Anthranylamidepyridine amides with selective effect as inhibitors of vegfr-2 and vegfr-3

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to anthranylamidepyridine amides of selective effect as inhibitors of VEGFR-2 and VEGFR-3. Invention describes compounds of the general formula (I): wherein A, B and D represent independently of one another nitrogen atom or carbon atom wherein at least one nitrogen atom is in a ring; E represents aryl comprising 6-12 ring carbon atoms or heteroaryl comprising 5 or 6 ring atoms and comprising in ring instead carbon atom similar or different heteroatoms chosen from nitrogen or sulfur atoms, or represents group -COOR8, -CONR2R3 or -C≡C-R9; G represents nitrogen atom or group -C-X; L represents nitrogen atom or group -C-X; M represents nitrogen atom or group -C-X; Q represents nitrogen atom or group -C-X and wherein a ring comprises maximally one nitrogen atom; X represents hydrogen atom; W represents hydrogen or halogen atom; R1 represents aryl similarly or differently optionally mono- or multi-substituted with halogen atom, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl or group =O and wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 16 ring atoms and comprising in ring instead carbon one or more similar or different heteroatoms, such as oxygen, nitrogen or sulfur and it can be mono-, bi- or tricyclic and condensed additionally condensed with benzene ring; R2 and R3 represent independently of one another hydrogen atom or aryl similarly or differently mono- or multi-substituted with halogen atom, cyano-group, (C1-C6)-alkyl, phenyl, hydroxy-(C1-C6)-alkyl, halogen-(C1-C6)-alkyl or group -NR6R7, -OR5, (C1-C6)-alkyl-OR5-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkenyl wherein aryl comprises 6-12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms and comprising in ring instead carbon one or more heteroatoms, such as nitrogen or sulfur; or R2 and R3 in common with nitrogen atom form (C3-C8)-ring that can comprise optionally one more nitrogen or oxygen atom or it can comprise group -N(R10); R5 represents hydrogen atom; R6 and R7 represent independently of one another hydrogen atom or (C1-C6)-alkyl; R8 represents (C1-C6)-alkyl mono- or multi-substituted optionally with halogen atom or benzyl; R9 represents hydrogen atom or tri-(C1-C6)-alkylsilyl; R10 represents hydrogen atom or (C1-C6)-alkyl, and their isomers, enantiomers and salts also. Also, invention describes a medicinal agent based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 162 ex

 

The present invention relates to internallygenerated electoral act as inhibitors of VEGFR-2 and VEGFR-3, to their preparation and application as pharmaceuticals for the treatment of diseases caused by persistent angiogenesis.

Persistent angiogenesis (development of blood vessels) may cause various diseases, such as psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, endometriosis, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney disease, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, tribomechanically, graft rejection and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with proliferation mesangial cells, and arteriosclerosis, or may lead to the progression of these diseases.

Persistent angiogenesis induced by VEGF (vascular endothelial growth factor) through its receptor. For the manifestation of the VEGF this action requires that VEGF was associated with a receptor and initiate the phosphorylation of tyrosine.

The direct or indirect inhibition of VEGF-receptor can be used to treat such diseases and other induced VEGF pathological Angie is ESA, and also disorders associated with impaired vascular permeability, such as vascularization of tumors. For example, it is known that the use of soluble receptors and antibodies to VEGF can inhibit the growth of tumors.

From the application WO 00/27819 known Anthranilic acid amides, which are used as medicines for the treatment of psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, tribomechanically, graft rejection and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with proliferation mesangial cells, arteriosclerosis, injuries to nerve tissue, and for inhibiting the re-occlusion of vessels after treatment with use of balloon catheters, prosthetic vessels or after the application of mechanical devices, such as stents, to save lumen (patency) of the vessels.

Intense angiogenesis is a prerequisite for excessive growth (proliferation) of ectopic endometrium in endometriosis. Due to this suppression of angiogenesis can also be used for therapy of this form of the disease, abusable the surrounding soreness which often leads to infertility.

Known connections though, as a rule, and effective for the above indications, however, that their effectiveness is accompanied by toxicity and poor tolerability of the drug. With this in mind, remains an urgent need, on the one hand, more efficient, and on the other hand, more toxicologically harmless compounds which must be different better portability.

In the claimed invention, it was found that the above disadvantages can be resolved by compounds of General formula I

in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents an optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, C1-C6alkoxygroup, halo,-C1-C6the alkyl or the group-OR5, -SR4, -SOR4or-SO2R4aryl or hetaryl, or is a group-COOR8, -CONR2R3, -SR4, -SOR4, -SO2R4, -SCN, -PO(OR12)(OR13), -CH-CH-COR9or-C≡C-R9,

G represents a nitrogen atom or a group-S-X,

L represents a nitrogen atom or a group-S-X,

M represents the second nitrogen atom or a group-S-X,

Q represents a nitrogen atom or a group-S-X,

in the ring is a maximum of one nitrogen atom,

X represents hydrogen, halogen or unsubstituted or optionally one or mnogozalny halogen, C1-C6alkyl, C1-C6alkyloxy or C1-C6-carboxyethyl,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxyaryl, aralkylamines, C1-C6the alkyl and/or the group-NR2R3branched or non-branched C1-C12alkyl or C2-C12alkenyl, or represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxy, C1-C6the alkyl and/or the group-NR2R3C3-C10cycloalkyl or C3-C10picloader, or represents optionally identical or different one or mnogozalny halogen, cyano, hydroxy-group, C1-C6alkyloxy, C2-C6alkenyl, aryl-C1-C6-alkyloxy, aralkylamines, C1-C6by alkyl, halo,-C1-C6-alkyl or a group =O, -SO2R4, -OR5, -R5or-PO(OR1 )(OR13) aryl or hetaryl,

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5C1-C6alkyl-PR3, -SR4, -SOR4or-SO2R4C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkenyl, aryl or hetaryl or

R2and R3together with the nitrogen atom form a C3-C8the ring, which optionally may contain another nitrogen atom, sulfur or oxygen or may contain a group-N(R10and which may not necessarily be identical to or different one or mnogosloinym halogen, cyano, C1-C6by alkyl, halo,-C1-C6the alkyl, aryl or with the group-OR5, -SR4, -SOR4or-SO2R4,

R4represents a hydroxy-group, C1-C6alkyl, aryl, heteroaryl or the group-NR2R3,

R5represents hydrogen, C1-C12alkyl, halo,-C1-C6alkyl, C3-C6cycloalkyl or halo-C3-C6cycloalkyl or represents a C1-C12alkyl, which can be the t to be single or repeatedly broken by oxygen, or

represents a group -(CH2)2NR2R3, -CH2CN or-CH2CF3,

R6and R7independently from each other represent hydrogen or C1-C6alkyl or

R6and R7together form a 5-7-membered ring which may contain oxygen atom or sulfur, or a group-N(R10)-,

R8represents hydrogen or optionally one or mnogozalny halogen, C1-C6alkyl, C1-C6alkoxygroup, benzyl, aryl or hetaryl,

R9represents hydrogen, C1-C6alkyl, tri-C1-C6alkylsilane, aryl, or hetaryl group,- COR11,

R10represents hydrogen, C1-C6alkyl or aryl,

R11represents hydrogen, C1-C6alkyl or the group-NR2R3and

R12and R13independently from each other represent hydrogen or C1-C6alkyl, as well as their isomers, enantiomers and salts.

Proposed in the invention compounds inhibit tyrosine phosphorylation, respectively suppress persistent angiogenesis and thereby stop the growth and spread of tumors, and in the first place they differ lesser degree of inhibition of isoforms of cytochrome P 450 (2S9 and 2C19).

Many medicine is by means of split under the action of these isoforms. When the inhibition data isoforms increased levels of these drugs in plasma, which can lead to undesirable side effects.

Under the alkyl is meant respectively remotemachine or branched alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

Under alkoxygroup mean respectively pravarasena or branched alkoxygroup, such as metiloksi, acyloxy, propyloxy, isopropoxy, bucalossi, isobutoxy, sec-Butylochka, pentyloxy, isopentylamine, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy.

Under cycloalkyl refers to monocyclic alkyl ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclonona or cyclodecyl, and also bicyclic or tricyclic ring, such as adamantyl.

Under cycloalkenyl mean respectively cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclododecyl or cyclodecyl, and joining can occur both double and simple (single) relations.

Under the halogen is meant matched with the public fluorine, chlorine, bromine or iodine.

Under alkenyl mean respectively remotemachine or branched alkanniny the residue containing 2-6, preferably 2-4 C-atoms. As examples the following alkeneamine remains: vinyl, propen-1-yl, propen-2-yl, but-1-EN-1-yl, but-1-EN-2-yl, but-2-EN-1-yl, but-2-EN-2-yl, 2-methylprop-2-EN-1-yl, 2-methylprop-1-EN-1-yl, but-1-EN-3-yl, but-3-EN-1-yl and allyl.

Aryl residue contains respectively 6-12 carbon atoms, and as examples naphthyl, biphenyl and especially phenyl.

Heteroaryl residue comprises from 3 to 16 ring atoms instead of carbon may contain in the ring one or more identical or different heteroatoms, such as oxygen, nitrogen or sulphur, and can be mono-, bi - or tricyclic, and may further be condensed with a benzene nucleus.

As examples we can mention thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, oxadiazolyl, thiazolyl, thiadiazolyl etc. and their lansoprozole, such as benzofuranyl, benzothiazol, benzoxazolyl, benzimidazolyl, indazoles, indolyl, isoindolyl and others, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl etc. and their lansoprozole, such as chenail, ethanolic and others, or asocial, indolizinyl purines and other and benzoperylene, or cinnoline, phthalazine, hintline, honokalani, naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazinyl, phenoxazines, xantener, examiner and other

Aryl and heteroaryl residue may be respectively identical or different one-, two - or tizamidine hydroxy-group, halogen, C1-C4alkoxygroup,1-C4the alkyl or C1-C4the alkyl, one or mnogosloinym in turn by halogen.

In the presence of acidic functional groups as suitable salts of physiologically compatible salts of organic and inorganic bases, such as having good solubility of salts of alkaline and alkaline earth metals, as well as N-methylglucamine, dimethylglycine, ethylparaben, lysine, 1,6-hexadien, ethanolamine, glucosamine, sarcosine, serinol, trihydroxypyrimidine, aminopropanol, the basis of sowaka (Sovak) and 1-amino-2,3,4-butanetriol.

If the main functional groups are suitable physiologically compatible salts of such organic and inorganic acids as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, etc.

Proposed in the invention compounds of General formula I can also be a taut the situations forms and include the E - or Z-isomers, or in the presence of a chiral center, the racemates and enantiomers.

As a particularly effective proven such compounds of General formula I, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents an optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, C1-C6alkoxygroup, halo,-C1-C6the alkyl or the group-OR5, -SR4, -SOR4or-SO2R4aryl or hetaryl, or is a group-COOR8, -CONR2R3, -SR4, -SOR4, -SO2R4, -SCN, -PO(OR12)(OR13), -CH=CH-COR9or-C≡C-R9,

G represents a nitrogen atom or a group-S-X,

L represents a nitrogen atom or a group-S-X,

M represents a nitrogen atom or a group-S-X,

Q represents a nitrogen atom or a group-S-X,

in the ring is a maximum of one nitrogen atom,

X represents hydrogen, halogen or unsubstituted or optionally one or mnogozalny halogen, C1-C6alkyl, C1-C6alkyloxy or C1-C6-carboxyethyl,

R1represents not necessarily identical to or different the one or mnogozalny halogen, by cyano, hydroxy-group, C1-C6alkyloxy, C2-C6alkenyl, aryl-C1-C6alkyloxyaryl, aralkylamines, C1-C6by alkyl, halo,-C1-C6the alkyl or a group =O, -SO2R4, -OR5, -R5or-PO(OR12)(OR13) aryl or hetaryl,

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5C1-C6alkyl-OR5, -SR4, -SOR4or-SO2R4C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkenyl, aryl or hetaryl or

R2and R3together with the nitrogen atom form a C3-C8the ring, which optionally may contain another nitrogen atom, sulfur or oxygen or may contain a group-N(R10and which may not necessarily be identical to or different one or mnogosloinym halogen, cyano, C1-C6by alkyl, halo,-C1-C6the alkyl, aryl or with the group-OR5, -SR4, -SOR4or-SO2R4,

R4represents a hydroxy-group, C1- 6alkyl, aryl, heteroaryl or the group-NR2R3,

R5represents hydrogen, C1-C12alkyl, halo,-C1-C6alkyl, C3-C6cycloalkyl or halo-C3-C6cycloalkyl or represents a C1-C12alkyl, which may be single or repeatedly broken by oxygen, or

represents a group -(CH2)2NR2R3, -CH2CN or-CH2CF3,

R6and R7independently from each other represent hydrogen or C1-C6alkyl or

R6and R7together form a 5-7-membered ring which may contain oxygen atom or sulfur, or a group-N(R10)-,

R8represents hydrogen or optionally one or mnogozalny halogen, C1-C6alkyl, C1-C6alkoxygroup, benzyl, aryl or hetaryl,

R9represents hydrogen, C1-C6alkyl, tri-C1-C6alkylsilane, aryl, or hetaryl group,- COR11,

R10represents hydrogen, C1-C6alkyl or aryl,

R11represents hydrogen, C1-C6alkyl or the group-NR2R3and

R12and R13independently from each other represent hydrogen or C1-C6alkyl, as well as their isomers, enantiomers and salts.

