Derivatives of 2-aminonicotine amide and their using as inhibitors of tyrosine kinase vegf receptors

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to derivatives of 2-aminonicotine amide of the formula (I): , to methods of their synthesis and a pharmaceutical composition based on thereof inhibiting activity of receptor tyrosine kinase vessel endothelial growth factor (VEGF) and to corresponding method for inhibition of activity of VEGF-receptor tyrosine kinase. It is suggested that this activity will allow offering the curative effect in proliferative diseases associated with angiogenesis, in particular, in treatment of tumors, retinopathy or age degeneration of yellow (corneal) spot.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 42 ex

 

The invention relates to the use of derivatives of 2-aminonicotinamide, alone or in combination with one or more other pharmaceutically active compounds, to pharmaceutical compositions for use in therapy of a disease sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase, especially a tumor disease, retinopathy or age-related macular degeneration; to a method of treatment of such diseases in mammals, especially human; to new derivatives of 2-aminonicotinamide and methods for their preparation.

The number of known diseases associated with impaired angiogenesis, for example, a disease caused by neovascularization of the eye, such as retinopathy (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, endometriosis and, above all, neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemia).

According to the latest data from the Central place in the system of regulation of growth and differentiation of the vascular system and its components during embryonic development and normal growth in a variety of pathological anomalies and diseases is an angiogenic factor known as "endothelial growth factor vascular" (VGEF, originally called the factor vascular permeability", VPF), along with its cellular receptors (see review Breier G., and others. Trends in Cell Biology, 6, 454-456 (1996), and other documents cited in the description of the application).

VEGF is a dimeric, linked by disulfide bonds glycoprotein with MM 46 kDa, produced by the lines of normal and tumor cells. It is a specific mitogen for endothelial cells, has angiogenic activity in test systems in vivo (e.g., on the cornea of the rabbit), has chemotactic properties of endothelial cells and monocytes and induces formation of endothelial cell plasminogen activators, which then participate in the proteolytic degradation of extracellular matrix during the formation of capillaries. Known for a number of isoforms of VEGF, which have similar biological activity, but differ in the type of secreting their cells and heparin-binding activity. In addition, other known members of the VEGF family, such as placental growth factor" (PLGF) and VEGF-C.

The VEGF receptors are transmembrane receptor tyrosine kinases. They are characterized by an extracellular domain containing seven immunoglobulin like domains and an intracellular domain with tyrosinekinase activity. There are various types of VEGF receptor, such as VEGFR-1, VEGFR-2 and VEGFR-3.

For many kinds of swelled the lei man, first of all gliomas and carcinomas, characterized by a high level of expression of VEGF and its receptors. This led to the hypothesis that VEGF produced by tumor cells, can stimulate the growth of blood capillaries and proliferation of tumor endothelium by paracrine mechanism of regulation and, thus, due to improved blood flow, accelerate tumor growth. Increased expression of VEGF may explain the occurrence of brain edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo obtained in the inhibition of expression or activity of VEGF. This is achieved through the use of antibodies inhibiting VEGF activity, mutant, dominant-negative VEGFR-2, which inhibit the transmission of a signal or antisense VEGF-PHK. All approaches lead to a decrease in the growth of cell lines gliomas or other lines of tumor cells in vivo results in suppression of tumor angiogenesis.

Angiogenesis is the absolute prerequisite for such tumors, in which growth exceeds the maximum diameter of approximately 1-2 mm, because until that limit oxygen and nutrients can enter tumor cells by diffusion. Thus, each tumor, regardless of its origin and causes, after reaching a definite the x size depends on angiogenesis, necessary for further growth.

When the effects of angiogenesis inhibitors on tumor great importance are the three main mechanisms: 1) inhibition of the growth of vessels, especially capillaries, in the direction of avascular resting tumors, which prevents the overall growth of the tumor due to the balance between apoptosis and proliferation; 2) prevention of the migration of tumor cells due to the absence of blood flow in the direction of the tumor and back, and 3) inhibition of proliferation of endothelial cells and, thus, the exception paracrine growth stimulation effects on the surrounding tissue endothelial cells, usually adjacent to the vessels.

Unexpectedly, it was found that nicotinamide derivatives of formula I, described below, are a new class of compounds which possess useful pharmacological properties and inhibit, for example, the activity of VEGF-receptor tyrosine kinase, tumor growth and VEGF-dependent cell proliferation, and other above - and below of the disease.

The compounds of formula I provide unexpected new therapeutic approach, for example, primarily to the treatment of diseases, therapy, as well as in the prevention, inhibition of angiogenesis and/or VEGF-receptor tyrosine kinase has a therapeutic effect.

The invention relates to is the label of the compounds of formula I

where

n is from 1 to 6, inclusive;

W denotes O or S;

R1and R3independently from each other and each means hydrogen, (ness.)alkyl or (ness.)acyl;

R2means the group cycloalkyl, an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or mono - or polyamideimide;

R and R' independently from each other and each means hydrogen or (ness.)alkyl;

X means an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or mono - or polyamideimide;

and its N-oxide or a possible tautomer,

or pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions for use in therapy of a disease that is sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase.

