2-phenylethyl)nicotinamide (2.0 g, of 8.92 mmol) was dissolved in KOH (1M solution in MeOH, 36 ml, 35,67 mmol) and then stirred at room temperature for about 4 hours in nitrogen atmosphere. To the mixture was added 100 ml of distilled water and was extracted with twice 150 ml of methylene chloride. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. The obtained residue was purified by chromatography on a column of silica gel (10% MeOH/MC) and received 1.66 g (83%) of 4-styrylnicotinic in the form of a solid white product.

1H NMR (300 MHz, DMSO-d6) δ 7,33-of 7.60 (m, 7H), 7,68 (Sirs, 1H), 7,82 (d, 1H, J=5.4 Hz), 8,10 (Sirs, 1H), 8,59 (d, 1H, J=5.4 Hz), 8,62 (c, 1H).

Example 120

Synthesis of 3-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she (a) and 3-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it (b)

Sterilisation (1.2 g, to 5.35 mmol) was dissolved in 10 ml of phosphoric acid and then stirred at 120°C for about 8 hours. The mixture was poured into 200 ml of distilled water, neutralized by addition of a saturated solution of sodium carbonate, with stirring at 0°C, and then was extracted with twice 200 ml of methylene chloride. The organic with the Oh was dried with anhydrous sodium sulfate, was filtered and then concentrated. The obtained residue was purified by chromatography on a column of silica gel (5% MeOH/MC) and received 408 mg (34%) of 3-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-she (a) and 160 mg (13%) 3-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it (b), respectively, in the form of a solid white product.

3-phenyl-3,4-dihydropyrano[3,4-c]pyridine-1-he:

1H NMR (300 MHz, CDCl3) δ 3,13 is 3.40 (m, 2H), 5,57-5,62 (m, 1H), 7,25 (d, 1H, J=5,1 Hz), 7,37-7,49 (m, 5H), 8,76 (dJ1H, J=5,1 Hz), 9,31 (c, 1H).

3-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he:

1H NMR (300 MHz, CDCl3) δ 3,10-3,26 (m, 2H), 4,86 to 4.92 (m, 1H), 6,06 (Sirs, 1H), 7,14 (d, 1H, J=5,1 Hz), 7,34 was 7.45 (m, 5H), 8,66 (d, 1H, J=5,1 Hz), 9,26 (c, 1H).

Example 121

Synthesis of 2H-[2,7]naphthiridine-1-it

4-Methylnicotinamide (2.0 g, 16,93 mmol) was dissolved in 20 ml of anhydrous DMF, was added dropwise N,N-dimethylformamide, dimethylacetal (4,5 ml, 33,86 mmol) and then stirred at 120°C in nitrogen atmosphere for about 2 hours. The mixture was concentrated under reduced pressure, was added to distilled water and then was extracted twice with 100 ml of EtOAc. The obtained organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and then concentrated. The concentrated residue was dissolved in a mixed solution of 10 ml of acetic acid and 10 ml of sulfuric acid and stirred at 110°C for about 1 hour. The mixture was then cooled is about room temperature, was poured into 200 ml of distilled water and neutralized by slowly adding the potassium carbonate with stirring at 0°C. Then was extracted 6 times with 150 ml of 20% MeOH/MC. The obtained organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on a column of silica gel (10% MeOH/MC) and received 1,49 g (60%) 2H-[2,7]naphthiridine-1-it is in the form of a solid of light yellow color.

1H NMR (300 MHz, DMSO-d6) δ 6,55 (d, 1H, J=7,2 Hz), the 7.43 (d, 1H, J=7,2 Hz), EUR 7.57 (d, 1H, J=5.4 Hz), 8,69 (d, 1H, J=5.4 Hz), of 9.30 (c, 1H), 11,59 (Sirs, 1H).

Example 122

Synthesis of 2-benzyl-2H-[2,7]naphthiridine-1-it

2H-[2,7]Naphthiridine-1-he (200 mg, 1,368 mmol) suspended in 6 ml of anhydrous DMF was added NaH (60% dispersion in mineral oil, 82 mg, 2,053 mmol) under stirring at 0°C under nitrogen atmosphere. The mixture was cooled to room temperature for about 2 hours, was added dropwise benzylchloride (0,19 ml, 1,642 mmol) at 0°C and then stirred at room temperature for about 2 hours. To the mixture was added 5 ml of a saturated solution of ammonium chloride and 5 ml of distilled water under stirring at 0°C, and was extracted twice with 30 ml EtOAc. The obtained organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate, filtered and then concentrated. Received the same the way the residue was subjected to chromatography on a column of silica gel (5% MeOH/MC) and got 288 mg (89%) of 2-benzyl-2H-[2,7]naphthiridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, CDCl3) ∆ 5,22 (c, 2H), 6.42 per (d, 1H, J=7,2 Hz), 7,26-7,39 (m, 7 H), 8,72 (d, 1H, J=5,1 Hz), 9,65 (c, 1H).

Example 123

Synthesis of 8-methyl-6-methyl-2H-[2,7]naphthiridine-1-it

Received 1,91 g (56%) of 8-methyl-6-phenyl-2H-[2,7]naphthiridine-1-it is in the form of a solid of light yellow color, using the same method as in example 121, except that instead of 4-methylnicotinamide used 2,4-dimethyl-6-familycommunity (3,01 g, accounted for 14.45 mmol).

1H NMR (300 MHz, DMSO-d6) δ 3,02 (c, 3H), 6,53 (d, 1H, J=6.9 Hz), was 7.36 (d, 1H, J=6.9 Hz), 7,44-of 7.55 (m, 3H), 7,98 (c, 1H), 8,16-to 8.20 (m, 2H), 11,35 (Sirs, 1H).

Example 124

Synthesis of 8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it

8-Methyl-6-phenyl-2H-[2,7]naphthiridine-1-he (500 mg, 2,116 mmol) suspended in anhydrous ethanol, was added 5% Pd/C (400 mg) and then stirred at room temperature in a hydrogen atmosphere for about 72 hours. The mixture was filtered and then concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (2% MeOH/MC) and received 462 mg (92%) of 8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it is in the form of a solid white product.

1H NMR (300 MHz, DMSO-d6) δ and 2.83 (s, 3H), 2.95 and (t, 2H, J=6.3 Hz), 3,31-3,70 (m, 2H), 7,43-rate of 7.54 (m, 3H), 7,79 (c, 1H), 8,01 (Sirs, 1H), 8,11-to 8.14 (m, 2H).

Example 125

Synthesis of 2,8-dimethyl-6-phenyl-2H-[2,7]naphthiridine-1-it

Received 320 mg (86%) 2,8-dimethyl-6-phenyl-2H-[2,7]NAF is iridin-1-he 320 mg (86%) as a solid light-yellow using the same method as in example 122 except that instead of 2H-[2,7]naphthiridine-1-she benzylchloride used 8-methyl-6-phenyl-2H-[2,7]naphthiridine-1-he (350 mg, 1,481 mmol) and itmean (of 0.11 ml, 1,777 mmol).

1H NMR (300 MHz, CDCl3) δ 3,20 (c, 3H), to 3.58 (c, 3H), 6.42 per (d, 1H, J=7,2 Hz), 7,24 (d, 1H, J=7,2 Hz), 7,41-7,52 (m, 3H), EUR 7.57 (c, 1H), 8,08-to 8.12 (m, 2H).

Example 126

Synthesis of 2,8-dimethyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it

Received 195 mg (87%) 2,8-dimethyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it is in the form of a solid white product, using the same method as in example 124, except that instead of 8-methyl-6-phenyl-2H-[2,7]naphthiridine-1-she used 2,8-dimethyl-6-phenyl-2H-[2,7]naphthiridine-1-he (220 mg, 0,879 mmol).

1H NMR (300 MHz, CDCl3) δ of 3.00 (s, 3H), 3,01 (t, 2H, J=6.3 Hz), 3,18 (s, 3H), of 3.57 (t, 2H, J=6.3 Hz), 7,38 (s,1H), 7,4 2-7,50 (m, 3H), 8,02-with 8.05 (m, 2H).