Osobenno effective are further such compounds of General formula I, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents an optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, C1-C6alkoxygroup, halo,-C1-C6the alkyl or the group-OR5, -SR4, -SOR4or-SO2R4aryl or hetaryl, or is a group-COOR8, -CONR2R3, -SR4, -SOR4, -SO2R4, -SCN, -PO(OR12)(OR13), -CH=CH-COR9or-C≡C-R9,

G represents a nitrogen atom or a group-S-X,

L represents a nitrogen atom or a group-S-X,

M represents a nitrogen atom or a group-S-X,

Q represents a nitrogen atom or a group-S-X,

in the ring is a maximum of one nitrogen atom,

X represents hydrogen or halogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxyaryl, aralkylamines, C1-C6by alkyl, halo,-C1-C6the alkyl or the group-SO2R4, -OR5, -R5or-PO(OR12)(OR13) aryl or hetaryl,

R2and R3independently from each other before the represent hydrogen or optionally identical or different one or mnogozalny halogen, by cyano, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5C1-C6alkyl-OR3, -SR4, -SOR4or-SO2R4C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkenyl, aryl or hetaryl or

R2and R3together with the nitrogen atom form a C3-C8the ring, which optionally may contain another nitrogen atom, sulfur or oxygen or may contain a group-N(R10and which may not necessarily be identical to or different one or mnogosloinym halogen, cyano, C1-C6by alkyl, halo,-C1-C6the alkyl, aryl or with the group-OR5, -SR4, -SOR4or-SO2R4,

R4represents a hydroxy-group or the group-NR2R3,

R5represents hydrogen, C1-C12alkyl or C1-C12alkyl, which may be single or repeatedly broken by oxygen, or represents a group -(CH2)2NR2R3, -CH2CN or-CH2CF3,

R6and R7independently from each other represent hydrogen or C1-C6alkyl or

R6and R7together form a 5-7-membered ring that may contain at the m oxygen or sulfur or a group-N(R 10)-,

R8represents hydrogen or optionally one or mnogozalny halogen, C1-C6alkyl, C1-C6alkoxygroup, benzyl, aryl or hetaryl,

R9represents hydrogen, C1-C6alkyl, tri-C1-C6alkylsilane, aryl, or hetaryl group,- COR11,

R10represents hydrogen, C1-C6alkyl or aryl,

R11represents hydrogen, C1-C6alkyl or the group-NR2R3and

R12and R13independently from each other represent hydrogen or C1-C6alkyl, as well as their isomers, enantiomers and salts.

Effective properties are also compounds of General formula I, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents an optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, C1-C6alkoxygroup, halo,-C1-C6the alkyl or the group-OR5, -SR4, -SOR4or-SO2R4hetaryl or represents a group-COOR8, -CONR2R3, -SR4, -SOR4, -SO2R4, -SCN, -PO(OR12)(OR13), -CH=CH-COR9or-C≡C-R9,

<> G represents a group-S-X,

L represents a group-S-X,

M represents a group-S-X,

Q represents a nitrogen atom or a group-S-X,

X represents hydrogen or halogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxyaryl, aralkylamines, C1-C6by alkyl, halo,-C1-C6the alkyl or the group-SO2R4, -OR5, -R5or-PO(OR12)(OR13) phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline or substituted by the group

,,

or

in which T represents hydrogen, C1-C6alkyl or C1-C6alkoxygroup,

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5C1-C6alkyl-OR5, -SR4, -SOR4or-SO2R4C1-C6alkyl, C3-C6 cycloalkyl, C3-C6cycloalkenyl, aryl or hetaryl or

R2and R3together with the nitrogen atom form a C3-C8the ring, which optionally may contain another nitrogen atom, sulfur or oxygen or may contain a group-N(R10and which may not necessarily be identical to or different one or mnogosloinym halogen, cyano, C1-C6by alkyl, halo,-C1-C6the alkyl, aryl or with the group-OR5, -SR4, -SOR4or-SO2R4,

R4represents a hydroxy-group or the group-NR2R3,

R5represents hydrogen, C1-C12alkyl, halo,-C1-C6alkyl, C3-C6cycloalkyl or halo-C3-C6cycloalkyl or represents a C1-C12alkyl, which may be single or repeatedly broken by oxygen, or represents a group -(CH2)2NR2R3, -CH2CN or-CH2CF3,

R6and R7independently from each other represent hydrogen or C1-C6alkyl or

R6and R7together form a 5-7-membered ring which may contain oxygen atom or sulfur, or a group-N(R10)-,

R8represents hydrogen or optionally one or mnogozalny halogen, C1-C6 alkyl, C1-C6alkoxygroup, benzyl, aryl or hetaryl,

R9represents hydrogen, C1-C6alkyl or C1-C6alkylsilane and

R12and R13independently from each other represent hydrogen or C1-C6alkyl, as well as their isomers, enantiomers and salts.

Exceptional for its efficiency properties of these compounds of General formula I, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents thienyl, pyridyl or a group-COOR8, -CONR2R3or-C≡C-R9

G represents a group-S-X,

L represents a group-S-X,

M represents a group-S-X,

Q represents a nitrogen atom or a group-S-X,

X represents hydrogen or halogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxyaryl, aralkylamines, C1-C6by alkyl, halo,-C1-C6the alkyl or the group-SO2R4, -OR5, -R5or-PO(OR12)(OR13) phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline or Deputy who existed in the group

,,

or

in which T represents hydrogen, C1-C6alkyl or C1-C6alkoxygroup,

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, C1-C6the alkyl, phenyl or a group-NR6R7, -OR5or C1-C6alkyl-OR5C1-C6alkyl, C3-C6cycloalkyl, phenyl or pyridyl, or

R2and R3together with the nitrogen atom form a C3-C8the ring, which optionally may contain another nitrogen atom or oxygen and which may not necessarily be identical to or different one or mnogosloinym C1-C6the alkyl,

R4represents a hydroxy-group or the group-NR2R3,

R5, R6and R7independently from each other represent hydrogen or C1-C6alkyl or

R6and R7together form a 5-7-membered ring which may contain oxygen atom or sulfur,

R8represents hydrogen, C1-C6alkyl or benzyl,

R9represents hydrogen, C1-C6alkyl or C1-C6 alkylsilane and

R12and R13independently from each other represent hydrogen or C1-C6alkyl, as well as their isomers and salts.

Proposed in the invention compounds as well as their physiologically compatible salts inhibit the phosphorylation of tyrosine, respectively suppress persistent angiogenesis and thereby stop the growth and spread of tumors, and in the first place they differ lesser degree of inhibition of isoforms of cytochrome P 450 (2S9 and 2C19). Therefore, treatment with compounds according to the invention can be carried out without risk and in those cases, when you apply both additional ("certificates") of the medicinal product, split under the action of these isoforms.

The compounds of formula I and their physiologically compatible salts due to their inhibitory activity against the phosphorylation of VEGF receptor can be used as medicines. The profile of their actions allows the use proposed in the invention compounds for treatment of diseases caused or stimulated by persistent angiogenesis.

Since the compounds of formula I are identified as inhibitors of tyrosinekinase VEGFR-1 and VEGFR-2, they are primarily suitable for the treatment of such diseases, which are caused or development which promotes the duty to regulate initiated through VEGF receptor persistent angiogenesis or increased permeability of blood vessels.

The object of the present invention is also the application of its proposed compounds as inhibitors tyrosinekinase VEGFR-1 and VEGFR-2, respectively KDR and FLT.

The object of the present invention in accordance with this are also medicines for the treatment of tumors and the use of such devices.

Proposed in the invention compounds can be used either individually or as part of a proper composition as medicines for the treatment of psoriasis, Kaposi's sarcoma, restenosis, such as restenosis induced by the stent, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thromboangiitis, graft rejection and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with the proliferation mesangial cells, arteriosclerosis, injuries to nerve tissue, and for inhibition of re-occlusion of vessels after treatment with use of balloon catheter, the prosthesis of the vessel or after application of mechanical devices, such as stents, DL the save terrain clearance) vessels, as immunosuppressants, as an aid, contributing bezrucova the healing of wounds, senile spots and contact dermatitis.

In the treatment of lesions of the nervous tissue with the use of the compounds according to the invention is able to prevent the rapid scarring in the affected areas, i.e. scarring can prevent up to that moment, when axons will restore the relationship with each other. This, obviously, facilitates the recovery of the nerve pathways and connections.

Using the proposed in the invention compounds can be suppressed, in addition, the formation of ascites in patients. Equally with their help it is possible to suppress the swelling caused by VEGF.

Lymphangiogenesis plays an important role in lymphogenous metastasis (see Tographer and others, Cancere Res. for March 1, 2001, 61 (5), cc.1786-1790, .Veikkola and others, EMBO J. 15 March 2001, 20 (6), cc.1223-1231).

Proposed in the invention compounds are also extremely highly effective as inhibitors of VEGFR kinase 3 and it may be successfully used as active inhibitors of lymphangiogenesis. Treatment with compounds according to the invention allows not only to reduce the spread of metastases, but to reduce their number.

Proposed in the invention compounds exhibit its effectiveness and diseases that are associated with chrismer the m lymphangiogenesis and which are for this reason to the syndrome lymphangiectasia and dysplasia.

Medicines of this type, compositions containing them and their use are also the object of the present invention.

In accordance with this invention further relates to the use of compounds of General formula I to obtain drugs, respectively, to the use of this medicinal product for the treatment of psoriasis, Kaposi's sarcoma, restenosis, such as restenosis induced by the stent, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thromboangiitis, graft rejection and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with proliferation mesangial cells, arteriosclerosis, injuries to nerve tissue, and for inhibition of re-occlusion of vessels after treatment with use of balloon catheter, the prosthesis of the vessel or after application of mechanical devices, such as stents to maintain patency (clearance) vessels, as immunosuppressants, as an aid, contributing bezrucova tag the implementation of the RAS, senile spots and contact dermatitis.

In addition, using the proposed in the invention compounds can, as mentioned above, to suppress the formation of ascites in patients. Equally with their help it is possible to suppress the swelling caused by VEGF.

For the application of compounds of the formula I as a drug they are moved into the appropriate dosage form, i.e. the manufacture of a pharmaceutical preparation containing along with the active ingredient for enteral or parenteral application suitable for such purposes pharmaceutical organic or inorganic inert fillers such as, for example, water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like, the Pharmaceutical preparations can be produced in solid form, for example in the form of tablets, pills, suppositories, capsules or in liquid form, for example in the form of solutions, suspensions or emulsions. Optionally, the composition may include, in addition, excipients, such as preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or buffers.

For parenteral administration are especially suitable solutions for injection or suspension, primarily aqueous solutions of AK is active compounds in polyhydroxyserratane castor oil.

As systems-carriers can be used as surface-active excipients such as salts of bile acids or phospholipids of animal or vegetable origin, as well as their mixtures, as well as liposomes or their components.

For oral administration suitable especially tablets, coated tablets or capsules with talc and/or hydrocarbon filler or binders such as lactose, corn or potato starch. Can also be used in liquid dosage forms, such as medicine, to which if necessary add sweetener or one or more flavouring substances.

The dosage of active ingredients can vary depending on the method of administration of drugs, age and weight of the patient, type and severity of the particular disease and the like factors. Daily dose of from 0.5 to 1000 mg, preferably from 50 to 200 mg, and this dose can be assigned to a single dose or can be divided into two or more daily doses.

The above compositions and dosage forms are also object of the present invention.

Proposed in the invention may obtain the connection principle by known methods. So, for example, to obtain the compounds of General formula I, the compound of the General the formula II

in which a, b, D, G, L, M, Q, W and R1have the meanings mentioned for the General formula I, a E represents a COOH-group of the carboxylic acid are known from the literature methods in an appropriate solvent and an appropriate organic base interaction with the amine of General formula III

,

where R8and R9have the meanings indicated in the General formula I or, if E represents a nitrile group, a nitrile omelet with the formation of amide, or a compound of General formula IV

in which a, b, D, G, L, M, Q, W, R8and R9have the meanings mentioned for the General formula I, a Rxdenotes ester or acid group, is transferred to the corresponding amide.

The formation of amide carried out by methods known from the literature. For example, for the formation of amide can come from the corresponding complex ester. This ester as described in Journ. Org. Chem. (1995), s, the method is subjected to interaction with aluminization and the corresponding amine in solvents such as toluene, at temperatures between 0°C to the boiling point of the used solvent. In the presence of the molecule in the two ester groups, both of these groups are transferred in the same amide. the place of luminitzera can also be used hexamethyldisilazide sodium.