Unless specified otherwise, the General terms used above and below, preferably have the following meanings.

Priest is the WHC "ness." means radical, containing from 1 up to 7, inclusive, above all up to 4, inclusive, carbon atoms, and mentioned radicals are linear or branched with single or multiple branching.

If to refer to compounds, salts, etc. used the plural, it should be assumed that it also means a single compound, salt, etc.

Any asymmetric carbon atoms (for example, in the compound of formula I, where R or R' means (ness.)alkyl) can be represented as (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. Thus, the compounds may be presented in the form of mixtures of isomers or as pure isomers, preferably in the form of diastereoisomers, not containing enantiomers.

In addition, the invention relates to the possible tautomers of the compounds of formula I.

X preferably denotes pyridyl or phenyl, most preferably 3 - or 4-pyridyl.

In a preferred embodiment of the invention X is substituted by a group (ness.)alkoxy.

In another predominantly preferred embodiment of the invention X is a substructure of X'

where

Rx means hydrogen or (ness.)alkyl.

R2preferably means phenyl, mono - or disubstituted by the group number (NISS.)alkyl, (ness.)quinil, halogen, p is edocfile fluorine and trifluoromethyl; or cycloalkyl, preferably cyclohexyl, substituted (ness.)the alkyl, preferably tert-bootrom.

R3preferably means hydrogen.

W means preferably O.

Integer n preferably denotes 1 or 2, more preferably 1.

(Ness.)alkyl preferably denotes alkyl containing from and including 1 up to and including 7, preferably from and including 1 to 5 inclusive, carbon atoms and which is linear or branched; preferably (ness.)alkyl means of pentyl, such as n-pentyl, butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferably, ness.)alkyl means methyl, propyl or tert-butyl.

(Ness.)acyl means preferably formyl or acetyl.

"Aryl" means an aromatic radical, associated with the molecules of the chemical bond through a carbon atom of the aromatic ring. In a preferred embodiment of the invention the aryl means an aromatic radical containing from 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrene, and the specified radical is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from a range of amino, mo is about - or disubstituted amino, halogen, (ness.)alkyl, substituted alkyl, (ness.)alkenyl, (ness.)quinil, (ness.)alkanoyl, hydroxy, simple or ester of the hydroxy-group, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, (ness.)alkylthio, phenyl, phenoxy, phenylthio, phenyl(ness.)alkylthio, alkalinity, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylresorcinol, (ness.)alkanesulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylphenolates, halogen(ness.)allylmercaptan, halogen(ness.)alkylsulfonyl, such as, first of all, trifloromethyl, dihydroxybis(-B(OH)2), heterocyclyl and (ness.)alkylenedioxy associated with the adjacent carbon atoms in the cycle, such as methylenedioxy. More preferably the aryl means phenyl or naphthyl, which in each case is unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine or bromine; hydroxy; hydroxy, esterified (ness.)the alkyl, such as stands, or halogen(ness.)the alkyl, such as trifluoromethyl; (ness.)alkyl, for example methyl or propyl; (ness.)alkenyl, such as 1-PROPYNYL; the esterified carboxypropyl primarily (ness.)alkoxycarbonyl, for example the er methoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl; N-monosubstituted carbarnoyl, for example, carbarnoyl, monosubstituted (ness.)the alkyl, such as stands, n-propylene or isopropyl; substituted alkyl, especially (ness.)alkyl, for example methyl or ethyl, substituted (ness.)alkoxycarbonyl, such as methoxycarbonyl or etoxycarbonyl; and halogen(ness.)alkyl, most preferably trifluoromethyl.

As the aryl in the form of a phenyl, which is substituted by a group (ness.)alkylenedioxy associated with two adjacent carbon atoms, such as methylenedioxy preferred 3,4-methylenedioxyphenyl.

Group cycloalkyl preferably means cyclopentyl, cyclohexyl or cycloheptyl, and group cycloalkyl may be unsubstituted or substituted by one or more, especially one or two substituents selected from the group mentioned above as substituents of aryl, most preferably (ness.)the alkyl, such as methyl, (ness.)alkoxy, such as methoxy or ethoxy, or hydroxy group.

Substituted alkyl means alkyl having values specified in the previous paragraph, above all (ness.)alkyl, preferably methyl; and which may contain one or more, especially up to 3, substituents, mainly from a group selected from the series halogen, especially fluorine, amino, N-(ness.)alkylamino, ,N-di(ness.)alkylamino, N-(ness.)alkanolamine, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl and phenyl(ness.)alkoxycarbonyl. Above all, preferred trifluoromethyl.