Example 127

Synthesis of 2-benzyl-8-methyl-6-phenyl-2H-[2,7]naphthiridine-1-it

Received 265 mg (96%) of 2-benzyl-8-methyl-6-phenyl-2H-[2,7]naphthiridine-1-it is in the form of a solid white product, using the same method as in example 122 except that instead of 2H-[2,7]naphthiridine-1-it used 8-methyl-6-phenyl-2H-[2,7]naphthiridine-1-he(200 mg, 0,846 mmol).

1H NMR (300 MHz, CDCl3) δ is 3.21 (s,3H), 5,19 (c, 2H), 6,41 (d, 1H, J=7.5 Hz), 7,24 (d, 1H, J=7.5 Hz), 7,27-7,39 (m, 5H), 7,40-7,52 (m, 3H), 7,56 (c, 1H), 8,08-to 8.12 (m, 2H).

Example 128

Synthesis of 2-benzyl-8-methyl-6-Hairdryer is l-3,4-dihydro-2H-[2,7]naphthiridine-1-it

Received 295 mg (82%) of 2-benzyl-8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-it is in the form of a solid white product, using the same method as in example 122 except that instead of 2H-[2,7]naphthiridine-1-it used 8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he (260 mg, 1,091 mmol).

1H NMR (300 MHz, CDCl3) δ of 2.92 (t, 2H, J=6.3 Hz), 3,03 (s, 3H), 3,49 (t, 2H, J=6.3 Hz), 4,80 (s,2H), 7,27-7,37 (m, 6H), 7,39-to 7.50 (m, 3H), 8,01-with 8.05 (m, 2H).

Example 129

Synthesis of 6-cyclohexyl-2-methoxy-4-methylnicotinamide

Received of 2.23 g (88%) of 6-cyclohexyl-2-methoxy-4-methylnicotinamide, using the same method as in example 101, except that instead of n-Propylamine bromide was added 2.0 g of 6-chloro-2-methoxy-4-methylnicotinamide together with cyclohexylaniline.

1H NMR (300 MHz, CDCl3) δ 6,68 (c, 1H), 4.04 the (c, 3H), 2,55-of 2.64 (m, 1H), 2,48 (c, 3H), 1,71-of 1.94 (m, 5H), 1,26-of 1.57 (m, 5H).

Example 130

Synthesis of methyl ester (3-cyano-6-cyclohexyl-2-methoxypyridine-4-yl)acetic acid

Received 2,43 g (87%) of methyl ester of (3-cyano-6-cyclohexyl-2-methoxypyridine-4-yl)acetic acid in the form of a yellow oil, using the same method as in example 1, except that instead of 4-methylnicotinamide used of 2.23 g of 6-cyclohexyl-2-methoxy-4-methylnicotinamide.

1H NMR (300 MHz, CDCl3) δ 6,77 (c, 1H), 4.04 the (c, 3H), of 3.78 (d, J=3.0 Hz, 2H), 3.75 to (c, 3H), 2.57 m-to 2.67 (m, 1H) 1,71-of 1.93 (m, 5H), 1,26-of 1.57 (m, 5H).

Example 131

Synthesis of 6-cyclohexyl-4-(2-hydroxyethyl)-2-methoxynicotinate

Received 2,11 g (96%) of 6-cyclohexyl-4-(2-hydroxyethyl)-2-methoxynicotinate in the form of colorless, using the same method as in example 2, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 2,43 g methyl ester (3-cyano-6-cyclohexyl-2-methoxypyridine-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 6.75 in (s,1H), was 4.02 (c, 3H), 3,91-of 3.96 (m, 3H), of 3.00 (t, J=6.5 Hz, 2H), 2,55-to 2.65 (m, 1H), 1,69-of 1.92 (m, 5H), 1,26-of 1.57 (m, 5H).

Example 132

Synthesis of 6-cyclohexyl-8-hydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received of 1.80 g (90%) of 6-cyclohexyl-8-hydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid product is light yellow in color, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide used 2,10 g of 6-cyclohexyl-4-(2-hydroxyethyl)-2-methoxynicotinate.

1H NMR (300 MHz, DMSO-d6) δ 1,85 (c, 1H), 6,09 (c, 1H), 4,29 (t, J=5,9 Hz, 2H), and 2.83 (t, J=5,9 Hz, 2H), 2,42 is 2.51 (m, 1H), 1,65-to 1.82 (m, 5H), of 1.16 to 1.47 (m, 5H).

Example 133

Synthesis of methyl ester of 6-cyclohexyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid

Received 307 mg (88%) of methyl ester of 6-cyclohexyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid in the form of a solid product is white in color, using the same method as in example 21, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 300 mg of 6-cyclohexyl-8-hydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 7,02 (c, 1H), 4,51 (t, J=6.0 Hz, 2H), 3,05 (t, J=5,9 Hz, 2H), 2,66 was 2.76 (m, 1H), 2,4 (c, 3H), 1,74-2,04 (m, 5H), 1,23-of 1.55 (m, 5H).

Example 134

Synthesis of 8-chloro-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 814 mg (76%) of 8-chloro-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 20, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-she was using 1.0 g of 6-cyclohexyl-8-hydroxy-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 7,01 (c, 1H), 4,48 (t, J=5,9 Hz, 2H), 3,05 (t, J=5,9 Hz, 2H), 2,68-2,78 (m, 1H), 1,75-of 1.94 (m, 5H), 1,24-to 1.63 (m, 5H).

Example 135

Synthesis of 6-cyclohexyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 173 mg (98%) of 6-cyclohexyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-C]pyridine-1-it is in the form of a solid white product, using the same method as in example 32, except that instead of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-she used 150 mg of 8-chloro-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ of 6.31 (s, 1H), 4,39 (t, J=5.7 Hz, 2H), 3,51 (Sirs, 4H), 287 (t, J=5,9 Hz, 2H), 2,46 is 2.55 (m, 1H), 1,81-of 1.92 (m, 4H), 1,59-of 1.66 (m, 7H), 1.18 to 1.55V (m, 5H).

Example 136

Synthesis of 6-cyclohexyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 498 mg (90%) of 6-cyclohexyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 32, except that instead of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she and piperidine used 400 mg of 8-chloro-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-he, along with 4-methoxybenzylamine.

1H NMR (300 MHz, CDCl3) δ 8,46 (Sirs, 1H), 7,3l (d, J=8,4 Hz, 2H), PC 6.82-6.87 in (m, 2H), 6.22 per (c, 1H), 4,71 (d, J=5.7 Hz, 2H), 3,79 (c, 3H), 2,87 (t, J=5,9 Hz, 2H), 2,48 is 2.55 (m, 1H), 1,72-1,90 (m,5H), 1.18 to 1.57 in (m, 5H).

Example 137

Synthesis of 8-amino-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 190 mg (92%) of 8-amino-6-cyclohexyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 53, except that instead of 8-(4-methoxybenzylamine)-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 307 mg of 6-cyclohexyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 6,32 (c, 1H), to 4.62 (t, J=6.0 Hz, 2H), 2,90 (t, J=5,9 Hz, 2H), 2,44-2,52 (m, 5H), 1,72 is 1.91 (m, 5H), 1,19-of 1.57 (m, 5H).

Example 138

Synthesis of 6-isopropyl-2-methoxy-4-methylnicotinamide

Got 1,g (65%) of 6-isopropyl-2-methoxy-4-methylnicotinamide in the form of a colorless oil, using the same method as in example 101, except that instead of n-propylaniline was added 1.5 g of 6-chloro-2-methoxy-4-methylnicotinamide together with magnesium chloride.

1H NMR (300 MHz, CDCl3) δ 6,68 (c, 1H), was 4.02 (c, 3H), 2,93 (quintet, J=6,8 Hz, 1H), 2,46 (c, 3H), of 1.26 (d, J=6.9 Hz, 6H).

Example 139

Synthesis of methyl ester (3-cyano-6-isopropyl-2-methoxypyridine-4-yl)acetic acid

Received of 1.41 g (83%) of methyl ester of (3-cyano-6-isopropyl-2-methoxypyridine-4-yl)acetic acid as a solid yellow product, using the same method as in example 1, except that instead of 4-methylnicotinamide used 1.29 g of 6-isopropyl-2-methoxynicotinate.