For the formation of amide, in addition to the above, can be used all methods known from the chemistry of peptides. Thus, in particular, the appropriate acid in an aprotic polar solvents such as dimethylformamide, via the activated derivative of the acid obtained, for example, using hydroxybenzotriazole and a carbodiimide, such as diisopropylcarbodiimide, or using the pre-generated reagents, such as GATA (Chem. Comm. (1994), C) or BTU, at temperatures in the range from 0°C to the boiling point of the used solvent, preferably at 80°With, is subjected to the interaction with the amine. For the formation of amide suitable method using mixed acid anhydride, imidazole or azide.

NITRILES using known literature methods can omelet with obtaining as a result of amides. Highly effective is the exchange reaction described in Synthesis (1989), s, using potassium carbonate and hydrogen peroxide in an aprotic polar solvent such as dimethylsulfoxide, preferably at room temperature.

Another opportunity to get proposed in the invention compounds of General formula I consists in the fact that the compound of General formula IIa

in which a, b, D, G, L, M, Q, W and R1matter, alazanies General formula I, a E is a halogen or O-sulfonate, such as a chlorine atom, bromine or iodine, O-triftorbyenzola or O-methylsulfonate,

a) is subjected to interaction with an appropriately substituted terminal alkenes by the reaction of Hakka (see "Palladium Reagents in Organic Syntheses", published by Academic Press (1985), New York, c.179 and forth) or vinylboronate acids or esters vinylboronic acid in the Suzuki reaction (see Tetrahedron Lett. 39 (1983), cc.3271 and forth) or vinylstyrene by the reaction of Style (see Pure &Appl. Chem. 57 (1985), C), or

b) subjecting the reaction combination with any manner of substituted terminal alkynes, for example by the method of Stephen Castro (see Journ. Org. Chem. 28 (1963), cc.3313 and forth), or a palladium catalysis method Sonogashira (see "Comprehensive Organic Synthesis: Carbon-Carbon σ-Bond Formation", published by Pergamon Press (1991), Oxford UK, volume 3, cc.551 and forth), or

C) subjecting the reaction combination with aryl - and getallbyname acids or their esters by the method of Suzuki (see Acc.Chem.Res. 63 (1991), cc.419 and forth, or Journ. Am. Soc. 122 (2000), cc.4020 and forth), or with aryl - and getinstancename according to the method of Stille (see Angew. Chem. 98 (1986), cc.504 and forth, or Angew. Chem. Int. Ed. (international edition) 38 (1999), cc.2411 and forth), or with aryl and getrolename compounds Grignard or similar tsinkorganicheskih derived by the method of Negishi (see "Metal-catalyzed Cross-coupling Reaction", Ed. by Diederich/Stang, published by Wiley-VCH (1998), New York, Chapter 1, or Journ. Am. Soc. 13 (2001), cc.2719 and forth), or

g) translated by palladium catalyzed carbonylation in the atmosphere of carbon monoxide at a pressure of from 1 to 20 bar in dimethylformamide in the presence of an appropriate alcohol (see "Palladium Reagents in Organic Syntheses", published by Academic Press (1985), New York, cc.352 and forth or Synth. Comm. 27 (1997), cc.515 and forth) in the corresponding ether carboxylic acid, or

d) translated by palladium catalyzed carbonylation in the atmosphere of carbon monoxide at a pressure of from 1 to 20 bar in mixtures of dimethylformamide and water to the corresponding carboxylic acid (see Journ. Org. Chem. 46 (1981), cc.4614 and beyond); carboxylic acids can also be obtained by saponification of the corresponding esters of carboxylic acids, or

e) is subjected to palladium catalyzed carbonyliron in an atmosphere of carbon monoxide at a pressure of from 1 to 20 bar in dimethylformamide in the presence of amines with the corresponding amides of carboxylic acids (see "Palladium Reagents in Organic Syntheses", published by Academic Press (1985), New York, cc.352 and forth, Tetrahedron Lett. 23 (1982), cc.3383 and beyond); the synthesis of amides of carboxylic acids can also be made on the basis of esters of carboxylic acids, particularly effective for this purpose has proved method Weinrebe (Weinreb) (see Tetrahedron Lett. 17 (1977), cc.4171 and forth, Journ. Org., Chem. 60 (1995), cc.8414 and beyond); amides of carboxylic acids can also be synthesized from the obtained in section e) carboxylic acid is t, using this purpose, in principle, all methods known from the chemistry of peptides (see Synthesis (1972), cc.453-463, or "Comprehensive Organic Transformations", published by Wiley-VCH (1989), New York, cc.972-976); for example, the corresponding carboxylic acid can be in aprotic polar solvents such as dimethylformamide, via the activated carboxylic acid derivative, obtained, for example, by the addition of carbonyldiimidazole, at temperatures in the range from 0 to 120°C, preferably at room temperature interaction with amines, such in particular as GATA (see Chem. Comm. (1994), s), or

g) interaction with thioalkyl-aalami-Getriebe directly, in the presence of bases, such as hydride or potassium tert-butanolate potassium, or transition metals, such as copper shavings, chloride or bromide of copper, or palladium dichloride, in an aprotic solvent, such as dimethylformamide, N-organic, dimethylsulfoxide or xylene, at temperatures in the range from 20 to 200°transferred to the corresponding sulfide; however, it may be appropriate to carry out this reaction in a microwave oven (see Tetrahedron 39 (1983), cc.4153 and below); 2-tizanidine peredelnye derivatives can also be obtained from 2-Spiridonovka derived after theonlyone pentasulfide phosphorus (see Bull. Soc. Chim.Fr. (1953), cc.1001 and forth) or reagent Losson (see Tetrahedron 40 (1984), cc.2047 and forth) and subsequent alkylation with alkylhalogenide, preferably by alkylidene (see Journ. Org. Chem. 64 (1999), cc.7935-7939) or alkyl sulphonates, preferably alkylarylsulfonate.

Further, the following possible actions:

C) oxidation of sulfides conventional oxidants such as hydrogen peroxide, periodate sodium tert-butoxyethanol, sodium chlorite, metachlorobenzoic acid, cryptocercus acid, dimethyldioxirane, ammoniumnitrate cerium or nitric acid (see "Oxidations in Organic Chemistry", published by ACS, Washington (1990), cc.252-263), in solvents such as dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide, N-organic, dimethylsulfoxide, dimethoxyethane, diglyme, tetralin or water, at temperatures in the range from 20°C to the boiling point of the used solvent can be obtained corresponding sulfoxidov. Thus obtained sulfoxidov can be further oksidirovanii to the corresponding sulfones; this operation is carried out, for example, using oxidizing agents such as hydrogen peroxide, potassium permanganate, perborate sodium or hydropersulfides potassium (see Tetrahedron Lett. 22 (1981), cc.1287 and beyond), in solvents such as dichloromethane, dichloroethane, PI is reform, tetrahydrofuran, acetonitrile, dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or water, at temperatures in the range from 20°C to the boiling point of the used solvent. Processing sulphides excess of the aforementioned oxidants leads directly to the corresponding sulfones (see "The chemistry of sulphones and sulfoxides" in Patai, the publishing house Wiley, New York (1988), cc.165-231).

and) oxidation obtained in section g) of thiols can be obtained chlorosulphonate, especially effective when this proved to oxidation with chlorine in aqueous hydrochloric acid (see Journ. Org. Chem. 64 (1999), cc.5896-5903)or carbon tetrachloride (see Journ. Med. Chem. 43)2000), cc.843-858), or sodium hypochlorite sulfuric acid (see Tetrahedron Asymm. 8 (1997), cc.3559-3562).

C) interaction with a mixture of copper thiocyanate and potassium thiocyanate in polar aprotic solvents, such as acetonitrile, dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, diglyme, tetralin or N-organic, can be obtained corresponding thiocyanates (see Journ. Chem. Soc. Chem. Comm. (1989), cc.81 and forth). Of these thiocyanates in turn by oxidation with hypochlorite can be obtained the corresponding acid chlorides of sulfonic acids.

l) interaction mentioned in section I) chlorosulfonated with amines in solvents such as dichloromethane, dichloroethane, chloroform, tetrahydrofuran, shall tracecut, acetonitrile, dimethylformamide, N-organic, N,N-dimethylacetamide, dimethoxyethane or water, at temperatures in the range from 0°C to the boiling point of the used solvent can be obtained from the corresponding sulfonamides (see Tetrahedron 56 (2000), cc.8253-8262).

m) by hydrolysis obtained in the section) chlorosulfonated in water or in an aqueous liquor at temperatures in the range from 5 to 100°get the corresponding sulfonic acids.

n) catalyzed by palladium interaction with Oh,O-dialkylphosphate in aprotic solvents, such as dimethylformamide, N-organic, N,N-dimethylacetamide, dimethylsulfoxide or toluene, in the presence of a base, such as triethylamine or diisopropylethylamine, at temperatures in the range from 0°C to the boiling point of the used solvent, preferably at 80°S, can be obtained corresponding phosphonates (see Bull. Chem. Soc. Jpn. 55 (1982), cc.909 and later).

o) by metallation, for example using n-utility, sec-utility, tert-utility, metallice, diisopropylamide lithium or ethylacetamide, in aprotic solvents, such as diethyl ether, tetrahydrofuran or dioxane, at temperatures in the range from -100°0°C, preferably at -78°in tetrahydrofuran, and the reaction with the isocyanates can be the particular appropriate amides of carboxylic acids.

p) reaction, as described in section o), and carbon capture metallizovannyh intermediates ether Harborview acid can be obtained the corresponding esters of carboxylic acids.

p) reaction, as described in section o), and carbon capture metallizovannyh intermediate products of dimethylformamide, ethyl formate or N-formylmorpholine can be obtained from the corresponding aldehydes.

(C) by a reaction similar to that described in section o), and carbon capture metallizovannyh intermediate products alkylhalogenide or alkyl sulphonates, preferably by alkylidene or alkylarylsulfonate can be obtained corresponding pyridylamine derivatives.

t) by reduction with hydrogen in the presence of catalytic amounts of palladium, Nickel or rhodium, or salts of these metals, for example palladium on charcoal, in a polar-proton solvents or mixtures of solvents, such as methanol - glacial acetic acid, obtained in section a) pyridylamine and obtained under b) pyridylamine can be translated into the appropriate pyridylamine.

The steps described stages of the method can in all cases be varied.

Getting proposed in the invention compounds

Following receipt of the clusters according to the invention is illustrated in more detail by way of examples, which do not limit its scope.

Example 1

Getting propylamide 5-{[2-(isoquinoline-3-ylcarbonyl)phenyl-amino]methyl}pyridine-2-carboxylic acid

In 2.5 ml of dimethylformamide in an argon atmosphere and eliminating the access of moisture injected 50 mg made (0.13 mmole) of 5-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid and 42 mg (0,26 mmole) of carbonyldiimidazole and stirred for 30 min at room temperature. Then to this mixture is added 15 mg (0,26 mmole) of n-Propylamine and within 12 hours continue stirring at room temperature. Then dilute with water to volume of about 30 ml and shaken out three times with ethyl ether, acetic acid, its portions to 20 ml of the Collected organic phase is dried, filtered and concentrated, and the residue chromatographic on the column for the Express chromatography (5 g of material Isolute flash silica, firm Separtis) by gradient elution, starting with 100%hexane and ending with a mixture of hexane and ethyl ester of acetic acid in the ratio 50%:50%. The result is 45 mg (79% of theory) of propylamide 5-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid with molar peak in the MS (mass spectroscopy) m/e=439.