Mono - or disubstituted amino means, first of all, amino group, substituted by one or two radicals independently of one another selected from the series (NISS.)alkyl, such as methyl; hydroxy(ness.)alkyl, such as 2-hydroxyethyl; phenyl(ness.)alkyl; (ness.)alkanoyl, such as acetyl; benzoyl; substituted benzoyl in which the phenyl radical is substituted by one or more, preferably one or two substituents selected from the series nitro, amino, halogen, N-(ness.)alkylamino, N,N-di(ness.)alkylamino, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl and carbarnoyl; and phenyl(ness.)alkoxycarbonyl, in which the phenyl radical is unsubstituted or, especially, substituted by one or more, preferably one or two substituents selected from the series nitro, amino, halogen, N-(ness.)alkylamino N,N-di(ness.)alkylamino, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl and carbarnoyl; and means preferably N-(ness.)alkylamino, such as N-methylamino, hydroxy(ness.)alkylamino, such as 2-hydroxyethylamino, phenyl(ness.)alkylamino, such as benzylamino, N,N-di(ness.)alkylamino, N-phenyl(ness.)alkyl-N-(ness.)alkylamino, N,N-d is(ness.)alkylenediamine, (ness.)alkanolamine, such as acetylamino, or Deputy, selected from the group consisting of benzoylamino and phenyl(ness.)alkoxycarbonyl, in which the phenyl radical in each case is unsubstituted or, especially, substituted, nitro group or amino, or in addition, the group halogen, amino, N-(ness.)alkylamino, N,N-di(ness.)alkylamino, hydroxy, cyano, carboxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, carbarnoyl or aminocarbonyl.

Halogen means fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

Esterified hydroxy (ester group) means, above all, With8-C20alkyloxy, such as n-decyloxy, (ness.)alkoxy (preferably), such as methoxy, ethoxy, isopropoxy or n-pentyloxy, phenyl(ness.)alkoxy, such as benzyloxy, or in addition, phenyloxy, or in another embodiment, or in addition to the above group C8-C20alkyloxy, such as n-decyloxy, halogen(ness.)alkoxy, such as cryptometrics or 1,1,2,2-tetrafluoroethoxy.

Esterified hydroxy group (simple ether) means, first of all, (ness.)alkanoyloxy, benzoyloxy, (ness.)alkoxycarbonyl, such as tert-butoxycarbonylamino, or phenyl(NISS)alkoxycarbonyl, such as benzyloxycarbonyloxy.

Esterified carboxy Osnach the em first of all, (ness.)alkoxycarbonyl, such as tert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or etoxycarbonyl, phenyl(ness.)alkoxycarbonyl or phenoxycarbonyl.

Alkanoyl mainly means alkylsulphonyl primarily (ness.)alkanoyl, for example acetyl.

N-mono - or N,N-disubstituted carbarnoyl means, above all, limit the nitrogen atom, substituted by one or two substituents, independently selected from the series (NISS.)alkyl, phenyl(ness.)alkyl and hydroxy(ness.)alkyl.

Alkalinity means, first of all, (ness.)alkalinity.

Alkylphenolates means, first of all, (ness.)alkylphenolates.

Alkylresorcinol means, first of all, (ness.)alkylresorcinol.

Mono - or bicyclic heteroaryl group containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or mono - or polyamideimide means a heterocyclic residue, which is unsaturated in the loop connecting the heteroaryl radical to the rest of the molecule of formula I, and preferably means a cycle, where at least in the connecting loop, and in addition, not necessarily in any condensed cycle, one or more, preferably from 1 to 4, Nai is more preferably 1 or 2, carbon atom, are each replaced by a heteroatom selected from the group comprising nitrogen, oxygen and sulfur; where the binding cycle preferably contains from 5 to 12, more preferably from 5 to 7 atoms in the cycle; and may be unsubstituted or substituted by one or more, preferably one or two substituents selected from the group mentioned above as substituents in the aryl group, most preferably (ness.)the alkyl, such as methyl, (ness.)alkoxy, such as methoxy or ethoxy, or hydroxy; preferably mono - or bicyclic heteroaryl group selected from a number of 2N-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazoles, purinol, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-hemolysins, ethanolic, hinely, phthalazine, naphthyridine, Minoxidil, hintline, chinoline, pteridinyl, indolizinyl 2N-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, tetrazolyl, furutani and benzo[d]pyrazole. More preferably mono - or bicyclic heteroaryl group selected from the group including pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, indazoles, primarily 5-indazoles, pyridyl, especially 2-, 3 - or 4-pyridyl, ethenolysis, primarily 3-ethenolysis, chinoline, primarily 4-chinoline, indolyl, especially 3-indolyl, thiazolyl Il is benzo[d] pyrazole. In one preferred embodiment of the invention, pyridyl radical is substituted by a hydroxy group in ortho position to the nitrogen atom and, therefore, there are at least partly in the form of a corresponding tautomer, which means pyridine-(1H)-2-he.