1H NMR (300 MHz, CDCl3) δ 6,78 (c, 1H), 4,05 (c, 3H), 3,79 (c, 2H), 3.75 to (c, 3H), 2,97 (quintet, J=6,8 Hz, 1H), 2,17 (c, 3H), of 1.28 (d, J=6.9 Hz, 6H).

Example 140

Synthesis of 4-(2-hydroxyethyl)-6-isopropyl-2-methoxynicotinate

Received 1,89 g (97%) of 4-(2-hydroxyethyl)-6-isopropyl-2-methoxynicotinate in the form of oil is light yellow in color, using the same method as in example 2, except that instead of methyl ester (3-cyano-4-yl)acetic acid was used 2.20 g of methyl ester of (3-cyano-6-isopropyl-2-methoxypyridine-4-yl)acetic acid.

1H NMR (300 MHz, CDCl3) δ 6,77 (c, 1H), 4.04 the (c, 3H), of 3.96 (t, J=5.3 Hz, 2H), 2.91 in totaling 3.04 (m, 3H), 1.27mm (d, J=6.6 Hz, 6H).

Example 141

Synthesis of 8-hydroxy-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 1.20 g (80%) of 8-hydroxy-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 3, except that instead of 4-(2-hydroxyethyl)nicotinanilide used to 1.60 g of (4-(2-hydroxyethyl)-6-isopropyl-2-methoxynicotinate.

1H NMR (300 MHz, DMSO-d6) δ 11,89 (Sirs, 1H), 6,12 (c, 1H), 4,29 (t, J=6.2 Hz, 2H),2,74-of 2.86 (m,3H), 1,19 (d, J=6.9 Hz, 6H).

Example 142

Synthesis of methyl ester of 6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-8-luxusni acid

Received 208 mg (87%) of methyl ester of 6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-luxusni acid in the form of a solid white product, using the same method as in example 21, except that instead of 8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she used 200 mg of 8-hydroxy-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ? 7.04 baby mortality (s,1H), 4,51 (t, J=6.0 Hz, 2H), 3,02-3,11 (m, 3H), 2,41 (c, 3H), of 1.31 (d, J=6.6 Hz, 6H).

Example 143

Synthesis of 8-chloro-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 740 mg (85%) of 8-chloro-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 20, except that instead of 8-hydroxy-6-meth is l-3,4-dihydropyrano [3,4-c]pyridine-1-it used 800 mg, 8-hydroxy-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-it.

1H NMR (300 MHz, CDCl3) δ 7.03 is (c, 1H), 4,49 (t, J=6.2 Hz, 2H), 3,03-of 3.12 (m, 3H), 1,32 (d, J=6.6 Hz, 6H).

Example 144

Synthesis of 6-isopropyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-c]pyridine-1-it

Received 481 mg (95%) 6-isopropyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-c]pyridine-1-it is in the form of a solid white product, using the same method as in example 32, except that instead of 8-chloro-6-methyl-3,4-dihydropyrano[3,4-c]pyridine-1-she and piperidine used 350 mg of 8-chloro-6-isopropyl-3,4-dihydropyrano[3,4-c]pyridine-1-she and 4-methoxybenzylamine.

1H NMR (300 MHz, CDCl3) δ 8,48 (Sirs, 1H), 7,29-7,33 (m, 2H), 6,83-6,87 (m, 2H), 6,23 (s, 1H), 4,71 (d, J=6.0 Hz, 2H), of 4.44 (t, J=6.3 Hz, 2H), 3,79 (c, 3H), 2,84-of 2.86 (m, 3H), 1,24 (d, J=6.0 Hz, 6H).

Meanwhile, the compound represented by the above formula 1, according to the present invention, can be obtained in various forms according to the assigned tasks. The following are just a few of the illustrative methods of obtaining pharmaceutical preparations containing compounds represented by the above formula 1, as an active ingredient, and therefore should not be considered as limiting the scope of the present invention.

Getting 1

Obtain tablets (direct compression)

5.0 mg of the active ingredient was sieved and then mixed with a 14.1 mg of lactose, 0.8 mg crosspovidone the USNF and 0.1 mg of magnesium stearate. The mixture is extruded and got the pill.

Getting 2

Obtain tablets (wet granulation)

5.0 mg of the active ingredient was sieved and then mixed with 16.0 mg of lactose and 4.0 mg of starch. In water was dissolved 0.3 mg of Polysorbate 80 and the resulting solution was then added to the above mixture to micromilieu. After drying, 2.7 mg of colloidal silicon dioxide were mixed with 2.0 mg of magnesium stearate. Microtrenching the mixture is extruded and got the pill.

Getting 3

Obtaining powders and capsules

5.0 mg of the active ingredient was sieved and then mixed 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate to obtain mixed powder. Gelatin capsules No.5 filled with powder, using the right equipment.

Experimental example 1

The experiment inhibitory activity against cytokines

1)Inhibitory activity against cytokines in whole blood of man

Five healthy volunteers, male or female, who did not take anti-inflammatory drugs within the last two weeks, collecting 20 ml of whole venous blood, respectively, and added heparin. Selected 1 ml of each blood sample, respectively, and transferred to the experimental tubes in which the blood was mixed with the test substance is m The above mixture was pre-cultured at 37°C for about 1 hour. Then to the mixture was added 1 μg/ml LPS (lipopolysaccharide), left to interact at the same temperature for from about 4 to about 12 hours and then centrifuged at 4°C at a speed of 3000 rpm for about 10 minutes. Thus obtained plasma was collected, respectively, and counted the number of TNF-α in each plasma sample using an ELISA kit for human TNF-α, on the basis of the number of recombinant TNF-α human. Used the tablet was covered with a monoclonal IgG antibodies against TNF-α human. Similarly, in the case of the experiment with IL-1α, counted the number of IL-1α in each plasma sample using the above plasma sample and the ELISA kit for human IL-1α, based on the amount of recombinant IL-1α person. Used the tablet was covered with a monoclonal IgG antibodies against human IL-1α. Then, in the experiment with PGE2, in each plasma sample was calculated amount of PGE2 using the above plasma sample and a set of ELISA for PGE2, based on the amount of recombinant PGE2 person. Used the tablet was covered with a monoclonal antibody IgG against human PGE2. In each of the above tests received the degree of inhibition of expression of each cytokine and compared them with the data for indometacin. The results shown in table 1.

Table 1
The analyzed connectionThe degree of inhibition of TNF-α (conc.)The degree of inhibition of IL-1α (conc.)The degree of inhibition of PGE2(conc.)
Indometacin37%
(200 µg/L)
25%
(200 ág/ml)
37%
(200 ág/ml)
The compound of example 390%
(100 ng/ml)
95%
(100 ng/ml)
24%
(300 µg/ml)
The compound of example 684%
(100 ng/ml)
90%
(100 ng/ml)
23%
(300 µg/ml)
The compound of example 982%
(100 ng/ml)
93%
(100 ng/ml)
38%
(300 µg/ml)

As shown above in table 1 inhibitory activity against cytokine in whole human blood derived from pyridine, obtained according to the present invention, is higher than that of indomethacin, commercially the available anti-inflammatory and analgesic means, in particular, in relation to the production of TNF-α and IL-1α inhibitory activity than approximately two to three times. In addition, the compound of example 9 has the same level of inhibitory activity with indomethacin product PGE2.

2)Inhibitory activity against cytokine in animal models

Rats, Sprague Dawley (SD) body weight from about 180 to about 200 g were not fed (free access to drinking) and then tested. The compounds were administered orally in the amount of 40 mg/kg) and then injected intraperitoneally together LPS 1 µg/ml after 1 hour. After 2 hours, the rats were killed and blood was collected from the peritoneum of Vienna, kept at room temperature for about 2 hours and then centrifuged at 12000 rpm for about 2 minutes. Thus obtained plasma, respectively, were collected and each plasma sample was calculated amount of TNF-α using ELISA kit for mouse TNF-α, based on the number of recombinant TNF-α in rats. Used the tablet was covered with a monoclonal IgG antibodies against TNF-α rat. Similarly, in the case of the experiment, IL-1α, counted the number of IL-1α in each plasma sample using the above plasma sample and a set of ELISA for mouse IL-1α, based on the amount of recombinant IL-1α. Used the tablet was covered with a monoclonal IgG antibodies against TNF-the rat. Similarly, in the case of the experiment with IL-6 were calculated amounts of IL-6 in each plasma sample using the above plasma sample and a set of ELISA for mouse IL-6, based on the amount of recombinant IL-6 mouse. Then, in the experiment with INF-γ, in each plasma sample was calculated the number of INF-γ, using the above plasma sample and a set of ELISA for INF-γ mouse, on the basis of the number of recombinant INF-γ in mouse. Used the tablet was covered with a monoclonal antibody IgG against murine INF-γ. In each of the above tests received the degree of inhibition of expression of each cytokine and compared them with data for indometacin. The results are shown in the following tables 2 and 3.