Similar methods are also compounds of the following examples:

Example No.AndBDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.1N-CH3-CH3425,49
1.2N-CH(CH3)2N439,52resin/439
1.3NN437,50resin/437
1.4N-CH2CF3N
1.5N-(CH2)2-HEN441,49resin/441
1.6 N-(CH2)3HEN455,52resin/455
1.7N-(CH2)4OHN469,54resin/469
1.8NN455,52155
1.9NN455,52resin/455
1.10NN455,52109
1.11NN455,5282
1.12N483,87resin/483
1.13N-(CH2)2N(CH3)2N468,/468
1.14N-(CH2)3N(CH3)2N482,59/469
Example No.AInDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.15N-CH3-CH3425,49106

Example No.AndBDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.16N-CH3N411,46180
1.17N-C2H5N425,49165
1.18NN437,50172
1.19N-(CH2)2-HEN441,49136
1.20NN474,52207
1.21NN465,5594
1.22NN473,53187
1.23N-C3H7N439,5296
1.24N-CH(CH3)2N439,52174
1.25N N455,52103
1.26NN455,52110
1.27NN455,52105
1.28NN455,52100
1.29NN479,58110
1.30NN491,52204
1.31NN487,56151
1.32N-(CH2)3-HEN455,5265
1.33N-(CH2)5-HEN 483,5770
1.34N-(CH2)4-HEN469,5470
1.35N-(CH2)2N(CH3)2N455,5298
1.36N-(CH2)3N(CH3)2N482,5995
1.37NN503,56190

Example No.AndBDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.38NN474,52190
1.39NN474,52105
1.40N N483,5775
1.41NN469,5450
1.42NN469,54170
1.43N-(CH2)2OCH3N455,5267
1.44NN483,5786
1.45NN497,686
1.46NN483,5766
1.47NN495,58148
1.48NN517,58/td> 78
1.49NN517,5891
1.50NN471,5185
1.51NN497,5998
1.52NCH2CF3N479,4696
1.53NN495,58127
1.54NN497,5996

Example No.AndInDR2R3MMtPL[°]/malarney peak in the MS (m/e)
1.55N N469,5478
1.56NN469,5478
1.57NN510,59
1.58NN524,62
1.59NN469,54
Example No.AndBDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.60N-CH(CH2OH)2N488,4697
1.61N-(CH2)3HE500,52125
1.62N-(CH2)2-OMeN472,4667
1.63N-(CH2)5OHN500,5292
1.64N-(CH2)4OHN486,4973
1.65NN472,4682
1.66NN472,4673
1.67NN472,4687
1.68NN472,4693
1.69NN486,4967
1.70NN500,5267
1.71N-(CH2)2N(CH3)2N485,5182
1.72N-(CH2)3N(CH3)2N499,5374

Example No.AndBDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.73NN491,47142
1.74NN491,47104
1.75N N491,4773
Example No.AInDZMMtPL[°]/molar peak in the MS (m/e)
1.76N-CH3480,5799
Example No.AndInDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.77NN473,50
1.78NN473,50
1.79NN473,50
1.80N N473,50
1.81N-(CH2)3N(CH3)2N486,54

Example No.AndBDR2R3MMtPL[°]/molar peak in the MS (m/e)
1.82N-(CH2)3HEN500,5280
1.83NN472,4650
1.84NN472,4683
1.85NN472,46129
1.86N N491,47150
1.87NN491,47148
1.88N-(CH2)5OHN500,52101
1.89N-CH(CH2OH)2N488,46144
1.90N-(CH2)3N(CH3)2N499,53117
1.91N-(CH2)2-OMeN472,4654
1.92NN491,47121
1.93N-(CH2)2N(CH3)2N485,51139
1.94N 500,5270
1.95NN486,4988
1.96NN472,4676
1.97N-(CH2)4OHN488,52

Example No.AndBDR1R2R3MMtPL[°]/molar peak in the MS (m/e)
1.98NN459,50
1.99NN458,51
1.100NN458,51
1.101NN444,49
1.102NN444,49
1.103NN458,51
1.104NN458,51
1.105NN444,49
1.106N N444,49

Example No.AndBDR1R2R3MMtPL[°]/molar

the peak in the MS (m/e)
1.107NH459,50160,7
1.108NH459,50123,8
1.109NH459,50123
1.110NH459,50
1.111N H502,52199,2
1.112NH502,52180,4
1.113NH502,52
1.114NH499,56
1.115NH499,56174
1.116NH499,56173,8
1.117NH 458,51
1.118NH458,51

Example No.AndInDR1R2R3MMtPL[°]/molar peak in the MS (m/e)
1.119NH458,51
1.120NH458,51
1.121NH444,49
1.122NH444,49#x0200A;
1.123NH444,49
1.124NH444,49
1.125NH502,52

Example 2.0

Getting pyridine-3-ylamide 5-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

120 mg (0.3 mmole) of 5-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid is dissolved in an atmosphere of argon in 5 ml of absolute dimethylformamide, mixed with 56 mg (0.6 mmole) of 3-aminopyridine, 76 mg (0.75 mmole) of N-methylmorpholine and 136 mg (0,36 mmole) of hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (GATA) and stirred for 48 h at room temperature. Then concentrated in vacuo and the residue chromatographic on the column for the Express chromatography (5 g of material Isolute flash silica, firm Sepostis) by gra is inert elution, using as eluent methylene chloride:ethanol in a ratio of 100:0-95:5. The result pyridine-3-ylamide 5-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid.

MS (m/e 474).

A similar technique also receive the following connections:

Example No.AndInDR2R3MMtPL[°]/molar peak in the MS (m/e)
2.1NN474,52474 (m/e)
2.2NN474,52474 (m/e)

Example 3.0

Getting amide 5-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

36 mg (0,09 mmole) 2-[(6-cyano-3-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamide mixed in 1 ml of dimethyl sulfoxide with 30 mg (0.22 mmole) of potassium carbonate and 0.05 ml (at 0.42 mmole) of hydrogen peroxide (30%) and stirred for 3.5 h at room tempera is ur. Then diluted with water and extracted with ethyl ester of acetic acid.

The organic phase is washed, dried, filtered and concentrated. The remainder is shared by mixing with warm methanol. The result is 5 mg (11% of theory) amide 5-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid.

A similar technique also receive the following connections:

Example 3.1

Amide 4-{[2-(7-methoxy-3-methylinosine-2-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.2

Amide 4-{[2-(7-methoxy-2-oxo-2H-chromen-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.3

Amide 5-{[2-(7-methoxy-2-oxo-2H-chromen-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.4

Amide 5-{[2-(7-methoxy-3-methylinosine-2-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.5

Amide 4-{[2-(isoquinoline-3-ylcarbonyl)-6-azafenidin]methyl}pyridine-2-carboxylic acid

Example 3.6

Amide 5-{[2-(2-oxo-2,3-dihydro-1H-indole-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.7

Amide 4-{[2-(2-methyl-2H-and dasol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.8

Amide 4-{[2-(1H-indazol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.9

Amide 4-{[2-(1-methyl-1H-indazol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 3.10

Amide 5-{[2-(isoquinoline-3-ylcarbonyl)-6-azafenidin]methyl}pyridine-2-carboxylic acid

Example 3.11

Amide 4-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example 4.0

Obtain N-tert-butylamide 4-{[2-(isoquinoline-3-ylcarbonyl)-6-azafenidin]methyl}pyridine-2-carboxylic acid

In 5 ml of toluene in a protective gas atmosphere and eliminating the access of moisture 72 mg (0.5 mmole) 3-aminoisoquinoline mixed with 0.25 ml of trimethylaluminum (0.5 mmole, 2-molar in toluene) and stirred for 30 min at room temperature. Then add 120 mg (0.45 mmole) of the methyl ester of 2-[(2-tert-butylcarbamoyl-4-ylmethyl)amino]nicotinic acid for 2 h, heated to 120°C. After cooling, mixed with 30 ml of dilute sodium hydrogen carbonate solution and extracted three times with ethyl ether, acetic acid, its portions 30 ml. Collected oxynoe the IRNA phase is washed with water, dry, filter and concentrate. The remainder chromatographic on silica gel, using as eluent methylene chloride: ethanol in a ratio of 95:5. After repeated chromatography on silica gel, using as eluent hexane: ethyl ester of acetic acid in the ratio of 1:1, receive 70 mg (30% of theory) of N-tert-butylamide 4-{[2-(isoquinoline-3-ylcarbonyl)-6-azafenidin]methyl}pyridine-2-carboxylic acid with a melting point 201°C.

Example 5.0

Receive (2-hydroxypropyl)amide of 4-{[2-(isoquinoline-3-ylcarbonyl)-6-azafenidin]methyl}pyridine-2-carboxylic acid

283 mg (1 mmol) of 2-chloro-N-isoquinoline-3-iniatiated mixed in 5 ml of pyridine with approximately of 1.66 mmole (2-hydroxypropyl)amide of 4-aminomethylpyridine-2-carboxylic acid for 2 h, heated to 100°C. After concentration was dissolved in water and extracted three times by shaking with ethyl ether acetic acid its portions to 30 ml of the Collected organic phase is washed with water, dried, filtered and concentrated. The remainder chromatographic on silica gel, using as eluent methylene chloride: acetone in the ratio 1:1. The result is 40 mg (9% of theory) of (2-hydroxypropyl)amide of 4-{[2-(isoquinoline-3-ylcarbonyl)-6-azafenidin]methyl}pyridine-2-carboxylic acid in the form of resin.

Example 6.0

Obtaining the foreign N-(isoquinoline-3-yl)-2-[3-(pyridin-3-yl)pyridine-4-ylmethylamino]benzoic acid

94 mg (0.22 mmole) of amide N-(isoquinoline-3-yl)-2-[3-bromopyridin-4-ylmethylamino]benzoic acid sequentially mixed in 3.7 ml of toluene with 0.73 ml of ethanol, 0,36 ml of 2-molar sodium carbonate solution, 6 mg of palladium(0)tetranitroaniline and 32 mg of pyridine-3-Bronevoy acid for 6.5 h was heated to a temperature bath 120°C. Then diluted with water to a volume of 25 ml and extracted three times with ethyl ether, acetic acid, its portions 25 ml. Collected exploiting phase is dried, filtered and concentrated. The remainder chromatographic on silica gel using as elution solvent of methylene chloride and ethanol in a ratio of 10:1. The result is 45 mg (47% of theory) of amide N-(isoquinoline-3-yl)-2-[3-(pyridin-3-yl)pyridine-4-ylmethylamino]benzoic acid in the form of resin.

1H-NMR (d6-DMSO): is 10.68 (s, 1H), of 9.21 (s, 1H), 8,72 (s, 1H), 8,64 (d, J=3,8, 1H), to 8.57 (d, J=5,1, 1H), 8,54 (s, 1H), 8,48 (s, 1H), 8,11-7,94 (m, 4H), a 7.85 (d, J=7,6, 1H), 7,74 (t, J≈and 7.3, 1H), to 7.59-7,47 (m, 3H), of 7.23 (t, J≈and 7.5, 1H), 6,63 (t, J=7,5, 1H), to 6.39 (d, J=8,3, 1H), 4,45 (d, J=5,0, 2H).

MC (CI-NH3): 432 (80%, [M+H]+).

Example 6.1

Getting amide N-(isoquinoline-3-yl)-2-[3-(Tien-3-yl)pyridine-4-ylmethylamino]benzoic acid

A similar technique also receive amide N-(isoquinoline-3-yl)-2-[3-(Tien-3-yl)pyridine-4-ylmethylamino]benzoic acid

MC (CI-NH3): 437 (100%, [M+H]+ ).

Example 6.2

Getting amide N-(isoquinoline-3-yl)-2-[2-aminocarbonylmethyl-4-ylmethylamino]benzoic acid

130 mg (0,34 mmole) amide N-(isoquinoline-3-yl)-2-[2-cyano-4-ylmethylamino]benzoic acid are mixed in 2.5 ml of dimethyl sulfoxide with 126 mg of potassium carbonate and 0.25 ml of hydrogen peroxide (30%) and stirred for 1 h at room temperature. Then mixed with water and precipitated precipitated product is separated by vacuum filtration. The residue is stirred in a mixture of methylene chloride and ethanol and separated by vacuum filtration. The result is 96 mg (71% of theory) of amide N-(isoquinoline-3-yl)-2-[2-aminocarbonylmethyl-4-ylmethylamino]benzoic acid with a melting point of 200°C.

1H-NMR (d6-DMSO): of 10.73 (s, 1H), which 9.22 (s, 1H), at 8.60 (s, 1H), 8,56 (d, J=4,7, 1H), 8,25 (.s, 1H), 8,10-of 8.04 (m, 3H), 7,95 (d, J=8,0, 1H), 7,88 (d, J=6,9, 1H), 7,74 (t, J≈7,4, 1H), 7,63-EUR 7.57 (m, 3H), 7,25 (t, J≈7,0, 1H), only 6.64 (t, J≈and 7.5, 1H), is 6.54 (d, J=8,4, 1H), 4,62 (.d, J=5,5, 2H).

MC (EI): 397 (38%, [M]+).

Example 6.3

Getting amide N-(isoquinoline-3-yl)-2-[(2-aminocarbonylmethyl-5-yl)methylamino]benzoic acid

A similar technique also receive amide N-(isoquinoline-3-yl)-2-[(2-aminocarbonylmethyl-5-yl)methylamino]benzoic acid

MC (ESI): 398 (78%, [M+H]+).

Example 6.4

Getting amide N-(isoquinoline-3-yl)-2-[(2-methoxycarbonyl pyridin-4-yl)methylamino]benzoic acid

20 mg (0.05 mmole) of amide N-(isoquinoline-3-yl)-2-[2-bromopyridin-4-ylmethylamino]benzoic acid, 1.6 mg (0,003 mmole) bis(diphenylphosphine)ferrocene (DFFF), 0.35 mg (0.0015 mmole) of palladium acetate(II), 14 μl (0.1 mmole) of triethylamine are suspended in a mixture of 1 ml of methanol and 1 ml of dimethylformamide and within 5 h stirred autoclave in the atmosphere (3 bar) at 50°C. Then the reaction the mixture is filtered through a membrane filter, concentrate, and at the end chromatographic on silica gel, using as eluent hexane: EtOAc in a ratio of 3:7. The result is 12 mg (58% of theory) of amide N-(isoquinoline-3-yl)-2-[(2-methoxycarbonylmethyl-4-yl)methylamino]benzoic acid.