Heterocyclyl means preferably five - or six-membered heterocyclic system with 1 or 2 getrootname selected from the group comprising nitrogen, oxygen and sulfur, and the system can be unsaturated or fully or partially saturated and is unsubstituted or substituted, first of all, (ness.)the alkyl, such as methyl; preferred radical selected from the range of 2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolane-2-yl, 1H-pyrazole-3-yl and 1-methylpyrazole-3-yl.

Salt primarily mean pharmaceutically acceptable salts of compounds of formula I.

Such salts are formed, for example, in the form of an acid additive salts, preferably by reaction of compounds of formula I having a basic nitrogen atom, with an organic or inorganic acids, primarily in the form of pharmaceutically acceptable salts. Appropriate inorganic acids are, for example, halogenated acids, such as hydrochloric acid, sulfuric acid or phosphoric acid. Acceptable organic acids include, for example, the R, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, dekanovu acid, dodekanisou acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, timelineview acid, cork acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, hydroxymaleimide acid, methylmaleimide acid, cyclohexanecarbonyl acid, adamantanecarbonyl acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, almond acid, cinnamic acid, methane - or econsultancy acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonate acid, benzosulfimide acid, 2-naphtalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3 - or 4-methylbenzenesulfonic acid, metallinou acid, atelierul acid, dodecylthio acid, N-cyclohexylsulfamic acid, N-methyl, N-ethyl or N-propylsulfonyl acid, or other organic protonic acids, such as ascorbic acid.

When the molecule is negatively charged groups, such as carboxy or sulfo, connections can about razvivat salts with bases, for example, metal salts or ammonium salts, such as salts of alkaline or alkaline earth metals, for example salts of sodium, potassium, magnesium or calcium, or ammonium salts with ammonia or the corresponding organic amines, such as Quaternary monoamines, for example triethylamine or three(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethylpiperidine or N,N'-dimethylpiperazine.

If the molecule contains a basic and an acid group, the compound of formula I may also form internal salts.

The purpose of separation or purification it is also possible to use pharmaceutically unacceptable salts, for example the picrate or perchlorates. For therapeutic applications, the use of only pharmaceutically acceptable salts or free compounds (which are applicable in the form of drugs), and therefore, these salts and compounds are preferred.

Due to the similarity between the new compounds in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds above and below should be taken as referring also to the corresponding salts, as appropriate and expedient is.

The compounds of formula I and their N-oxides have valuable pharmacological properties, as described above and below.

The effectiveness of the compounds according to the invention as inhibitors of the activity of VEGF-receptor tyrosine kinase can be demonstrated as follows.

Determination of inhibitory activity of compounds against VEGF-receptor tyrosine kinase. The analysis is performed using a VEGF-receptor tyrosine kinase Flt-1. Below is a detailed description of the methodology. 30 ál of kinase solution (10 ng of the kinase domain of Flt-1, see Shibuya and others, Oncogen, 5, 519-524 (1990)) in a buffer solution containing 20 mm Tris•HCl, pH 7.5, 3 mm manganese dichloride (MnCl2), 3 mm magnesium chloride (MgCl2), 10 μm sodium Vanadate, 0.25 mg/ml polyethylene glycol (PEG) 20000, 1 mm dithiotreitol and 3 μg/ml poly(Glu, Tyr) 4:1 (firm Sigma, Buchs, Switzerland), 8 μm [33P]ATP (or 0.2 µci), 1% dimethyl sulfoxide, and 0 to 100 μm of the analyzed compounds, incubated at room temperature for 10 min, then the reaction is stopped by adding 10 ál of 0.25 M solution of ethylenediaminetetraacetate (EDTA) at pH 7. Then multichannel pipette-dispenser (firm Lab Systems, USA) selected aliquot parts by volume of 20 μl, which through microtiter filter Gibco-BRL put on polyvinyldifluoride membrane Immobilon P (firm Millipor, USA) and connected to a vacuum line. After the floor is wow removal liquid membrane four times consecutively washed in the bath, containing 0.5% solution of phosphoric acid (H3PO4), and washed once with ethanol, incubare in each case, with shaking for 10 min, and then placed in the pulse counter TopCount Manifold (Hewlett Packard) and after adding 10 μl of scintillation fluid Microscint (account βpulses) measured radioactivity. The values of the IC50calculated using linear regression analysis of percentage inhibition of each compound at three concentrations (typically of 0.01, 0.1 and 1 Microm). IC50compounds of formula I have values in the range from 1 to 1000 nm, preferably in the range from 1 to 100 nm.

Antitumor activity of the compounds according to the invention can be demonstrated in vivo by the following method.