Table 2
The analyzed connectionThe degree of inhibition of TNF-α (conc.)
Indometacin46% (200 mg/kg)
The compound of example 375% (40 mg/kg)
The compound of example 639% (40 mg/kg)
The compound of example 959% (40 mg/kg)
The compound of example 2193% (40 mg/kg)
The compound of example 3079% (40 mg/kg)
The compound of example 3274% (40 mg/kg)
The compound of example 3390% (40 mg/kg)
The compound of example 5353% (40 mg/kg)
The compound of example 7766% (40 mg/kg)
The compound of example 7868% (40 mg/kg)
The compound of example 7978% (40 mg/kg)
The compound of example 11543% (40 mg/kg)
The compound of example 11769% (40 mg/kg)
table 3
The analyzed connectionThe degree of inhibition of IL-α (conc.)The degree of inhibition of IL-6 (conc.)The degree of inhibition of INF-γ (conc.)
Indometacin24%(200mg/kg)60% (200 mg/kg)13 % (200 mg/kg)
The compound of example 365% (40 mg/kg)71% (40 mg/kg)48% (40 mg/kg)
The compound of example 652% (40 mg/kg)78% (40 mg/kg)51% (40 mg/kg)
The compound of example 962% (40 mg/kg)43% (40 mg/kg)45% (40 mg/kg)

As shown above in tables 2 and 3, the inhibiting activity against cytokine in the model rats derived from pyridine, obtained according to the present invention, is higher than that of indomethacin, in particular, in relation to the production of TNF-α, IL-α, IL-6 and INF-γ, inhibiting activity than approximately two times. In addition, the inhibitory activity of the compounds of examples 21, 30, 32, 33 and 79 1.5 or 2 times higher inhibitory activity is indometacina in relation to production of TNF-α.

3)Inhibitory activity against cytokines in cells

Main reagents were purchased from Sigma-Aldrich chem. Co. and inhibitory activity against cytokines used in the following way. Media and reagents used in cell culture were purchased from GIBCO BRL (USA), ELISA kit for mouse TNF-α was purchased from R&D system (USA). Used equipment was ELISA reader (Spectra max Plus 384, Molecular Device, USA).

Murine cell line macrophages RAW 264.7 was kindly provided Tissue Korean Culture Center (KTCC). The cell line was cultured in DMEM containing 10% FBS, in the device for cell culture under conditions of 37°C, 5% CO2. First, murine RAW 264.7 were cultured in DMEM containing 10% FBS for about 24 hours, and cells were sown in the amount of 200 μl in each well of 96-well plate with a concentration of 5×105/ml and were cultured for about 24 hours. Then the compounds were treated with various concentrations and then interacted at 37°C for about 1 hour, during which the wells was added 1 μg/ml of lipopolysaccharide (LPS) and the interaction was continued at 37°C for about 12 hours. The supernatant was isolated and counted the number of mouse TNF-α in the medium using an ELISA kit. As positive and negative controls, respectively, were used to t lidomide for comparison activities the results are presented in the following tables 4a-4c.

td align="center"> 36
Table 4a
The compoundsAnalyzed conc.The degree of inhibition of TNF-α (%)The compoundsAnalyzed conc.The degree of inhibition of TNF-α (%)
Thalidomide1 mm21Example 31 mm44
100 mm20100 mm43
10 µm1210 µm35
1 micron81 micron34
Example 61 mm38Example 91 mm41
100 mm100 mm39
10 µm3510 µm38
1 micron301 micron37
Example 201 mm41Example 211 mm77
100 mm31100 mm34
10 µm2110 µm15
1 micron151 micron9
Example 221 mm30Example 261 mm28
100 mm17100 mm17
10 µm10 µm6
1 micron_1 micron-
Example 271 mm81Example 281 mm59
100 mm68100 mm37
10 µm4310 µm27
1 micron301 micron8
Example 291 mm30Example 301 mm100
100 mm18100 mm100
10 µm1510 µm100
1 micron 101 micron100

Example 311 mm100Example 321 mm100
100 mm100100 mm89
10 µm10010 µm78
1 micron1001 micron69
Example 331 mm29Example 341 mm80
100 mm18100 mm70
10 µm910 µm62
1 micron-1 micron58
Example 351 mm32Example 371 mm89
100 mm26100 mm78
10 µm1710 µm69
1 micron91 micron54
Example 391 mm40Example 461 mm29
100 mm31100 mm19
10 µm2210 µm9
1 micron91 micron3

Table 4b
The compoundsAnalyzed conc.The degree of inhibition of TNF-α (%)The compoundsAnalyzed conc.The degree of inhibition of TNF-α (%)
Example 501 mm25Example 511 mm30
100 mm19100 mm21
10 µm910 µm15
1 micron51 micron9
Example 531 mm100Example 601 mm78
100 mm100100 mm56
10 µm10010 m is M 48
1 micron851 micron39
Example 611 mm100Example 621 mm100
100 mm100100 mm89
10 µm10010 µm78
1 micron871 micron60

Example 681 mm76Example 731 mm80
100 mm65100 mm72
10 µm5810 µm63
1 µm 501 micron56
Example 771 mm100Example 781 mm100
100 mm89100 mm98
10 µm7610 µm85
1 micron681 micron79
Example 791 mm100Example 961 mm63
100 mm94100 mm56
10 µm810 µm46
1 micron761 micron38
Example 971 mm100Example 981 mm87
100 mm93100 mm72
10 µm8410 µm64
1 micron751 micron56
Example 991 mm35Example 1001 mm29
100 mm22100 mm18
10 µm1910 µm9
1 micron91 micron-
Example 1121 mm35Example 113 1 mm42
100 mm33100 mm28
10 µm2810 µm19
1 micron241 micron10
Example 1151 mm78Example 1161 mm29
100 mm65100 mm18
10 µm5910 µm10
1 micron501 micron-

Table 4c
The compoundsAnalyzed conc.The degree of inhibition of TNF-α (%)slideme connection Analyzed conc.The degree of inhibition of TNF-α (%)
Example 1171 mm35Example 120A1 mm85
100 mm29100 mm66
10 µm1810 µm54
1 micron101 micron43
Example 120b1 mm42
100 mm32
10 µm30
1 micron26

As shown above in tables 4a-4c, derivatives of pyridine according to the present invention show high inhibitory activity against the production of INF-α in cell line RAW 264.7. In particular, inhibitory activity is any of the compounds of examples 30, 31, 53, 61, 62, 77, 78, 79 and 97 above inhibitory activity of the control connections.

Experimental example 2

Anti-inflammatory and analgesic effects in animal models

1)Experiment with ear oedema induced by Croton oil

Studied male mice of the ICR (Institute of Cancer Research) weighing from about 20 to 30 grams in each group was 6 mice. Within 1 hour after oral administration the compounds one ear smeared with oil of Croton (in acetone solution). After 4 hours the thickness of the swollen ear in the treated group was compared with Neopolis ear and received the average value of the increased thickness of the ear affected by processing. The above increase was compared with the placebo group, the results shown in table 5.

Table 5
The compoundsTreatment (mg/kg)The degree of inhibition (%)
Celecoxib10035
Example 3233
1056
5057
Example 6217
1039
5069
Example 9225
1044
5037

2)Experiment with ear oedema induced by arachidonic acid

Studied male mice of the ICR (Institute of Cancer Research) weighing from about 20 to 30 grams in each group was 6 mice. Within 1 hour after oral administration the compounds one ear smeared arachidonic acid (in acetone solution). After 1 hour, the thickness of the swollen ear in the treated group was compared with Neopolis ear and received the average value of the increased thickness of the ear affected by processing. The above increase was compared with the placebo group, the results shown in table 6.