1H-NMR (CDCl3): 9,12 (.s, 1H), to 8.94 (s, 1H), 8,67 (s, 1H), 8,61 (d, J=5,1, 1H), at 8.36 (.s, 1H), of 8.09 (s, 1H), 7,87 (d, J=8,5, 1H), 7,81 (d, J=8,5, 1H), 7,71 (d, J=7,7, 1H), to 7.64 (t, J≈7,8, 1H), 7,49-7,44 (m, 2H), 7.24 to 7,19 (m, 1H), of 6.68 (t, J≈7,8, 1H), 6.42 per (d, J=8,0, 1H), 4,50 (.s, 2H), 3,93 (s, 3H).

MC (ESI): 413 (100%, [M+H]+).

Example 6.5

Getting amide N-(isoquinoline-3-yl)-2-[(2-benzyloxycarbonylamino-4-yl)methylamino]benzoic acid

A similar technique also receive amide N-(isoquinoline-3-yl)-2-[(2-benzyloxycarbonylamino-4-yl)methylamino]benzoic acid

1H-NMR (CDCl3): 9,00 (s, 1H), 8,76 (.s, 1H), 8,68 (d, J=5,0, 1H), 8,66 (s, 1H), 8,39 (t, J≈6,1, 1H), 8,14 (s, 1H), to $ 7.91 (d, J=7,9, 1H), a 7.85 (d, J=8,0, 1H), 7,69 to 7.62 (m, 2H), 7,53-7,46 (m, 4H), 7,38-7,25 (m, 4H), 6.73 x (t, ≈ 7,2, 1H), 6.48 in (d, J=7,8, 1H), 5,44 (s, 2H), 4,56 (d, J=6,0, 2H).

MC (CI-NH3): 489 (85%, [M+H]+).

Example 6.6

Getting amide N-(isoquinoline-3-yl)-2-[(2-hydroxycarbonylmethyl-4-yl)methylamino]benzoic acid

a) 20 mg (0.05 mmole) of amide N-(isoquinoline-3-yl)-2-[(2-methoxycarbonylmethyl-4-yl)methylamino]benzoic acid are mixed in a mixture of 1 ml of tetrahydrofuran and 1 ml of methanol with 10.2 mg (0.25 mmole) of lithium hydroxide in water for 4 h, stirred at 22°C. Then the reaction mixture was filtered through a membrane filter, and concentrate chromatographic on silica gel, using as eluent toluene, acetic acid and water in the ratio 10:10:1. The result is 14 mg (69% of theory) of amide N-(isoquinoline-3-yl)-2-[(2-hydroxycarbonylmethyl-4-yl)methylamino]benzoic acid.

b) 433 mg (1 mmol) of amide N-(isoquinoline-3-yl)-2-[(2-bromopyridin-4-yl)methylamino]benzoic acid, 50 mg (0,09 mmole) bis(diphenylphosphine)ferrocene (DFFF), 10 mg (of 0.045 mmole) of palladium(II)acetate, 280 μl (2 mmole) of triethylamine are suspended in a mixture of 5 ml of water and 10 ml of dimethylformamide and within 5 h stirred autoclave in the atmosphere (3 bar) at 50°C. Then the reaction mixture was filtered through a membrane filter, concentrated, dissolved in dichloromethane, mixed with activated carbon, heated, filtered and concentrated. The obtained solid is the second substance is recrystallized from dichloromethane. The result 283 mg (71% of theory) of amide N-(isoquinoline-3-yl)-2-[(2-hydroxycarbonylmethyl-4-yl)methylamino]benzoic acid.

1H-NMR (d6-DMSO): of 10.73 (s, 1H), which 9.22 (s, 1H), 8,63 (d, J=4,9, 1H), at 8.60 (s, 1H), they were 8.22 (.t, J≈6,0, 1H), 8,10 (d, J=8,0, 1H), 8,04 (s, 1H), 7,94 (d, J=8,1, 1H), 7,87 (d, J=6,8, 1H), 7,74 (t, J≈7,5, 1H), 7,60-rate of 7.54 (m, 2H), 7,25 (t, J≈7,0, 1H), 6,65 (t, J≈and 7.6, 1H), is 6.54 (d, J=8,4, 1H), 4,62 (.d, J=5,5, 2H). Proton not observed or closed.

MS (CI-NH3): 399 (75%, [M+H]+).

Melting point: 185°C.

Example 6.7

Getting amide N-(isoquinoline-3-yl)-2-[(2-morpholinosydnonimine-4-yl)methylamino]benzoic acid

A mixture of 40 mg (0.1 mmole) of amide N-(isoquinoline-3-yl)-2-[(2-hydroxycarbonylmethyl-4-yl)methylamino]benzoic acid and 9 μl (0.1 mmole) of the research in 1 ml portions of dimethylformamide is mixed with 34 mg (0.2 mmole) of carbonyldiimidazole. After 4 hours stirring at 22°the mixture is concentrated and the residue is dissolved in 5 ml of dichloromethane, washed with 1-molar aqueous solution of potassium carbonate (2 ml), dried over MgSO4filter and concentrate. The result is a colorless resin (38 mg, 81% of theory).

1H-NMR (CDCl3): of 9.02 (s, 1H), 8,71 (.s, 1H), 8,64 (s, 1H), 8,51 (d, J=5,1, 1H), at 8.36 (t, J≈6,0, 1H), 8,01 (s, 1H), 7,93-of 7.82 (m, 2H), 7,69-to 7.64 (m, 2H), 7,50 (t, J≈7,8, 1H), 7,39 (d, J=6,1, 1H), 7,28-7,20 (m, 1H), 6.73 x (t, J≈7,8, 1H), of 6.52 (d, J=8,1, 1H), 4,55 (d, J=6,0, 2H), 3,79-3,62 (m, 8H).

MC (EI): 467 (15%, [M+H]+

Example 6.8

Getting amide N-(isoquinoline-3-yl)-2-[(3-trimethylsilylethynyl-4-yl)methylamino]benzoic acid

108 mg (0.25 mmole) of amide N-(isoquinoline-3-yl)-2-[(3-bromopyridin-4-yl)methylamino]benzoic acid are mixed in 1 ml of dimethylformamide with 1 ml of triethylamine, 5 mg (0.026 mmole) of copper iodide(I), 9 mg (0,008 mmole) of paradimethylaminobenzaldehyde and 0.07 ml of trimethylsilylacetamide and then in argon atmosphere, excluding the access of moisture, heated for 3.5 h to a temperature bath of 70°C. Then stirred into 40 ml of water and extracted three times ethyl ester of acetic acid its portions 25 ml. Exploiting phase is washed with water, dried, filtered and concentrated. The remainder chromatographic on silica gel, using as eluent ethyl ester acetic acid:hexane in a ratio of 1:1. The result is 38 mg (33.6% of theory) of amide N-(isoquinoline-3-yl)-2-[(3-trimethylsilylethynyl-4-yl)methylamino]benzoic acid as an amorphous solid.

1H-NMR (d6-DMSO): 10,71 (s, 1H), which 9.22 (s, 1H), to 8.62 (s, 1H), 8,58 (s, 1H), 8,49 (d, J=4,9, 1H), 8,21 (.t, J≈6,1, 1H), of 8.09 (d, J=8,2, 1H), 7,92 (d, J=8,0, 1H), 7,88 (d, J=7,9, 1H), 7,74 (t, J≈8,0, 1H), EUR 7.57 (t, J≈and 7.7, 1H), 7,40 (d, J=5,1, 1H), 7,28 (t, J≈and 7.5, 1H), 6,65 (t, J≈and 7.7, 1H), is 6.54 (d, J=8,1, 1H), 4,58 (d, J=6,0, 2H), 0,27 (s, 3H).

MC (EI): 450 (105%, [M]+).

Example 6.9

Getting amide N-(isoquinoline-3-yl)-2-[(2-trimethy similarerin-4-yl)methylamino]benzoic acid

According to the method similar to that described in example 9, also receive amide N-(isoquinoline-3-yl)-2-[(2-trimethylsilylethynyl-4-yl)methylamino]benzoic acid

Obtaining initial and intermediate connections

If the production of intermediate compounds is not described, it is assumed that these compounds are known or can be obtained analogously to known compounds or using the steps described in the present application methods.

Example

Stage 1 of the method

A-1) preparation of 2-bromopyridin-5-carbaldehyde

2-bromopyridin-5-carbaldehyde receive according to the method described F.J.Romero-Salguerra and others in THL 40 (1999), s.

A-2) Obtaining 2-bromoisonicotinic acid

160 g (of 0.93 mol) of 2-bromo-4-methylpyridine added dropwise to 152 g (of 0.96 mol) of potassium permanganate in 4 l of water. Then after one-hour stirring under reflux re-add 152 g (of 0.96 mol) of potassium permanganate. After a further 2 hours of stirring under reflux was filtered while hot through celite and washed with water. The aqueous phase is shaken out three times with dichloromethane. Then the aqueous phase is concentrated to half its volume and using concentrated hydrochloric acid, the pH is adjusted to a value of 2. Bypass the e precipitated solid is separated by vacuum filtration and 70° With dried under vacuum. The result of 56.5 g (28% of theory) 2-bromoisonicotinic acid in the form of a solid white product.

A-3) Obtaining 2-bromo-4-hydroxymethylbenzene

To 56,5 g (280 mmol) of 2-bromoisonicotinic acid in 1.2 l of tetrahydrofuran (THF) is added to 30.2 ml (295 mmol) of triethylamine. Then cooled to -10°and dropwise mix from 38.2 ml (295 mmol) of isobutyl ether of Harborview acid. After one-hour stirring at -10°the mixture is cooled to -70°and dropwise mixed with 590 ml (590 mmol) of a solution of lithium aluminum hydride (LiAlH4) (1-molar in THF). After one-hour stirring at -70°With the temperature allowed to rise to -40°C. Next, add 600 ml of 50%acetic acid. During the night stirred at room temperature. Insoluble components are separated by vacuum filtration and the filtrate concentrated. The residue is purified on silica gel with hexane and hexane/ethyl ester of acetic acid in the ratio of 1:1. The result of 28.0 g (55% of theory) of 2-bromo-4-hydroxymethylbenzene as zatverdevaya oil white.

A-4) to Obtain 2-bromo-4-formylpyridine

To 28,0 g (148,9 mmole) of 2-bromo-4-hydroxymethylbenzene in 500 ml of dichloromethane added dropwise within 6 h 149 g (1714 mmol) of pyrolusite. Then use the e stirred for 48 h at room temperature. Next off by vacuum filtration through celite and concentrated. The result of 16.4 g (60% of theory) of 2-bromo-4-formylpyridine as zatverdevaya oil white.

Stage 2 of the method

A-5) Obtaining 2-[(6-bromopyridin-3-ylmethyl)amino]-N-isoquinoline-3-ilasamaja

of 3.46 g (13,17 mmole) of 2-amino-N-isoquinoline-3-ilasamaja previously placed in 50 ml of methanol, then mixed with 1.5 ml of glacial acetic acid and 2.45 g (13,17 mmole) 2-bromopyridin-5-carbaldehyde, and then within 24 h was stirred at room temperature in an argon atmosphere, excluding the access of moisture. Further admixed 828 mg (13,17 mmole) of lamborginid sodium and continue stirring at room temperature during the next 24 hours After concentration under vacuum, the residue is dissolved in dilute sodium hydrogen carbonate solution and is separated by vacuum filtration. The obtained residue was stirred in a small amount of ethyl ester of acetic acid and again separated by vacuum filtration. Thus obtained residue chromatographic on silica gel, using as eluent hexane and ethyl ester of acetic acid in the ratio of 1:1. The result of 3.27 g (57% of theory) of 2-[(6-bromopyridin-3-ylmethyl)amino]-N-isoquinoline-3-ilasamaja.

A-6) obtaining the amide N-(isoquinoline-3-yl)-2-[3-bromo is iridin-4-ylmethylamino]benzoic acid

263 mg (1 mmol) of amide N-(isoquinoline-3-yl)-2-aminobenzoic acid sequentially mixed in 6 ml Meon with 0.06 ml of glacial acetic acid, 298 mg (1.6 mmole) of 3-bromopyridin-4-carbaldehyde (receiving according to Tetrahedron 2000, s) and stirred for 24 h at room temperature. Then add 100 mg (1.6 mmole) of lamborginid sodium and continue stirring for a further 24 hours Then stirred into 50 ml of dilute sodium hydrogen carbonate solution and precipitated precipitated product is separated by vacuum filtration. The remainder chromatographic on silica gel using as eluent a mixture of methylene chloride and ethanol in the ratio 95:5. The result amide FM-(isoquinoline-3-yl)-2-[3-bromopyridin-4-ylmethylamino]benzoic acid in the form of a resin. Used in the reaction of 3-bromopyridin-4-carbaldehyde receive according to the method described in Chem. Pharm. Bull., 38 (1970), s.