Activity in in vivo models naked xenotransplantation mice. Female Nude mice BALB/c mice (8-12 weeks, Novartis Animal Farm, Sisseln, Switzerland) containing sterile conditions with water and food on demand. Tumors induce or subcutaneous injection to mice of tumor cells (for example, cell lines DU 145 prostate cancer (ATSS No. NTV 81; see Cancer Res., 37, 4049-4058 (1978)) or by implantation of tumor fragments (approximately 25 mg) subcutaneously in the left side of the mouse using needles trocars 13 anesthesia drug Forene, Abbott, Switzerland). Analyzed connect the tion start typing at the moment when the tumor reaches an average volume of 100 mm3. Tumor growth was measured two or three times a week and 24 hours after the last treatment, sizing along two perpendicular axes. The volume of tumors expect, as described in the literature (see Evans and others, Brit. J. Cancer, 45, 466-468 (1982)). The effectiveness of antitumor activity is determined by dividing the average increase of tumor volume in animals treated with the analyzed connection, on the average increase in tumor volume in the control animals (not treated with the analyzed connection) and after multiplying by 100 represent as T/C%. Regression of tumors (%) represent the quotient of the minimum average tumor volume at the mean tumor volume at the beginning of treatment with the drug. The analyzed compound is administered daily by stomach tube.

In another embodiment, in a similar manner can also be used for other cell lines, for example:

cell line MCF-7 mammary adenocarcinoma (ATSS No. NTV 22; see also J. Natl. Cancer Inst. (Bethesda), 51, 1409-1416 (1973));

cell line MDA-MB 468 mammary adenocarcinoma (MCF-7 (ATSS No. NTV 132; see also In Vitro, 14, 911-915 (1978));

cell line MDA-MB 231 adenocarcinoma of the breast (ATSS No. NTV 26; see also J. Natl. Cancer Inst. (Bethesda), 53, 661-674 (1974));

cell line Colo 205 carcinoma of the colon (ATS the No. CCL 222; see also Cancer Res., 38, 1345-1355 (1978));

cell line HCT 116 carcinoma of the colon (ATSS No. CCL 247; see also Cancer Res., 41, 1751-1756 (1981));

cell line DU 145 prostate cancer (ATSS No. NTV 81; see also Cancer Res., 37, 4049-4058 (1978)); and

cell line PC-3 prostate cancer (ATSS No. CRL 1435; see also Cancer Res., 40, 524-534 (1980)).

Inhibition of autophosphorylation KDR-receptor induced by VEGF, can be confirmed by another experiment on cells in vitro. Transvestie cells SNO, constantly expressing the VEGF receptor human (KDR)in complete culture medium (containing 10% FBS) make 6-hole plates and incubated at 37°in the presence of 5% CO2to achieve 80% of confluently. Then the analyzed compounds dissolved in culture medium (containing no FBS, but containing 0.1% bovine serum albumin, BSA) and added to cells. The control environment includes not containing the analyzed compounds. Then incubated at 37°C for 2 h and added recombinant VEGF, and the final VEGF concentration is 20 ng/ml Incubated at 37°C for five min, then the cells washed twice with cooled in an ice bath of phosphate-saline buffer (FSB) and immediately are lysed by adding to the wells 100 ál lyse buffer solution. Then the lysates centrifuged, removing the cell nucleus, and determine the end is Tracey protein supernatant using a set of reagents for determination of protein the firm BioRad. Lysates can be used directly after preparation, or if necessary, they can be stored at -20°C.

Measuring the phosphorylation of KDR-receptor performed using enzyme-linked immunosorbent assay (ELISA) according to the following procedure. Monoclonal antibodies to KDR (for example, Mab 14985.12.14 received H.Towbin) immobilized on black pads for ELISA (OptiPlate™ HTRF-96-Packard company). Then the tablets are washed and free binding proteins plots saturate a 1% solution of BSA in PBS. Then in these tablets incubated cell lysates (20 μg protein in the hole) at 4°over night in a mixture with antibodies to phosphotyrosine conjugated with alkaline phosphatase (PY20:AP, production, Transduction Laboratories). Tablets are again washed, and then linking antiphosphotyrosine antibodies with immobilized phosphorylated receptor is determined visually using fluorescent AR substrate (CDP-Star, ready-to-use, mixed with Emerald II; firm Tropix). Luminescence was measured in a scintillation counter for microplates (Packard Top Count). The difference between the signal of the positive control (stimulated VEGF) and the signal of the negative control (not stimulated VEGF) corresponds to phosphorylation (=100%) KDR-receptor induced VEGF. The activity of the analyzed compounds calculated as the percentage of Engibarov is of phosphorylation of KDR-receptor, induced VEGF, while the concentration at which the observed inhibition equal to half of the maximum, is defined as the ED50 (effective dose that causes 50%inhibition). The compounds of formula I preferably have values of ED50 in the range from 0.25 nm to 1000 nm, preferably from 0.25 nm to 250 nm.