Table 6
The compoundsTreatment (mg/kg) The degree of inhibition (%)
Celecoxib10033
Example 3233
1051
5046
Example 6221
1036
5041
Example 9221
1029
5039

3)Test for pain relief

Studied male mice of the ICR (Institute of Cancer Research) weighing from about 20 to 30 grams in each group was 6 mice. Within 1 hour after oral administration the compounds were injected intraperitoneally acetic acid (distilled water). Within 10 minutes we noted the number of stretching in mice and compared with the number of stretching the placebo group, the results shown in table 7.

Table 7
The compoundsTreatment (mg/kg)The degree of inhibition (%)
Celecoxib10081
Example 31076
5092
Example 61076
5075
Example 91073
5076

As shown in the above tables 5 and 6, in animal models of anti-inflammatory effect of the pyridine derivatives of the present invention was compared with the effect of commercially available Celecoxib (100 mg/kg) at a concentration of 2 mg/kg and 10 mg/kg, respectively. However, the anti-inflammatory effects pyridine derivatives of the present invention were higher than the effect of Celecoxib at a concentration of 50 mg/kg in Addition, in the experiment on anesthesia, the above table 7, the derivatives of pyridine at present is the invention showed a little less but comparable analgesic effect compared with the effect of Celecoxib (100 mg/kg)and the compound of example 9 showed the same level of analgesic effect compared with the effect of Celecoxib.

Industrial applicability

As mentioned above, derivatives of pyridine above formula 1 of the present invention have excellent inhibitory effect on the production of cytokines, which are involved in inflammatory reactions, more specifically, they have excellent inhibitory effect on the production of TNF-α, IL-1α, IL-6, INF-γ, PGE2. In addition, their anti-inflammatory and analgesic effects of above-mentioned effects of commercially available indomethacin or Celecoxib. Therefore, derivatives of pyridine represented by the above formula 1, according to the present invention can be used as therapeutic agents for the treatment of diseases associated with inflammation, immune, chronic inflammation, as well as funds that have anti-inflammatory and analgesic effect.

1. The compound or pharmaceutically acceptable salt, represented by the following formula 1:

where R1, R2, R3, R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, halogen, amino, C1-C6lower alkyl, C 2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino,4-C9cyclooctylamino,4-C9heterocyclochain, C1-C10aralkylamines, arylamino, acylamino saturated heterocyclyl, aryloxy, aryl, heteroaryl,1-C10aralkyl, aryloxy;
X represents an oxygen atom or sulfur;
Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom;
the above aryl group selected from phenyl, naphthyl and condensed phenyl group;
the above heteroaryl and saturated heterocyclic groups represent a heterocyclic ring pentagonal or hexagonal shape, containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur atom; or a condensed heterocyclic ring; and
the above-mentioned aryl and heteroaryl groups are such that from 1 to 4 substituents selected from the group comprising halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted,
moreover, the above-mentioned compounds or their pharmaceutically acceptable salt of formula 1 are the following compounds
6-methyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
5-vinyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-methyl-8-furan-2-yl-3,4-d is hydroprene[3,4-C]pyridine-1-he,
3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthiridine-8-he and dimethyl (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthiridine-3,5-dicarboxylic acid.

2. The compound according to claim 1, where the specified X and Y independently represent an oxygen atom.

3. The compound according to claim 1, where the specified R1, R2and R3independently selected from the group comprising a hydrogen atom, halogen, amino, C1-C6alkylamino, arylamino, acylamino, saturated heterocyclic group, aryl, heteroaryl;
these R4, R5, R6and R7independently selected from the group consisting of a hydrogen atom, a C1-C6the lower alkyl and aryl group;
X represents an oxygen atom or sulfur;
Y represents an oxygen atom or N-R8where R9selected from the group comprising a hydrogen atom;
specified aryl group is a phenyl group;
these heteroaryl and saturated heterocyclic group selected from furan, thiophene, pyridine, piperidine, piperazine, research, pyrolidine and benzodioxole; and
these aryl and heteroaryl groups are such that from 1 to 4 substituents selected from the group comprising halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted.

4. The compound according to claim 1, represented by formula 1 selected from the group of Lucaya:
3,4-dihydropyrano[3,4-C]pyridine-1-he,
6,8-dichloro-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6,8-dihydroxy-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-hydroxy-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-chloro-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-silt ether acetic acid,
8-methoxy-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6,8-dimethyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-thiophene-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-pyridin-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-(4-forfinal)-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-(4-chlorophenyl)-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-morpholine-4-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-(4-methylpiperazin-1-yl)-3,4-dihydropyrido[3,4-C]pyridine-1-he,
6-methyl-8-(4-(pyrimidine-2-reparation-1-yl)-3,4-dihydropyrido[3,4-C]pyridine-1-he,
8-(4-forgenerating)-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-(4-chlorpheniramine)-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-(4-triptoreline)-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-p-tolylamino-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-phenylamino-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-phenethylamine-3,4-dihydropyrano[3,4-C]pyridine-1-he 8-[(benzo[1,3]dioxol-5-ylmethyl)amino]-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-8-phenoxy-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8 benzylamino-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-(4-methoxybenzylamine)-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-amino-6-methyl-3,4-dihydropyrano [3,4-C]pyridine-1-he,
8-acetamido-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8 benzamido-6-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-hydroxy-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-chloro-6-methyl-5-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-methyl-5-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-hydroxy-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-chloro-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-methyl-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
1-oxo-6-phenyl-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-silt ether acetic acid,
8-methoxy-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-methylamino-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-dimethylamino-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-phenyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-morpholine-4-yl-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-phenyl-8-pyrrolidin-1-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-(4-forgenerating)-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-(4-what ethoxybenzylidene)-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-amino-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-acetamido-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8 benzamido-6-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-hydroxy-8-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-chloro-8-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-methyl-6-(thiophene-2-yl)-3,4-dihydropyrido[3,4-C]pyridine-1-he,
6-(furan-2-yl)-8-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-(benzo[d][1,3]dioxol-6-yl)-8-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-(4-(dimethylamino)phenyl)-8-methyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-hydroxy-6-propyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-chloro-6-propyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-propyl-6-chloro-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-morpholine-4-yl-6-propyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-silt ether acetic acid,
8-(4-methoxybenzylamine)-6-propyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-amino-6-propyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
N-(1-oxo-6-propyl-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-yl)acetamide", she
3,4-dihydro-2-oxa-Aza-phenanthrene-1-he,
3,4-dihydropyrano[3,4-C]pyridine-1-tion,
2-(4-methoxybenzyl)-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
3,4-dihydro-2H-[2,7]naphthiridine-1-he,
2-benzyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
3-phenyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
3-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]nattered the n-1-he,
2,8-dimethyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
2-benzyl-8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
6-cyclohexyl-8-hydroxy-3,4-dihydropyrano[3,4-C]pyridine-1-he,
methyl ester of 6-cyclohexyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-luxusni acid,
8-chloro-6-cyclohexyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-cyclohexyl-8-piperidine-1-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-cyclohexyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-amino-6-cyclohexyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
8-hydroxy-6-isopropyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
methyl ester of 6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-luxusni acid,
8-chloro-6-isopropyl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-isopropyl-8-(4-methoxybenzylamine)-3,4-dihydropyrano[3,4-C]pyridine-1-he,
6-chloro-8-cyclohexyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
methyl ester of 1-oxo-6-thiophene-2-yl-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-luxusni acid,
6-ethyl-8-hydroxy-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
methyl ester 6-ethyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-luxusni acid,
8-chloro-6-ethyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-amino-6-ethyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-ethyl-8-(4-methoxy-benzylamino)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-ethyl-8-piperidine-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-amino-6-isopropyl-3,4-Digue is draw pyrano[3,4-C]-pyridine-1-he,
6-isopropyl-8-piperidine-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
2-ethyl-8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
8-furan-2-yl-6-phenyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-phenyl-8-thiophene-2-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-(4-forfinal)-6-phenyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-(4-forfinal)-6-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-chloro-8-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-isopropyl-6-piperidine-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-isopropyl-6-(4-methoxybenzylamine)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-chloro-8-cyclohexyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-cyclohexyl-6-piperidine-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-cyclohexyl-6-morpholine-4-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-cyclohexyl-6-(4-methoxybenzylamine)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-propyl-6-pyrrolidin-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-piperidine-1-yl-8-propyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-morpholine-4-yl-8-propyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-amino-8-propyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-(4-methoxybenzylamine)-8-propyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-hydroxy-8-propyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-(4-forfinal)-6-methyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
8-(4-forfinal)-2,6-dimethyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
2-ethyl-8-(4-forfinal)-6-methyl-3,4-dihydro-2H-[2,7]naphthas who ridin-1-he,
6-amino-8-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-amino-8-cyclohexyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
4-fluoro-N-(8-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-6-yl)-benzosulfimide,
4-chloro-N-(8-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-6-yl)-benzosulfimide,
N-(8-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-6-yl)-benzosulfimide,
N-(8-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-yl)-4-methoxy-benzosulfimide,
N-(8-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-yl)-4-methoxy-benzosulfimide,
8-[4-(2-hydroxyethyl)-piperazine-1-yl]-6-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-(4-benzylpiperazine-1-yl)-6-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-isopropyl-8-(4-phenylpiperazin-1-yl)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-[4-(2-ethoxyphenyl)-piperazine-1-yl]-6-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-[4-(2-chlorophenyl)-piperazine-1-yl]-6-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-isopropyl-8-(4-pyridin-2-yl-piperazine-1-yl)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-isopropyl-8-(4-methyl-piperazine-1-yl)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-isopropyl-8-morpholine-4-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-isopropyl-8-pyrrolidin-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-isopropyl-8-(methylphenethylamino)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-[1,4']bipiperidine-1'-yl-6-isopropyl-3,4-dihydro-pyrano[34-C]pyridine-1-he,
8-(4-benzylpiperidine-1-yl)-6-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
1-(6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-yl)-piperidine-3-carboxylate,
ethyl ester of 1-(6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-yl)-piperidine-3-carboxylic acid,
ethyl ester of 1-(6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-yl)-piperidine-4-carboxylic acid,
5-(6-isopropyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-8-ylamino)-pentane acid,
6-isopropyl-8-thiomorpholine-4-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-tert-butyl-8-piperidine-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-(1,1-dioxo-thiomorpholine-4-yl)-6-isopropyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-tert-butyl-8-chloro-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-methoxy-8-piperidine-1-yl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-chloro-8-ethyl 1-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
8-ethyl-6-(4-methoxybenzylamine)-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-amino-8-ethyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
methyl ester of 8-(4-forfinal)-6-methyl-1-oxo-3,4-dihydro-1H-[2,7]naphthiridine-2-carboxylic acid,
2-(2-dimethylaminoethyl)-8-(4-forfinal)-6-methyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
8-(4-forfinal)-6-methyl-2-(2-pyrrolidin-1-yl-ethyl)-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
8-(4-forfinal)-6-methyl-2-(2-morpholine-4-yl-ethyl)-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
8-(4-forfinal)-2-(2-hydroxyethyl)-6-methyl-3,4-dihydro-2H-[,7]naphthiridine-1-he,
ethyl ester [8-(4-forfinal)-6-methyl-1-oxo-3,4-dihydro-1H-[2,7]naphthiridine-2-yl]acetic acid,
8-(4-forfinal)-6-methyl-2-pyridin-2-yl-methyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
2-[1,3]dioxolane-2-yl-methyl-8-(4-forfinal)-6-methyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
2-(2-[1,3]dioxolane-2-yl-ethyl)-8-(4-forfinal)-6-methyl-3,4-dihydro-2H-[2,7]naphthiridine-1-he,
[8-(4-forfinal)-6-methyl-1-oxo-3,4-dihydro-1H-[2,7]naphthiridine-2-yl]-acetic acid,
N-(8-ethyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-6-yl)-4-fluoro-benzosulfimide,
N-(8-ethyl-1-oxo-3,4-dihydro-1H-pyrano[3,4-C]pyridine-6-yl)-3-fluoro-benzosulfimide;
and their pharmaceutically acceptable salts.