A similar technique also receive the following connections:

A-7) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-isoquinoline-3-ylbenzene

1H-NMR (CDCl3): 9,00 (s, 1H), 8,78 (s, 1H), 8,66 (s, 1H), 8,35 (t, J≈5,7, 1H), 8,30 (d, J=5,1, 1H), 7,92 (d, J=8,1, 1H), 7,86 (d, J=8,5, 1H), 7,70-the 7.65 (m, 2H), 7,53-of 7.48 (m, 2H), 7,33-7,26 (m, 2H), 6.75 in (t, J≈7,8, 1H), 6.48 in (d, J=8,5, 1H), 4,48 (d, J=5,9, 2H).

MS (Cl, NH3): 435 (100%), 433 (100%).

A-8) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(2-oxo-2,3-digitron-indol-6-yl)benzamid

A-9) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamid

A-10) 2-[(6-bromopyridin-3-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)benzamid

A-11) 2-[(6-bromopyridin-3-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamid

A-12) 2-[(6-bromopyridin-3-ylmethyl)amino]-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamid

A-13) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamid

A-14a) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(3-triptoreline)benzamid

A-14b) 2-[(6-bromopyridin-3-ylmethyl)amino]-N-(7-methoxy-3-methylinosine-2-yl)benzamid

Stage 3 ways

A-15) to Obtain 5-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

of 3.27 g (of 7.55 mmole) 2-[(6-bromopyridin-3-ylmethyl)amino]-N-isoquinoline-3-ilasamaja mixed in 75 ml of dimethylformamide with 2.2 ml of triethylamine, 36 ml of water, 362 mg (0.65 mmole) of bidimensionality and 75 mg (0,33 mmole) of palladium(II) acetate and shaken in an autoclave in an atmosphere of carbon monoxide at a pressure of 3 bar and a temperature of 50°C for 3 h P the following cooling carried out on silica gel vacuum filtration and the filtrate concentrated. The residue is dissolved in water, using glacial acetic acid pH is adjusted to a value of 5-6 off by vacuum filtration and the filter cake washed with hexane. The result at 3.35 g of 5-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid, which without further purification used in the subsequent exchange reaction.

A similar technique also receive the following connections:

A-16) 4-{[2-(isoquinoline-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-17) 4-{[2-(2-oxo-2,3-dihydro-1H-indole-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-18) 5-{[2-(2-oxo-2,3-dihydro-1H-indole-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-19) 4-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-20) 5-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-21) 5-{[2-(7-methoxy-2-oxo-2H-chromen-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-22) 4-{[2-(7-methoxy-2-oxo-2H-chromen-3-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-23) 4-{[2-(7-methoxy-3-methylinosine-2-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-24) 5-{[2-(7-methoxy-3-methylinosine-2-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-25) 5-{[2-(1-methyl-1H-indazol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-26) 4-{[2-(1-methyl-1H-indazol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-27) 4-{[2-(2-methyl-2H-indazol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-28) 5-{[2-(2-methyl-2H-indazol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-29) 4-{[2-(3-cryptomaterial)phenylamino]methyl}pyridine-2-carboxylic acid

melting point 151°C;

A-30) 4-{[2-(1H-indazol-6-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

A-31) 4-{[2-(1H-indazol-5-ylcarbonyl)phenylamino]methyl}pyridine-2-carboxylic acid

Example B

Stage 1 of the method

B-1) preparation of 5-nitro-1,3-dihydroindol-2-it

5-nitro-1,3-dihydroindol-2-he will get the method R.T.Courts, described in Journ. Org. Chem. 48 (1970), s.

B-2) obtaining the methyl ester dinitrophenolates acid

22,6 g (100 mmol) of 2,4-dinitrophenoxy acid dissolved in a mixture of 200 ml of methanol and 830 ml of toluene and, at room temperature mixed with 83 ml trimethylsilyldiazomethane (2-molar in toluene, 166 mmol) and then for 3 h and stirred at room temperature. After concentration to dryness, and drying at 70°under vacuum get 24 g (100% of theory) of methyl ether of 2,4-dinitrophenoxy acid.

B-3) Receiving 6-nitro-1,3-dihydroindol-2-it

20 g (83 mmole) methyl ester 2,4-dinitrophenoxy acid hydronaut in 400 ml of glacial acetic acid using 2.1 g of palladium on coal (10%) at a pressure of 20 bar of hydrogen for 1.5 h at room temperature. After filtering off the catalyst and concentrate intensively dried over solid potassium hydroxide under vacuum. The remainder chromatographic on silica gel with a gradient elution using as elution solvent a mixture of methylene chloride and ethanol in the ratio from a 97.5:2.5 to 90:10. After recrystallization from ethyl ether-acetic acid get 4 g (30% of theory) of 6-nitro-1,3-dihydroindol-2-one with a melting point of 206°C.

Stage 2 of the method

B-4) to Obtain 5-and the Ino-1,3-dihydroindol-2-it

356 mg of 5-nitro-1,3-dihydroindol-2-it hydronaut in 30 ml of a mixture of tetrahydrofuran and ethanol (ratio 1:1) using 400 mg of palladium on coal (10%) at room temperature and normal pressure for 1 h After removal of the catalyst by vacuum filtration on diatomaceous earth and concentration get 320 mg (100% of theory) of 5-amino-1,3-dihydroindol-2-it.

B-5) to Obtain 6-amino-1,3-dihydroindol-2-it

In a similar way, proceeding from the corresponding nitro compounds, receive a 6-amino-1,3-dihydroindol-2-it.

Stage 3 ways

B-6) 2-nitro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamid

In 1 ml of dimethylacetamide is dissolved 320 mg of 5-amino-1,3-dihydroindol-2-she dropwise and mixed with 371 mg (2 mmole) of 2-nitrobenzotrifluoride, thus there is a small temperature increase. After stirring overnight at room temperature, concentrated under vacuum and the residue is dissolved in ethyl ether, acetic acid and water. After removal of the vacuum filtration of insoluble solids obtain 130 mg (21,9% of theory) of 2-nitro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamide. After extraction by shaking the organic phase is washed, filtered and concentrated and the resulting re-obtain 400 mg (67% of theory) of 2-nitro-N-(2-oxo-2,-dihydro-1H-indol-5-yl)benzamide with a melting point of 265° C.

B-7) to Obtain 2-nitro-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)benzamide

By the method similar to stage 1 of the method, get the 2-nitro-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)benzamide with a melting point >300°C.

Stage 4 way

B-8) obtaining the amide of 2-amino-N-(indole-2-he-5-yl)benzoic acid

By the method similar to step 2 of the method, also receive amide of 2-amino-N-(indole-2-he-5-yl)benzoic acid with a melting point of 219°C.

B-9) obtaining the amide of 2-amino-N-(indol-2-one-6-yl)benzoic acid

By the method similar to stage 2, get amide of 2-amino-N-(indol-2-one-6-yl)benzoic acid with a melting point 230°C.

The example In

B-1) preparation of 2-amino-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamide

Stage 1 of the method

B-2) Obtaining 3-nitro-7-methoxypropan-2-it

13 g (85,4 mmole) of 2-hydroxy-4-methoxybenzaldehyde for 15 h heated in 300 ml of toluene using a water separator together with 9.8 g (102,5 mmole) of n-propellerhydrochloride and 11.5 ml (102,5 mmole) ethyl ester nitroxyl acid and boil further for 5 hours using a water separator. After cooling, diluted with ethyl ether, acetic acid and xtraceroute by shaking with water. Exploiting phase is dried, filtered and concentrated. The remainder chromatographic on silica gel using methylene chloride as eluent. The result 6,14 g (33% of theory) of 3-nitro-7-methoxypropan-2-it.

Stage 2 of the method

B-3) Receiving 3-amino-7-methoxypropan-2-it

By the method similar to step 2 of the method of example B, on the basis of 3-nitro-7-methoxypropan-2-she ethanol 3-amino-7-methoxypropan-2-it.

Stage 3 ways

B-4) obtaining the amide 2-nitro-N-(7-methoxybenzophenone-2-he-3-yl)benzoic acid

By the method similar to stage 3 of the method of example B, based on 2-nitrobenzaldehyde and 3-amino-7-methoxypropan-2-it, 2-nitro-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamide get amide 2-nitro-N-(7-methoxybenzophenone-2-he-3-yl)benzoic acid.

Stage 4 way

B-5) Obtaining 2-amino-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamide

By the method similar to step 2 of the method of example B, based on 2-nitro-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamide in toluene/tetrahydrofuran (ratio 5:2) to obtain 2-amino-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamide.

Example D

G-1) preparation of 2-[(6-cyano-3-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamide

219 mg (0.5 mmole) 2-[(6-bromopyridin-3-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamide placed in 7 ml of dimethylacetamide, adding 59 mg (0.5 mmole) of cyanide of zinc(II), 12 mg (0,013 mmole) of Tris(dibenzylideneacetone)diplodia, 10 mg (0,018 mmole) of bis(diphenylphosphino)ferrocene and 4 mg (0.06 mmole) of zinc powder in an argon atmosphere, excluding this access of moisture, stirred for 7.5 hours at a bath temperature of 150°C. After cooling, the mixture is diluted with water, shaken out with ethyl ether, acetic acid and the organic phase is dried, filtered and concentrated. The remainder chromatographic on silica gel by gradient elution using as elution solvent a mixture of methylene chloride/ethanol in a ratio of a 97.5:2.5 to 90:10. The result is 65 mg (30% of theory) of 2-[(6-cyano-3-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamide.

A similar technique also get the following connection:

G-2) 2-[(6-cyano-3-ylmethyl)amino]-N-(7-methoxy-2-oxo-2H-chromen-3-yl)benzamid

Example D

Stage 1 of the method

D-1) obtaining the methyl ester of 2-chloronicotinic acid

5.6 g of 2-chloronicotinic acid are dissolved in 280 ml of toluene and 80 ml of methanol, mixed with 37.4 ml (74.8 mmole) trimethylsilyldiazomethane (2-molar in hexane) and t is the increase stirred for 3 h at room temperature. After concentration of the mixture get 7 grams (100% of theory) of methyl ester of 2-chloronicotinic acid.

Stage 2 of the method

D-2) obtaining the methyl ester of 2-[(pyridine-4-ylmethyl)amino]nicotinic acid

4.0 g (23,3 mmole) of methyl ester of 2-chloronicotinic acid for 1.5 h heated 2,52 g (23,3 mmole) of 4-aminomethylpyridine to a temperature bath of 100°C. After cooling, diluted with 100 ml of dilute sodium hydrogen carbonate solution and extracted three times by shaking with ethyl ether acetic acid his portions of 50 ml the Combined organic phase is washed, dried, filtered and concentrated. The remainder chromatographic on silica gel, using as eluent a mixture of methylene chloride/ethanol in a ratio of 10:1. The result of 1.36 g (24% of theory) methyl ester 2-[(pyridine-4-ylmethyl)amino]nicotinic acid.

A similar technique also get the following connection:

D-3) methyl ester 2-[(pyridine-3-ylmethyl)amino]nicotinic acid

Stage 3 ways

D-4) methyl ester 2-[(1-oxypyridine-4-ylmethyl)amino]nicotinic acid

2,09 g (8,59 mmole) methyl ester 2-[(pyridine-4-ylmethyl)amino]nicotinic acid are mixed in 150 ml of methylene chloride with of 2.21 g (9,98 mmole) m-x what Obermenzing acid for 24 h and stirred at room temperature. Then add 50 ml of dilute sodium hydrogen carbonate solution, stirred and the organic phase is separated and extracted three times with methylene chloride him portions of 50 ml the Combined organic phase is washed, dried, filtered and concentrated. The result is 2.7 g (100% of theory) methyl ester 2-[(1-oxypyridine-4-ylmethyl)amino]nicotinic acid in the form of oil.

A similar technique also get the following connection:

D-5) methyl ester 2-[(1-oxopyridine-3-ylmethyl)amino]nicotinic acid

Stage 4 way

D-6) Obtaining methyl ester 2-[(2-cyano-4-ylmethyl)amino]nicotinic acid

2.7 g (of 10.4 mmole) methyl ester 2-[(1-oxypyridine-4-ylmethyl)amino] nicotinic acid for 8 h heated in 52 ml of dimethylformamide in a pressure vessel together with a 3.15 g (31,2 mmole) of triethylamine and 9,19 g (62,4 mmole) of trimethylsilylacetamide to the temperature of the bath 110°C. After concentration under vacuum, the residue is dissolved in 100 ml of dilute sodium hydrogen carbonate solution and extracted three times with ethyl ether, acetic acid, its portions of 100 ml the Combined organic phase is washed, dried, filtered and concentrated. The remainder chromatographic on the column for the Express chromatography (50 g, material Isoplute flash silica; the Irma Separtis) by gradient elution using as elution solvent a mixture of methylene chloride/ethanol in a ratio of from 100:0 to 95:5. The result of 1.31 g (47% of theory) methyl ester 2-[(2-cyano-4-ylmethyl)amino]nicotinic acid.

A similar technique also get the following connection:

D-7) to Obtain methyl ester 2-[(6-cyano-3-ylmethyl)amino]nicotinic acid

When receiving the specified connection at the same time in a small number also formed the methyl ester of 2-[(2-cyano-3-ylmethyl)amino]nicotinic acid.