The compound of formula I or its N-oxide in varying degrees also inhibit other tyrosine kinase involved in signaling, which is mediated by trophic factors, for example Abl kinase, kinases from the Src family, especially c-Src kinase, Lck, and Fyn; in addition, kinases of the EGF family, for example-rb2 kinase (HER-2)-rb3 kinase, C-rb4 kinase; receptor kinase insulin-like growth factor (IGF-1 kinase), primarily family members PDGF-receptor tyrosine kinase, such as PDGF-receptor kinase, CSF-1 receptor kinase, Kit-receptor kinase and VEGF receptor kinase; and serine/threonine kinases, each of which participates in growth regulation and transformation in mammalian cells, including human cells.

Inhibition of C-rb2 tyrosine kinase (HER-2) can be determined, for example, similar to measure the inhibition of EGF-R protein kinase (see House and others, Europ. J. Biochem., 140, 363-367 (1984)). rb2 Kinase can be selected, and its activity can be determined using izvestnyh methods (see article Takama and other Science, 232, 1644 (1986)).

The results of these tests, the compound of formula I according to the present invention has a therapeutic effect, first of all, when violations-dependent protein kinase, particularly in proliferative diseases.

Analgesic activity of the compounds of formula I can be demonstrated in the following model of pain perception. In this model, the hyperalgesia caused intrapleural injection of yeast, measured when exposed to mechanical pressure on the limb until such time as the animal will not vote or will not remove the paw from the presser pads. This model is sensitive to inhibitors SOH, and as a positive control, use diclofenac at a dose of 3 mg/kg of the test below.

Two hours before the injection to determine the working pressure needed to force the male rats Sprague Dawley (weighing approximately 180 g, supplied by the firm Iffa Credo, France) submit a vote or to remove the paw, then spend intraplantar injection of 100 ál of 20%suspension of yeast in the water in the hind paw. After 2 h (time 0 h) rats give the analyzed compound oral dose of 3, 10 or 30 mg/kg), diclofenac (3 mg/kg) or vehicle (saline) and a pressure test should be repeated after 1 and 2 h after dosing. This determines the pressure required is for voting or retrieve feet using standard instrument company Ugo Basile (Italy), and compare with the results obtained in animals treated with the media.

The results of these tests, the compound of formula I suddenly found suitable for reducing pain. The compounds of formula I or their N-oxides according to the invention also have therapeutic effect, first of all, when violations-dependent protein kinase, particularly in proliferative diseases.

Thanks inhibitory activity against VEGF receptor tyrosine kinase, the compounds of formula I, primarily inhibit the growth of blood vessels and, thus, for example, effective against a number of diseases associated with impaired angiogenesis, especially diseases caused by neovascularization of the eye, especially retinopathy, such as diabetic retinopathy or age-related macular degeneration, psoriasis, haemangioblastoma, such as hemangioma, proliferative disorders mesangial cells, such as chronic or acute renal diseases, e.g. diabetic nephropathy, malignant nephrosclerosis, syndromes, thrombotic microangiopathy, or transplant rejection, or, above all, inflammatory renal diseases, such as glomerulonephritis, especially mesangiocapillary glomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy, hypertensive nephrol the roses, atheroma (atherosclerotic plaque), arterial restenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma, and, above all, neoplastic diseases (solid tumors, but also leukemias and other so-called "liquid tumors", primarily associated with the expression of c-kit, KDR, flt-1 or Flt-3), such as, especially, breast cancer, colon cancer, lung cancer (especially small cell lung cancer), cancer of the prostate or Kaposi's sarcoma. The compound of formula I (or an N-acid) inhibits tumor growth and, above all, suitable for the prevention of metastasis of tumors and the growth micrometastases.

The compound of the formula I can be entered separately or in combination with one or more other therapeutic agents, possible concomitant therapy, i.e. the introduction of fixed combinations or the introduction of compounds according to the invention and one or more other therapeutic agents or alternately independently from each other, or co-administration of fixed combinations and one or more other therapeutic agents. The compound of the formula I can be entered separately or additionally, primarily in the treatment of tumors in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these approaches. Long-term therapy is equally possible in VI is e adjuvant therapy in combination with other of the above treatment strategies. Other possible treatments include the maintenance status of the patient after the regression of the tumor or even chemoprophylactic therapy, for example, in the case of patients with an increased risk.

Therapeutic agents for possible combination are, first and foremost, one or more compounds with cytostatic or toxic effects, for example, it may be a chemotherapeutic agent or several agents selected from the group comprising an inhibitor of the biosynthesis polyamine, an inhibitor of protein kinase, especially serine/threonine protein kinases such as protein kinase C, or tyrosylprotein, such as a receptor protein kinase epidermal growth factor, a cytokine, a negative growth regulator, such as TGF-β or IFN-β, aromatase inhibitor, classical cytostatic agent, and an inhibitor of the interaction of SH2 domain with a phosphorylated protein.

The connection according to the invention is intended not only to assist the person (prevention or treatment), but also for the treatment of other warm-blooded animals, such as commercial animals, such as rodents, such as mice, rabbits or rats, or Guinea pigs. This connection can also be used as a standard sample in the above analytical systems for comparison with other compounds.