5. The method of obtaining the compounds represented by the following formula 1, including:
(a) the interaction of the compounds represented by the following formula 2 with a compound Olkiluoto ether containing R6in the presence of a base, to obtain the compounds represented by the following formula 3;
(b) interaction of the compounds represented by the following formula 3, with regenerating agent or metal reagent containing R7at 0°C or room temperature, to obtain the alcohol compounds represented by the following formula 4; and
(c) carrying out cyclization specified alcohol compounds represented by the following formula 4, to obtain the compounds as the th following formula 1




where R1, R2, R3, R4, R5, R6and R7are as defined in claim 1, and X and Y each independently represents an oxygen atom.

6. The method of obtaining the compounds represented by the following formula 1, including:
(a) the interaction of the compounds represented by the following formula 2 with a compound of alkylcarboxylic represented by R6R7in the presence of a base to obtain the compounds represented by the following formula 4; and
(b) cyclization of the specified alcohol compounds represented by the following formula 4, to obtain the compounds represented by the following formula 1



where R1, R2, R3, R4, R5, R6and R7are as defined in claim 1, and X and Y each independently represents an oxygen atom.

7. The method according to claim 5, where the specified connection Olkiluoto ether containing R6presented R6SOON3.

8. The method according to claim 5, where the specified metal reagent containing R7representing a Grignard reagent represented by R7M, where M t is possessing an alkali metal, or R7MgX1where X represents a halogen atom.

9. The method according to claim 5 or 6, where the specified base, selected from the group comprising bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide, potassium diisopropylamide lithium, sodium hydride, potassium hydride and lithium hydride.

10. The method according to claim 5 or 6, where the specified cyclization is carried out using a strong acid conc. HCl.

11. The method of obtaining the compounds represented by the following formula 1, including:
(a) interaction of the compounds represented by the following formula 1, where X and Y each independently represents an oxygen atom, with an amine compound represented by R8NH2with obtaining compounds represented by the following formula 8; and
(b) cyclization of the compounds represented by the following formula 8, to obtain the compounds represented by the following formula 1, where X represents an oxygen atom, and Y represents N-R8


where R1, R2, R3, R4, R5, R6, R7, R8X and Y are as defined in claim 1.

12. The method according to claim 11, where this cyclization is carried out using diethylazodicarboxylate and triphenylphosphine.

13. Pharmaceutical composition having inhibitory action is receiving in respect of the formation of cytokines, where this composition contains a compound represented by the following formula 1, or its pharmaceutically acceptable salt,

where R1, R2, R3, R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino,4-C9cyclooctylamino,4-C9heterocyclochain, C1-C10aralkylamines, arylamino, acylamino saturated heterocyclyl, aryloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy;
X represents an oxygen atom or sulfur;
Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom;
the above aryl group selected from phenyl, naphthyl and condensed phenyl group;
the above heteroaryl and saturated heterocyclic groups represent a heterocyclic ring pentagonal or hexagonal shape, containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur atom; or a condensed heterocyclic ring; and
the above-mentioned aryl and heteroaryl groups are such that from 1 to 4 substituents selected from the group on the expectation by halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted,
moreover, the above-mentioned compounds or their pharmaceutically acceptable salt of formula 1 are the following compounds
6-methyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
5-vinyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthiridine-8-he and dimethyl (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthiridine-3,5-dicarboxylic acid.

14. The pharmaceutical composition according to item 13, where the indicated cytokine is a TNF-α.

15. Therapeutic agent containing the compound represented by the following formula 1, or its pharmaceutically acceptable salt, is effective in the treatment of inflammatory diseases,

where R1, R2, R3, R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino,4-C9cyclooctylamino,4-C9heterocyclochain, C1-C10aralkylamines, arylamino, acylamino saturated heterocyclyl, aryloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy;
X represents seboyeta oxygen or sulfur;
Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom;
the above aryl group selected from phenyl, naphthyl and condensed phenyl group;
the above heteroaryl and saturated heterocyclic groups represent a heterocyclic ring pentagonal or hexagonal shape, containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur atom; or a condensed heterocyclic ring; and
the above-mentioned aryl and heteroaryl groups are such that from 1 to 4 substituents selected from the group comprising halogen, C1-C6lower alkyl, C1-C6lower alkoxy, are zamienniki,
moreover, the above-mentioned compounds or their pharmaceutically acceptable salt of formula 1 are the following compounds
6-methyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
5-vinyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthiridine-8-he and dimethyl (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthiridine-3,5-dicarboxylic acid.