Stage 5 ways

D-8) to Obtain 2-[(2-cyano-4-ylmethyl)amino]-N-isoquinoline-3-iniatiated

In 10 ml of toluene in an argon atmosphere and eliminating the access of moisture stirred for 30 min at 4°277 mg (1,92 mmole) 3-aminoisoquinoline and 0,86 ml of trimethylaluminum (2-molar solution in toluene). Then add 468 mg (1,74 mmole) methyl ester 2-[(2-cyano-4-ylmethyl)amino]nicotinic acid, and then for 2 hours and heated under reflux. Next, add 30 ml of dilute sodium hydrogen carbonate solution and extracted three times by shaking with ethyl ether acetic acid its portions to 30 ml Combined organic phase is washed, dried, filtered and concentrated. The remainder chromatographic on the column for the Express chromatography (20 g material Iolute flash silica, the firm Separtis) by gradient elution using as elution solvent a mixture of methylene chloride/ethanol in a ratio of from 100:0 to 95:5. The result is 400 mg (60% of theory) of 2-[(2-cyano-4-ylmethyl)amino]-N-isoquinoline-3-iniatiated.

D-9) obtaining the amide N-(isoquinoline-3-yl)-2-[2-cyano-4-ylmethylamino]benzoic acid

920 g (2.5 mmole) of N-oxide, amide N-(isoquinoline-3-yl)-2-(4-pyridylmethyl)aminobenzoic acid sequentially mixed in a glass pressure vessel, where previously placed 20 ml of dimethylformamide, with 760 mg (7.5 mmole) of triethylamine and 1.24 g (12.5 mmole) of trimethylsilylacetamide, then for 10 h was heated to a temperature bath 110°C. the mixture is Then diluted with water to a volume of about 200 ml and extracted three times by shaking with ethyl ether acetic acid his portions of 50 ml. The collected organic phase is washed with 50 ml of water, dried, filtered and concentrated. The remainder chromatographic first on silica gel, using as eluent a mixture of ethyl ether/hexane in the ratio of 1:1 and then again on silica gel, but using as eluent a mixture of dichloromethane/ethanol in a ratio of 100:2. The result is 132 mg (14% of theory) of amide N-(isoquinoline-3-yl)-2-[2-cyano-4-ylmethylamino]benzoic acid in the form of resin.

If the prom is mediate compounds is not described, then, as mentioned above, it is understood that these compounds are known or can be obtained analogously to known compounds or using the steps described in the present application methods.

A similar technique also receive the following connections:

D-10) 2-[(2-cyano-3-ylmethyl)amino]-N-isoquinoline-3-iniatiated

D-11) 2-[(6-cyano-3-ylmethyl)amino]-N-isoquinoline-3-iniatiated

Example F

Stage 1 of the method

E-1) preparation of methyl ester of 2-[(2-bromopyridin-4-ylmethyl)amino]benzoic acid

6,04 g (40 mmol) of the methyl ester of Anthranilic acid in 600 ml of methanol is mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) 2-bromopyridin-4-carbaldehyde and during the night stirred at 40°C. After addition of 3.8 g (60 mmol) of lamborginid sodium continue stirring overnight at 40°C. Then added 3.8 g (60 mmol) of lamborginid sodium and during the weekend stirred at 40°C. Then stirred into water and concentrated almost to dryness. The aqueous phase is extracted with ethyl ether acetic acid, the combined organic phases are dried, filtered and concentrated. The crude product chromatographic on silica gel by gradient elution using is as an eluent of hexane and a mixture of hexane/ethyl ester of acetic acid in the ratio of 1:3 and a mixture of hexane/ethyl ester of acetic acid in the ratio of 1:1. The result is 10.0 g (78% of theory) methyl ester 2-[(2-bromopyridin-4-ylmethyl)amino]benzoic acid as a colourless oil.

Stage 2 of the method

E-2) obtaining the methyl ester of 2-[(2-pianophiles-4-ylmethyl)amino]benzoic acid

1.28 g (4.0 mmole) of the methyl ester of 2-[(2-bromopyridin-4-ylmethyl)amino]benzoic acid in 140 ml of dimethylacetamide mixed with 0,532 g (4,56 mmole) cyanide zinc(II), 0,072 g (0.08 mmole) of Tris(dibenzylideneacetone)diplodia, 0,088 g (0.16 mmole) of bis(diphenylphosphino)ferrocene and 0,029 g (0,46 mmole) of zinc powder. Further stirred for 6 h at 150°C. After cooling, the reaction mixture was poured onto water. Then extracted three times with ethyl ether acetic acid, the combined organic phases are dried over sodium sulfate and concentrated. The resulting product chromatographic on silica gel by gradient elution using as eluent a mixture of hexane/ethyl ester of acetic acid in a ratio of from 100:0 to 50:50. The result 0,887 g (83% of theory) methyl ester 2-[(2-cyano-4-ylmethyl)amino]benzoic acid in a solid yellow color.

Stage 3 ways

E-3) to Obtain 2-[(2-cyano-4-ylmethyl)amino]-N-(7-methoxy-3-methylinosine-2-yl)benzamide

When 0°With 0.25 g of trimate the aluminum (2-molar in toluene) are added dropwise to 0,094 g (0.5 mmole) of 7-methoxy-3-methylinosine-2-ylamine in 4 ml of toluene. After 10 minutes of stirring at 0°With added dropwise of 0.133 g (0.5 mmole) of the methyl ester of 2-[(2-cyano-4-ylmethyl)amino]benzoic acid in 2 ml of toluene. Then within 2 hours and stirred under reflux and overnight at room temperature. The precipitate was separated by vacuum filtration and suspended in a saturated solution of sodium bicarbonate. Then add ethylenediaminetetraacetic acid. Next, shaken out with ethyl ether, acetic acid, dried over sodium sulfate and concentrated. After purification column chromatography on silica gel by gradient elution using a mixture of hexane/acetone in a ratio of from 100:0 to 50:50 get 0,113 g (54% of theory) of 2-[(2-cyano-4-ylmethyl)amino]-N-(7-methoxy-3-methylinosine-2-yl)benzamide in the form of a foamy substance yellow color.

Example G

Stage 1 of the method

W-1) preparation of 2-[(2-bromopyridin-4-ylmethyl)amino]benzoic acid

10.0 g (31,2 mmole) methyl ester 2-[(2-bromopyridin-4-ylmethyl)amino]benzoic acid are dissolved in 290 ml of ethanol and mixed with 31,2 ml of 2-molar sodium hydroxide. After stirring overnight at room temperature, the ethanol was removed and the aqueous phase is shaken out with ethyl ether, acetic acid. The aqueous phase is acidified with concentrated is hydrochloric acid. The formed precipitate was separated by vacuum filtration and dried. The result is to 5.93 g (62% of theory) of 2-[(2-bromopyridin-4-ylmethyl)amino]benzoic acid in the form of a solid white color.

Stage 2 of the method

W-2) Obtaining 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(2-methyl-2H-indazol-6-yl)benzamide

0,500 g (1.6 mmole) 2-[(2-bromopyridin-4-ylmethyl)amino]benzoic acid, 0,471 g (3.2 mmole) of 2-methyl-2H-indazol-6-ylamine, 0.4 ml (3,68 mmole) N-methylmorpholine and advanced 0.729 g (1,92 mmole) of hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (GATA) in 25 ml of dimethylformamide is stirred for 16 h at room temperature. Then the dimethylformamide is removed in a vacuum generated by an oil pump. The resulting residue is dissolved in a saturated solution of sodium bicarbonate. Then extracted three times with ethyl ether, acetic acid and the combined organic phases are dried, filtered and concentrated. The remainder chromatographic on silica gel by gradient elution using as eluent a mixture of hexane/acetone in a ratio of from 100:0 to 50:50. The result 0,669 g (96% of theory) of 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(2-methyl-2H-indazol-6-yl)benzamide in the form of a foamy substance beige color.

A similar technique also receive the following connections:

W-3) 2-[(2-bromopyridin-4-yl is ethyl)amino]-N-(1-methyl-1H-indazol-6-yl)benzamid

W-4) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(1H-indazol-6-yl)benzamid

W-5) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(1H-indazol-5-yl)benzamid

W-6) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)benzamid

W-7) 2-[(2-bromopyridin-4-ylmethyl)amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)benzamid

Z-1) 4-(tert-butoxycarbonylamino)pyridine-2-carboxylic acid

4-(tert-butoxycarbonylamino)pyridine-2-carboxylic acid is obtained according to Chem Eur. J. 2 (2000), is based on tert-butyl ether (2-cyano-4-ylmethyl)carbamino acid.

C-2) Optically active tert-butyl ether [2-(2-hydroxypropylamino)pyridine-4-ylmethyl]carbamino acid

Optically active tert-butyl ether [2-(2-hydroxypropylamino)pyridine-4-ylmethyl]carbamino acid get in the way specified in example 2.0, based on 4-(tert-butoxycarbonylamino)pyridine-2-carboxylic acid and S-(+)-1-amino-2-propanol to yield 91%.

C-3) Optically active (2-hydroxypropyl)amide of 4-aminomethylpyridine-2-carboxylic acid

480 mg (1.7 mmole) of tert-butyl methyl ether [2-(2-hydroxypropylamino)pyridine-4-ylmethyl]karbaminovoi acid are mixed in 30 ml of ethanol and 17 ml of 1 N. hydrochloric acid and passing a stream of nitrogen for 3 h was heated to a temperature bath 110°C. the mixture is Then concentrated under vacuum, and dried without further purification used analogously to example 5.0.

C-4) 2-chloro-N-isoquinoline-3-iniatiated

2.9 g (20 mmol) 3-aminoisoquinoline suspended in 45 ml of tetrahydrofuran dropwise and mixed with a solution of 3.5 g (20 mmol) of 2-chloronicotinamide in 45 ml of tetrahydrofuran. After stirring over night at room temperature the mixture is separated by vacuum filtration and the residue washed with tetrahydrofuran. Then the rest Usacheva in water and again separated by vacuum filtration and dried. The result of 3.14 g (55% of theory) of 2-chloro-N-isoquinoline-3-iniatiated.

In the following examples for the application, which do not limit the scope of the invention are explained in more detail the biological effect of the proposed compounds and their application.

Used in the experiments solutions

The original solutions:

original solution: 3 mm ATP in water, pH 7.0 (-70°),

the original solution B: g-33 P-ATP (1 MCI/100 μl,

source solution: poly(Glu4yr) 10 mg/ml in water.

The solution for dilutions:

solvents substrates: 10 mm DTT, 10 mm manganese chloride, 100 mm magnesium chloride,

the enzyme solution: 120 mm Tris/HCl, pH 7.5, 10 μm oxide of nutrimentia.

the Example application 1

The suppression of activity of kinases KDR and FLT-1 in the presence of compounds according to the invention

In tapering at the ends titration microplate (without binding protein) add 10 ál of nutrient mixture (initial solution volume of 10 μl ATP +25 µci γ-R-ATP (approximately 2.5 ál of solution B) + source solution: 30 ál poly(Glu4yr) +1,21 ml solvent substrates), 10 μl of inhibitor solution (compounds in accordance with the dilutions, as control is 3%solution of DMSO in the solvent substrates) and 10 μl of an enzyme solution (11,25 µg initial solution of the enzyme (kinase KDR or FLT-1), diluted with 4°With 1.25 ml of an enzyme solution). These ingredients are thoroughly mixed and incubated for 10 min at room temperature. Then add 10 ál of stop solution (250 mm add, pH 7.0), mix and 10 μl of the solution is transferred to phosphocellulose filter type P 81, and then washed several times in 0.1-molar phosphoric acid. Filter paper is dried, cover with a layer of Meltilex and with the help of microscience beta particles measured radioactivity.

IC50values represent the values defined by the concentration of inhibitor required to inhibit the incorporation of phosphate by 50% from its embedding in the absence of inhibitor, minus the reference value obtained by a blind man on the Sabbath. ITA (reaction stopped using etc).

The results of the inhibition of the kinase (IC50values in nm) are presented in the following table 1.

Table 1
Example No.VEGFR II (KDR) [nm]
1.3240

Example application 2

Inhibition of cytochrome P450

Inhibition of cytochrome P450 conducted in accordance with the publication authors Crespi and other (Anal. Biochem. 248 (1997), cc.188-190) expressed using the baculovirus/insect cells isoenzymes of cytochrome P450 (1A2, 2S9, 2C19, 3A4) person.

The results are presented in the following table 2.

Inhibition of cytochrome P450 isoenzymes (IC50microns)

Table 2
Isoenzyme of cytochrome P4501A22S92S193A4
Example 2.54 from the application WO 00/278195,20,20,053,6
Example 1.32302,9a 4.925

The results clearly show that the proposed invention in connection with properties superior to the known compounds, i.e. proposed in the invention, the connection p is ablaut a substantially lesser degree, the inhibitory activity of the detoxifying system of cytochrome P450 in comparison with the known compounds, which leads to considerably weakened interaction with other active ingredients.