In common with what you learn, the invention relates also to the use of compounds of formula I or its N-oxide for inhibiting the activity of VEGF-receptor tyrosine kinase, in vitro or in vivo.

The compound of formula I or its N-oxide can also be used for diagnostic purposes, for example to study tumors, which were obtained from the "host" in the form of a warm-blooded animal, especially human, and were implanted in the body of the mouse for the analysis of growth after the introduction of such compounds to study the sensitivity of the tumor to the aforementioned compound and, thus, to search for and possible methods of treatment of neoplastic diseases in the host organism.

As for the groups of preferred compounds of formula I and their N-oxides, referred to in this description, to replace more General values on more specific or primarily on the values defined as preferred, it is advisable to use values of the substituents of the above General definitions.

In more detail, the invention relates to the use of compounds of formula I, where

n is from 1 to 6, inclusive;

W denotes O or S;

R1and R3independently from each other and each means hydrogen, (ness.)alkyl or (ness.)acyl;

R2means the group cycloalkyl, an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group including to slort and sulfur, thus groups in each case are unsubstituted or have up to three substituents selected from a range of amino, mono - or disubstituted amino, halogen, (ness.)alkyl, substituted alkyl, (ness.)alkenyl, (ness.)quinil, (ness.)alkanoyl, hydroxy, simple or ester of the hydroxy-group, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, (ness.)alkylthio, phenyl, phenoxy, phenylthio, phenyl(ness.)alkylthio, alkalinity, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylresorcinol, (ness.)alkanesulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylphenolates, halogen(ness.)allylmercaptan, halogen(ness.)alkylsulfonyl, dihydroxybis(-B(OH)2), heterocyclyl and (ness.)alkylenedioxy associated with the adjacent carbon atoms in the cycle;

R and R' independently from each other and each means hydrogen or (ness.)alkyl;

X means an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or may contain up to three substituents selected from a range of amino, mono - or d is substituted amino, halogen, (ness.)alkyl, substituted alkyl, (ness.)alkenyl, (ness.)quinil, (ness.)alkanoyl, hydroxy, simple or ester of the hydroxy-group, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, (ness.)alkylthio, phenyl, phenoxy, phenylthio, phenyl(ness.)alkylthio, alkalinity, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylresorcinol, (ness.)alkanesulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylphenolates, halogen(ness.)allylmercaptan, halogen(ness.)alkylsulfonyl, dihydroxybis(-B(OH)2), heterocyclyl and (ness.)alkylenedioxy associated with the adjacent carbon atoms in the cycle;

or its N-oxide or a possible tautomer;

or pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions for the treatment of diseases that are sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase.

More preferably, the invention relates to the use of compounds of formula I, where

n is from 1 to 3 inclusive;

W denotes O or S;

R1and R3independently from each other and each means hydrogen, (ness.)alkyl or (ness.)acyl;

R2means cyclohexyl, phenyl, indazoles, thiazolyl, benzo[d]thiazolyl, benzo[d]irsael or ethenolysis, which in each case is unsubstituted or mono - or disubstituted by (ness.)the alkyl, (ness.)alkenyl or (ness.)the quinil; and where each radical R2may be unsubstituted or mono - or polyamidine halogen;

R and R' independently from each other and each means hydrogen or (ness.)alkyl;

X is phenyl, pyridyl, pyrimidyl or chenail, which in each case is unsubstituted or mono - or polyamidine group of oxo, hydroxy, (ness.)alkyl or (ness.)alkoxy;

or its N-oxide or a possible tautomer;

or pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions for the treatment of diseases that are sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase.

One preferred embodiment of the invention relates to the compound of formula I where n is 1 or 2;

W means Of;

R1and R3mean hydrogen;

R2means cyclohexyl, phenyl, indazoles, thiazolyl or ethenolysis, which in each case is unsubstituted or mono - or disubstituted by (ness.)the alkyl or (ness.)the quinil; and where each radical R2may be unsubstituted or mono - or polyamidine halogen;

R and R' independently from each other and each means hydrogen or (ness.)alkyl;

X is phenyl, pyridyl, pyrimidyl or chinolin which in each case is unsubstituted or mono - or polyamidine oxo group, hydroxy, (ness.)alkyl or (ness.)alkoxy;

or its N-oxide or a possible tautomer;

or pharmaceutically acceptable salts of such compounds, which are used to obtain a pharmaceutical composition for the treatment of diseases that are sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase.

Primarily, the invention relates to the use of compounds of formula I

or its N-oxide or a possible tautomer or pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions for the treatment of diseases that are sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase, and the disease means cancer.

In another preferred embodiment, the invention relates to the use of compounds of formula I or its N-oxide or a possible tautomer or pharmaceutically acceptable salts of such compounds, to pharmaceutical compositions for the treatment of diseases that are sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase, and the disease means retinopathy or age-related macular degeneration.