16. Therapeutic agent according to item 15, where specified inflammatory diseases selected from the group comprising rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, the reaction is s "graft versus host", systemic lupus erythematosus, toxic shock syndrome, osteoarthritis and insulin-dependent diabetes mellitus.

17. therapeutic agent with anti-inflammatory and analgesic effect, containing the compound represented by the following formula 1, or its pharmaceutically acceptable salt,

where R1, R2, R3, R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino,4-C9cyclooctylamino,4-C9heterocyclochain, C1-C10aralkylamines, arylamino, acylamino saturated heterocyclyl, aryloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy;
X represents an oxygen atom or sulfur;
Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom;
the above aryl group selected from phenyl, naphthyl and condensed phenyl group;
the above heteroaryl and saturated heterocyclic groups represent a heterocyclic ring pentagonal or hexagonal shape, containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur atom; and a condensed heterocyclic ring; and
the above-mentioned aryl and heteroaryl groups are such that from 1 to 4 substituents selected from the group comprising halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted,
moreover, the above-mentioned compounds or their pharmaceutically acceptable salt of formula 1 are the following compounds
6-methyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
5-vinyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthiridine-8-he and dimethyl (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthiridine-3,5-dicarboxylic acid.

18. Therapeutic tool for the treatment of immune diseases containing a compound represented by the following formula 1, or its pharmaceutically acceptable salt,

where R1, R2, R3, R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino,4-C9cyclooctylamino,4-C9heterocyclochain, C1-C10aralkylamines, arylamino, acylamino saturated heterocyclyl, aryloxy, aryl, heteroaryl,1-C10aralkyl, ar is lexi;
X represents an oxygen atom or sulfur;
Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom;
the above aryl group selected from phenyl, naphthyl and condensed phenyl group;
the above heteroaryl and saturated heterocyclic groups represent a heterocyclic ring pentagonal or hexagonal shape, containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur atom; or a condensed heterocyclic ring; and
the above-mentioned aryl and heteroaryl groups are such that from 1 to 4 substituents selected from the group comprising halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted,
moreover, the above-mentioned compounds or their pharmaceutically acceptable salt of formula 1 are the following compounds
6-methyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
5-vinyl-3,4-dihydro-pyrano [3,4-C]pyridine-1-he,
6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthiridine-8-he and dimethyl (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthiridine-3,5-dicarboxylic acid.

19. Therapeutic agent for p where these immune disease selected from the group including glomerulonephritis, dermatitis, asthma, and the Soult, myocardial infarction, acute respiratory distress syndrome, post-traumatic multiple organ failure, purulent meningitis, necrotizing enterocolitis, paragenetically syndrome, septic shock and post-menopausal osteoporosis.

20. Therapeutic agent for the treatment of chronic inflammatory diseases containing a compound represented by the following formula 1, or its pharmaceutically acceptable salt,

where R1, R2, R3, R4, R5, R6and R7independently selected from the group comprising a hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino,4-C9cyclooctylamino,4-C9heterocyclochain, C1-C10aralkylamines, arylamino, acylamino saturated heterocyclyl, aryloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy;
X represents an oxygen atom or sulfur;
Y represents an oxygen atom or N-R8where R8selected from the group comprising a hydrogen atom;
the above aryl group selected from phenyl, naphthyl and condensed phenyl group;
the above heteroaryl and saturated heterocyclic groups are heterotic the practical ring pentagonal or hexagonal shape, containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur atom; or a condensed heterocyclic ring; and
the above-mentioned aryl and heteroaryl groups are such that from 1 to 4 substituents selected from the group comprising halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted,
moreover, the above-mentioned compounds or their pharmaceutically acceptable salt of formula 1 are the following compounds
6-methyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
5-vinyl-3,4-dihydro-pyrano[3,4-C]pyridine-1-he,
6-methyl-8-furan-2-yl-3,4-dihydropyrano[3,4-C]pyridine-1-he,
3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthiridine-8-he and dimethyl (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthiridine-3,5-dicarboxylic acid.

21. Therapeutic agent according to claim 20, where these chronic inflammatory disease are psoriatic arthritis, psoriasis, alkiliruushim spondylitis, of still's disease in adults, polymyositis, dermatomyositis and vasculitis, such as Behcet's disease and Wegener's granulomatosis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted of dihydropyranoindole-3,4-dione of formula I and formula II: where X stands for H, R1 stands for H, phenyl, benzyl, cycles of said phenyl and benzyl can be substituted with 1-3 substituents, selected independently on each other from group, which includes halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup; where R2 stands for H, -OH; R3 stands for H, phenyl, benzyl, benzyloxygroup, cycles of these groups can be optionally substituted with 1-3 substituents, selected independently on each other from group including phenyl, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup, pharmaceutically acceptable salts of said compounds. Compounds demonstrate activity of inhibiting plasminogene activator inhibitor (PAI-1), which allows using them for production of medication for treatment of pathological states resulting from fibrinolytic disorders.

EFFECT: obtaining compounds, demonstrating activity in inhibiting plasminogene activator inhibitor which allows using them in pharmacology.

23 cl, 1 dwg, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the agent strongly inhibiting thrombocyte aggregation, it doesn't inhibit COX-1 or COX-2. The invention offers the compounds of formula (I) or their pharmaceutically acceptable salts, where residuals and groups in the specified structure of the compounds have the values denoted in the formula of the invention. The pharmaceuticals containing any of the compounds of formula (I) or their pharmaceutically acceptable salts, and phylactic and/or therapeutic agents for coronary heart disease, which contain any of the compounds of formula (I) or their pharmaceutically acceptable salts are suggested. Moreover, application of the compounds and their pharmaceutically acceptable salts for preparation of the medicine having anti-thrombotic potency, and method of the treatment of coronary heart disease are suggested.

EFFECT: production of the medicines having anti-thrombotic potency on basis of pyrazole.

12 cl, 1 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the common formula III: where, if X is selected from the group containing NH and S, R1, R2, R3, R4, R5, R6, R7, R8 and R9, each independently is selected from the group containing H, OH, OR', substituted or unsubstituted aryl, where substitutes independently correspond to H, OH, C1-C12alkoxy; where, if X means O, R1, R2, R3, R4, R5, R6, R7 and R8, each independently, selected from the group containing H, OH, OR', SH, SR', SOR', SO2R', OSO2R', NHR', N(R') CO2R', OC(=O)R'; and R9 independently selected from the group containing H, OR', unsubstituted or substituted with aminogroup or halogen C2-C12 alkenyl, unsubstituted C2- C12 alkenyl, unsubstituted thienyl and halogen; where each of the R' groups are independently selected from the group containing H, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted aryl; where substitutes are independently selected from the group containing halogen, OH, CN, C1-C12 alkoxy, phenyl; and the dotted line represents the simple or double bind; or its pharmaceutically compatible salt or complex ether. Other novel lamellarin analogs are described.

EFFECT: compounds have antitumor activity.

24 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new pyranoindazoles of the formula (1): wherein R1 and R2 are chosen independently from hydrogen atom or alkyl group; R3 and R4 represent independently hydrogen atom or alkyl group; R5, R6 and R7 mean hydrogen atom; R8 and R9 mean hydrogen atom, hydroxyl, alkoxy-group, -NR10R11, -OC(=O)NR1R2, -OC(=O)-(C1-C4)-alkyl or alkylthiol; R10 and R11 mean hydrogen atom; A means -(CH2)n, C=O; B means a simple or double bond; n = 0-2; Y means nitrogen atom (N); X means carbon atom C; dotted line means the corresponding simple or double bond. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), to a method for regulating normal or enhanced intraocular pressure, method for treatment of glaucoma and method for blocking or binding serotonine receptors. Invention provides preparing new pyranoindazoles possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 4 tbl, 22 ex

FIELD: organic chemistry, pharmacy, biochemistry.

SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: described is novel application of 2-methylthio-5-methyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-on. Substance possesses anti-viral activity with respect to flue A (H5N1) virus, West Nile virus and other viral infections. Wide-spectrum anti-viral activity is discovered for the first time.