1. Compounds of General formula I

in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents an aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising 5 or 6 ring atoms instead of carbon containing ring identical or different heteroatoms selected from nitrogen atoms, or sulfur, or represents a group-COOR8, -CONR2R3or-C≡C-R9,

G represents a nitrogen atom or a group-S-X,

L represents a nitrogen atom or a group-S-X,

M represents a nitrogen atom or a group-S-X,

Q represents a nitrogen atom or a group-S-X,

in the ring is a maximum of one nitrogen atom,

X represents hydrogen,

W represents hydrogen or halogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxy, C1-C6the alkyl or a group =O aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising from 3 to 16 ring atoms instead of carbon containing in the ring one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur, which may be mono-, bi - or tricyclic and may optionally be condensed with a benzene nucleus

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, cyano, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5C1-C6alkyl-OR5C1-C6alkyl, C3-C6cycloalkyl,3-C6cycloalkenyl aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms instead of carbon containing in the ring one or more heteroatoms, such as nitrogen, or sulfur, or

R2and R3together with the nitrogen atom form a3-C8the ring, which optionally may contain another nitrogen atom or oxygen, or may contain a group-N(R10),

R5represents hydrogen,

R6and R7independently from each other represent hydrogen or C1-C6alkyl

R8represents hydrogen or optionally one or mnogozalny halogen, C1-C6alkyl or benzyl,

R9is salavtore or three-C 1-C6alkylsilane,

R10represents hydrogen or C1-C6alkyl,

as well as their isomers, enantiomers and salts.

2. Compounds of General formula I according to claim 1, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents an aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising 5 or 6 ring atoms instead of carbon containing ring identical or different heteroatoms selected from nitrogen atoms, and sulfur, or represents a group-COOR8, -CONR2R3or-C≡C-R9,

G represents a nitrogen atom or a group-S-X,

L represents a nitrogen atom or a group-S-X,

M represents a nitrogen atom or a group-S-X,

Q represents a nitrogen atom or a group-S-X,

in the ring is a maximum of one nitrogen atom,

X represents hydrogen,

W represents hydrogen or halogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxy, C1-C6the alkyl or a group =O aryl containing 6 to 12 ring carbon atoms, Lieb is heteroaryl, containing from 3 to 16 ring atoms instead of carbon containing in the ring one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur, which may be mono-, bi - or tricyclic and may optionally be condensed with a benzene nucleus

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5C1-C6alkyl-OR5C1-C6alkyl, C3-C6cycloalkyl,3-C6cycloalkenyl aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms instead of carbon containing in the ring one or more heteroatoms, such as nitrogen, or sulfur, or

R2and R3together with the nitrogen atom form a3-C8the ring, which optionally may contain another nitrogen atom or oxygen or may contain a group-N(R10),

R5represents hydrogen,

R6and R7independently from each other represent hydrogen or C1-C6alkyl,

R8represents hydrogen or NeoMaster is but one or mnogozalny halogen, C 1-C6alkyl or benzyl,

R9represents hydrogen or C1-C6alkylsilane,

as well as their isomers, enantiomers and salts.

3. Compounds of General formula I according to claim 1, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents an aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising 5 or 6 ring atoms instead of carbon containing ring identical or different heteroatoms selected from nitrogen atoms, or sulfur, or represents a group-COOR8, -CONR2R3or-C≡C-R9,

G represents a nitrogen atom or a group-S-X,

L represents a nitrogen atom or a group-S-X,

M represents a nitrogen atom or a group-S-X,

Q represents a nitrogen atom or a group-S-X,

in the ring is a maximum of one nitrogen atom,

X represents hydrogen,

W represents hydrogen or halogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxyaryl,1-C6the alkyl aryl containing 6 to 12 ring carbon atoms, which for heteroaryl, containing from 3 to 16 ring atoms instead of carbon containing in the ring one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur, which may be mono-, bi - or tricyclic and may optionally be condensed with a benzene nucleus

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5C1-C6alkyl-OR5C1-C6alkyl, C3-C6cycloalkyl,3-C6cycloalkenyl aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms instead of carbon containing in the ring one or more heteroatoms, such as nitrogen, or sulfur, or

R2and R3together with the nitrogen atom form a3-C8the ring, which optionally may contain another nitrogen atom or oxygen or may contain a group-N(R10),

R5represents hydrogen,

R6and R7independently from each other represent hydrogen or C1-C6alkyl,

R8represents hydrogen or NeoMaster is but one or mnogozalny halogen With 1-C6alkyl or benzyl,

R9represents hydrogen or three-From1-C6alkylsilane,

R10represents hydrogen, C1-C6alkyl,

as well as their isomers, enantiomers and salts.

4. Compounds of General formula I according to claim 1, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents heteroaryl comprising 5 or 6 ring atoms instead of carbon containing ring identical or different heteroatoms selected from nitrogen atoms, or sulfur, or represents a group-COOR8, -CONR2R3or-C≡C-R9,

G represents a group-S-X,

L represents a group-S-X,

M represents a group-S-X,

Q represents a nitrogen atom or a group-S-X,

X represents hydrogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxyaryl,1-C6the alkyl phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline or substituted by the group

, ,

or

in which T represents hydrogen, C1-C6alkyl or C1-C6alkoxygroup,

R2and R3independently of one another represent hydrogen or optionally identical or different one or mnogozalny halogen, C1-C6the alkyl, phenyl, hydroxy-C1-C6by alkyl, halo,-C1-C6the alkyl or the group-NR6R7, -OR5With1-C6alkyl-OR5C1-C6alkyl, C3-C6cycloalkyl,3-C6cycloalkenyl aryl containing 6 to 12 ring carbon atoms, or heteroaryl comprising from 3 to 6 ring atoms instead of carbon containing in the ring one or more heteroatoms, such as nitrogen, or sulfur, or

R2and R3together with the nitrogen atom form a3-C8the ring, which optionally may contain another nitrogen atom or oxygen or may contain a group-N(R10),

R5represents hydrogen,

R6and R7independently from each other represent hydrogen or C1-C6alkyl,

R8represents hydrogen or optionally one or mnogozalny halogen, C1-C6alkyl or benzyl,

R9 represents hydrogen or three-From1-C6alkylsilane,

as well as their isomers, enantiomers and salts.

5. Compounds of General formula I according to claim 1, in which

A, b and D independently of one another represent a nitrogen atom or a carbon atom, at least one nitrogen atom contained in the ring,

E represents thienyl, pyridyl or a group-COOR8, -CONR2R3or-C≡C-R9,

G represents a group-S-X,

L represents a group-S-X,

M represents a group-S-X,

Q represents a nitrogen atom or a group-S-X,

X represents hydrogen,

R1represents optionally identical or different one or mnogozalny halogen, hydroxy-group, C1-C6alkyloxyaryl,1-C6the alkyl phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline or substituted by the group

,,

or

or in which T denotes hydrogen, C1-C6alkyl or C1-C6alkoxygroup,

R2and R3independently from each other represent hydrogen or not battelino identical or different one or mnogozalny halogen, C1-C6the alkyl, phenyl or a group-NR6R7, -OR5or1-C6alkyl-OR5C1-C6alkyl, C3-C6cycloalkyl, phenyl or pyridyl, or

R2and R3together with the nitrogen atom form a3-C8the ring, which optionally may contain another nitrogen atom or oxygen,

R5represents hydrogen,

R6and R7independently from each other represent hydrogen or C1-C6alkyl,

R8represents hydrogen, C1-C6alkyl or benzyl,

R9represents hydrogen or C1-C6alkylsilane,

as well as their isomers and salts.

6. Compounds according to one of claims 1 to 5, which together with excipients and fillers are used for preparation of the corresponding composition.

7. Drug containing at least one compound according to one of claims 1 to 5, with inhibitory activity against VEGFR-2 and VEGFR-3, intended for use in psoriasis, Kaposi's sarcoma, restenosis, such as, for example, restenosis induced by the use of the stent, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis, such as rheumatoid arthritis, when the hemangioma, angiofibroma, eye diseases is s, such as diabetic retinopathy, neovascular glaucoma, kidney disease, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, tribomechanically, graft rejection and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with proliferation mesangial cells, arteriosclerosis, injuries to nerve tissue, inhibition of re-occlusion of vessels after treatment with use of balloon catheter, the prosthesis of the vessel or the use of mechanical devices, such as stents, to save the lumen of the vessels, as well as immunosuppressants, as an aid, contributing bezrucova the healing of wounds, senile spots and contact dermatitis.

8. The drug according to claim 7, which further comprises excipients and fillers.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of thiophene of the general formula (I): , wherein R1 is chosen from group consisting of hydrogen atom (H), -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7)OR8, -C(O)N(R7)-R2-OR8, -C(O)N(R7)-Ph, -C(O)N(R7)-R-Ph, -C(O)N(R7)S(O)2R8, -R2-OR7, -R2-O-C(O)R7, -C(S)R7, -C(S)NR7R8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -CN, -OR7 and Het wherein Het represents tetrazolyl; Q1 represent group of the formula: -(R2)a-(Y1)b-(R2)c-R3 wherein a, b and a are similar or different and each means independently 0 or 1, and at least one among a or b means 1; n means 0, 1, 2, 3 or 4; Q2 represents group of the formula: -(R2)aa-(Y2)bb-(R2)cc-R4, or two adjacent Q2 groups represent -OR7 and in common with carbon atoms to which they are bound form 5-7-membered heterocycle comprising 1 or 2 heteroatoms chosen from oxygen atom (O); R5 is chosen from group consisting of H, alkyl and -NR7R8, or their pharmaceutically acceptable salts and solvates. Compounds can be used in treatment of states mediated by Polo-like kinase and sensitive neoplasm. Also, invention describes a method for synthesis of these compounds and preparing pharmaceutical compositions based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

27 cl, 1 tbl, 199 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel C-2'-methylated derivatives of paclitaxel of the formula (I): wherein R represents trifluoromethyl group, phenyl, 2-furyl, 2-thienyl; R1 represents tert.-butoxycarbonyl or benzoyl group; R2 represents hydroxy-group; R3 means hydrogen atom or in common with R2 forms residue of cyclic carbonate of the formula: under condition that when R3 means hydrogen atom then R is not phenyl. Also, invention relates to a pharmaceutical composition based on thereof and using for preparing medicinal agents possessing an antitumor activity. Invention provides preparing novel derivatives of paclitaxel that possess antitumor activity.

EFFECT: valuable medicinal property of derivatives and pharmaceutical composition.

4 cl, 1 tbl, 6 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes derivatives of 2-amino-1,3,5-triaziene of the formula (I): wherein R1 means phenyl or alkyl with from 1 to 6 carbon atoms that can be substituted with one or some radicals taken among halogen atom and cyano-group; R2 means unsubstituted cyclopropyl, cyclobutyl or cyclopentyl groups or substituted that with radical taken among halogen atom and alkyl with from 1 to 4 carbon atoms, or furyl, or tetrahydrofuryl; R3 means radical of the formula -N(B1-D1)(B2-D2); R4 means radical of the formula -B3-D3; A1 means direct alkylene with 1-5 carbon atoms or direct alkenylene with 2-5 carbon atoms; A2 means a direct bond or direct alkylene with 1-4 carbon atoms; B1, B2 and B3 mean a direct bond; D1, D2 and D3 mean hydrogen atom; (X)n means a number of X substitutes wherein X means independently halogen atom, nitro-group or unsubstituted alkyl with 1-6 carbon atoms or substituted that with one or some radicals taken among halogen atom and alkoxy-group with 1-6 carbon atoms; n = 0, 1 or 2 and wherein the total sum of carbon atoms in radicals A1 and A2-R2 is at least 6 carbon atoms. Also, invention describes the herbicide agent containing compound of the formula (I) and additives used usually for plants protection and a method for control of hazard plants and using the effective dose of compound of the formula (I) for treatment of plants or planting surface. Invention provides preparing effective herbicides.

EFFECT: valuable properties of compounds.

7 cl, 45 tbl, 4 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

The invention relates to new chemical compounds of the heterocyclic series, with pronounced anticalcium activity, which may find application in medical practice in the treatment and prevention of cardiovascular diseases and represent derivatives of 2-N-1-benzopyran-2-it General formula I

where R and R1have the meanings indicated in the claims

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to the field of chemistry of heterocyclic compounds and relates, in particular, a new chemical compound 2-isopropyl-4-[(furyl-2)metalinox] methylene-1,3-dioxolane exhibiting the properties of activator germination of wheat seeds and increases the resistance of seedlings to water stress

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1): , their pharmaceutically acceptable salts or hydrates wherein each among R1, R2 and R3 represents independently hydrogen atom, halogen atom, hydroxy-group, (C1-C8)-alkoxy-group; each among W1 and W2 represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR4, -COONR4 or -NR4CO; R4 represents hydrogen atom, (C1-C8)-alkyl, (C3-C6)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkoxy-group substituted with 1-3 halogen atoms, (C1-C8)-alkylthio-group, (C1-C8)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C1-C3)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 439 ex

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