EFFECT: obtaining anti-viral substance with wide spectrum of action.

1 cl, 8 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diazaindoledicarbonylpiperazinyl compounds of formula I, including its pharmaceutically acceptable salts, which possess antiviral activity and can be used for HIV-infection treatment. In compounds of formula I Q represents , T represents -C(O)- or -CH(CN)-; R1 represents hydrogen; R3 represents hydrogen; R5 is independently selected from group including halogen, cyano, XR9 and B; R2 and R4 are absent; R6 represents hydrogen; -- represents carbon-carbon bond; -Y- is selected from group including , each of R10, R11, R12, R13, R14, R15, R16 and R17 represents H; R18 is selected from group including C(O)-phenyl, isoquinolyl, quinazolyl; D is selected from group including cyano, 5-member heteroaryl containing 3 heteroatoms selected from nitrogen and oxygen; A is selected from group including phenyl, pyridinyl; B is selected from group including -C(O)CH3; piperazinyl; 5-, 6-member heteroaryl containing 1-3 N atoms and possibly O atom; where said heteroaryl optionally is substituted with from one to three similar or different substituents selected from F; F is selected from group including (C1-6)alkyl, phenyl, pyridinyl, COOR26, -COR21, and -CONR24R25; where phenyl is optionally substituted with (C1-6)alkoxy, CF3, or halogen atom; R9, R24, R25 and R26 each is independently selected from group including hydrogen and (C1-6)alkyl; X represents O; R27 represents piperazinyl, N-methylpiperazinyl, or 3-pirazolyl. Invention also relates to pharmaceutical composition.

EFFECT: obtaining compounds and pharmaceutically acceptable salts, which possess antiviral activity and can be used for treatment of HIV infection.

19 cl, 50 dwg, 4 tbl, 43 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: selective antituberculous agents represent substituted 7-aryl(heteryl)-4,7-dihydro-1,2,4-triazole/1,5-a/pyrimidines of general formula A or B or their pharmaceutically acceptable additive sodium or potassium salts of the compound B, where in the formula A R1 = hydrogen atom; R2= aryl selected from the possibly substituted phenyl or heteryl selected from the thienyl, pyridyl, indolyl, pyrrolyl with substituted phenyl having 1-3 substituting groups selected from the group including methoxy-, nitro- and hydroxyl- groups; in the formula B R1 = hydrogen atom, C1-C12 alkyl or C1-C12 thioalkyl; R2 = aryl selected from the possibly substituted phenyl or heteryl selected from the thienyl, pyridyl, indolyl, pyrrolyl with substituted phenyl having 1-3 substituting groups selected from the group including methylenedioxy-, hydroxyl-, bromine, C1-C6 alkyl and C1-C6 alkoxy groups and substituted heteryl having substituting group selected from bromine, C1-C6 alkoxy and C1-C6 alkyl groups. The invention refers also to the method for preparation of the compounds with general formula A including the heating of the equimolar amounts of aryl- or heteroarylaldehyde, acetoacetic ester and aminotriazole in the aliphatic alcohol under ultrasonic action and to the pharmaceutical composition.

EFFECT: in comparison with the analogues the claimed agents possess higher activity and lower toxicity.

4 cl, 8 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones with general formula (I), including all their enantiomeric and diastereomeric forms, as well as their pharmaceutically used salts, which inhibit undesirable or excessive excretion of cells of phlogistic cytokines, chosen from "ФНО-α" and "ИЛ-1β" and can be used for treating congestive heart failure, for example. In formula (I): R is: a) -O[CH2]kR3, where k=0; or b) -NR4aR4b; R3 is substituted or unsubstituted with phenyl, in which substitutes are chosen from halogen, C1-C4 alkyl; one of R4a and R4b is a independently a hydrogen atom; and the other of R4a and R4b is b) -[C(R5aR5b)]mR6; R5a and R5b each is independently a hydrogen atom, straight, or branched alkyl C1-C4, R6 is substituted or unsubstituted with alkyl C1-C4, in which substitutes are chosen from -OR7, cyano, phenyl, 6-member saturated heterocycle, containing a heteroatom in form of nitrogen, unsubstituted 5-6-member heteroaryl, containing 1-2 heteroatoms, chosen from nitrogen and oxygen; group R7 is a hydrogen atom, water soluble cation, alkyl C1-C4, index m assumes values from 0 to 5; R1 is: a) unsubstituted or substituted by 1-2 substitutes, chosen from halogen or C1-6alkyl, phenyl; L is a bridge group, chosen from: 1) -[C(R12)2]n-, where each R12 denotes hydrogen or together with two R12 groups form a carbonyl group, n= 1-2 ; 2) -[C(R12)2]nNR12[C(R12)2]n-, chosen from -[CH2]nNHC(O)- group, where n=1-2; and 3)-[C(R12)2]nO[C(R12)2]n-, where n=0; each R2 fragment is independently chosen from hydrogen; Z is O.

EFFECT: agents are highly effective.

24 cl, 4 dwg, 10 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new pyrrolopyrimidinone derivatives with formula (I) and their pharmaceutically used salts, with inhibition properties towards GSK-3, as well as to intermediate compounds with formula (Ic). In compounds with formula (I) and formula (Ic)

A1 is -(CH2)2- or -(CH2)3-; A is a single bond or a group, which links A1 and G1 in form of A1 -C(=O)-G1, A1- (C=O)-O-G1, A1 -(C=O)-NR101-G1, A1-O-(C=O)-G1, A1 -NR104-G1, A1-NR105-(C=O)-G1, A1-NR106-S(=O)2-G1, A1-NR107-(C=O)-O-G1 or A1-NR108-(C=O)-NR109-G1; G1 is a single bond or a bivalent group, which can be obtained through removal of two hydrogen atoms from any alicyclic hydrocarbon with 3-6 carbon atoms, phenylene, monocyclic or cyclic aromatic heterocyclic compound with 2-9 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N, or monocyclic heterocyclic compound 2-6 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N; A3 is a single bond or bivalent acyclic aliphatic hydrocarbon group with 1-3 carbon atoms, which links G1 with A4 of the same or different carbon atom; A4 is a single bond or a group, which links A3 with G2 in form of A3-C(=0)-G2, A3-C(=0)-0-G2, A3-C(=0)-NR121-G2, A3-O-G2, A3-NR124-G2, A3-NR125-C(=0)G2 or A3-S-G2. Description of other radical is given in the formula of invention.

EFFECT: compounds can be used in treating such diseases as diabetes, neurodegenerative diseases and others.

43 cl, 3 tbl, 513 ex

FIELD: pharmacology.

SUBSTANCE: described are C-6 modified indazolyl pyrrolotriaxolines of formula I and their pharmaceutically acceptable salts, where R is selected from group consisting of phenylm phenyl substituted with halogen atom, non-substituted oxazolyl, thienyl, thiazolyl, pyridyl, pyrazinyl; R1 is selected from group consisting of methyl, ethyl and isopropyl; R2 is selected from group consisting of benzyl, imidazolylethyl, (methylimidazolyl)-ethyl, pyperidinylethyl, pyridinylpropyl and other, given in item 1 of invention formula, X is selected from group consisting of bond, O, NR3; and N(R3)2; R3 is independently selected from group consisting of hydrogen, methoxyethyl, diethylaminoethyl, pyrrolidinylethyl. Also described are pharmaceutical composition for treatment of proliferative disease, methods of disease treatment. Compounds of formula I inhibit tyrosine kinase activity of growth factor receptors such as HER1, HER2 and HER4, which makes them useful as anti-cancer agents.

EFFECT: compounds are anti-cancer agents and are useful for treatment of other diseases connected with pathways of signal transduction acting through growth factor receptors.

23 cl, 4 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: described are 2,4,6-phenyl-substituted cyclic ketoenols of formula (I, in which W, X, Y and CKE are given in invention formula. Also described are esters of acylamino acids of formula (II), substituted derivatives of phenylacetic acid of formula (XXIX), (XXVII), (XXXI), which are intermediate compounds for obtaining formula (I) compound.

EFFECT: obtaining herbicidal preparation containing combinations of biologically active substances, including (a), formula (I) compound and (b') improving compatibility with cultural plants mefenpyr-diethyl, with weight ratio 5-1:1-7.7.

9 cl, 46 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

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