In addition, the invention relates to a method of treatment of a disease sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase, which includes the introduction of the compounds of formula I Riego N-oxide or pharmaceutically acceptable salt, where the radicals and symbols have the meanings specified above, in a quantity effective against the above diseases, the warm-blooded animal in need of such treatment.

In addition, the invention relates to compounds of formula I, where n is from 1 to 6, inclusive;

W denotes O or S;

R1and R3independently from each other and each means hydrogen, (ness.)alkyl or (ness.)acyl;

R2means the group cycloalkyl, an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or mono - or polyamideimide;

R and R' independently from each other and each means hydrogen or (ness.)alkyl,

X means an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or mono - or polyamideimide;

and their N-oxides or the possible tautomers;

and to pharmaceutically acceptable salts of such compounds, with the exception of the compounds of formula I where n is 1, W denotes O, R1, R3, R, R' means hydrogen, X is appoints phenyl, a R2mean 3-triptoreline or 2-methoxyphenyl.

More preferably, the invention relates to compounds of formula I, where

n is from 1 to 6, inclusive;

W denotes O or S;

R1and R3independently from each other and each means hydrogen, (ness.)alkyl or (ness.)acyl;

R2means the group cycloalkyl, an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or have up to three substituents selected from a range of amino, mono - or disubstituted amino, halogen, (ness.)alkyl, substituted alkyl, (ness.)alkenyl, (ness.)quinil, (ness.)alkanoyl, hydroxy, simple or ester of the hydroxy-group, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, (ness.)alkylthio, phenyl, phenoxy, phenylthio, phenyl(ness.)alkylthio, alkalinity, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylresorcinol, (ness.)alkanesulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylphenolates, halogen(ness.)allylmercaptan, halogen(ness.)alkylsulfonyl, dihydro what sebora(-B(OH) 2), heterocyclyl and (ness.)alkylenedioxy associated with the adjacent carbon atoms in the cycle;

R and R' independently from each other and each means hydrogen or (ness.)alkyl;

X means an aryl group or a mono - or bicyclic group heteroaryl containing one or more nitrogen atoms in the cycle, and is 0, 1 or 2 heteroatoms, independently from each other selected from the group comprising oxygen and sulfur, which groups in each case are unsubstituted or may contain up to three substituents selected from a range of amino, mono - or disubstituted amino, halogen, (ness.)alkyl, substituted alkyl, (ness.)alkenyl, (ness.)quinil, (ness.)alkanoyl, hydroxy, simple or ester of the hydroxy-group, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, (ness.)alkylthio, phenyl, phenoxy, phenylthio, phenyl(ness.)alkylthio, alkalinity, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylresorcinol, (ness.)alkanesulfonyl, phenylsulfonyl, phenyl(ness.)alkylsulfonyl, alkylphenolates, halogen(ness.)allylmercaptan, halogen(ness.)alkylsulfonyl, dihydroxybis(-B(OH)2), heterocyclyl and (ness.)alkylenedioxy associated with the adjacent carbon atoms in the cycle;

or N-oxides or possible tautomer is m;

or pharmaceutically acceptable salts of such compounds,

with the exception of the compounds of formula I where n is 1, W denotes O, R1, R3, R, R' means hydrogen, X is phenyl, a R2mean 3-triptoreline or 2-methoxyphenyl.

Preferred are the compounds of formula I, where

n is from 1 to 3 inclusive;

W denotes O or S;

R1and R3independently from each other and each means hydrogen, (ness.)alkyl or (ness.)acyl;

R2means cyclohexyl, phenyl, indazoles, thiazolyl, benzo[d]thiazolyl, benzo[d]pyrazolyl or ethenolysis, which in each case is unsubstituted or mono - or disubstituted by (ness.)the alkyl, (ness.)alkenyl or (ness.)the quinil; and

where each radical R2may be unsubstituted or mono - or polyamidine halogen;

R and R' independently from each other and each means hydrogen or (ness.)alkyl;

X is phenyl, pyridyl, pyrimidyl or chenail, which in each case is unsubstituted or mono - or polyamidine group of oxo, hydroxy, (ness.)alkyl or (ness.)alkoxy;

or N-oxides or tautomers;

or pharmaceutically acceptable salts of such compounds,

with the exception of the compounds of formula I where n is 1, W denotes O, R1, R3, R, R' means hydrogen, X is phenyl, a R2mean 3-triform tylenil or 2-methoxyphenyl.

Above all, preferred are the compounds of formula I where n is 1 or 2;

W means Of;

R1and R3mean hydrogen;

R2means cyclohexyl, phenyl, indazoles, thiazolyl or ethenolysis, which in each case is unsubstituted or mono - or disubstituted by (ness.)the alkyl or (ness.)the quinil;

and where each radical R2may be unsubstituted or mono - or polyamidine halogen;

R and R' independently from each other and each means hydrogen or (ness.)alkyl;

X is phenyl, pyridyl, pyrimidyl or chenail, which in each case is unsubstituted or mono - or polyamidine group of oxo, hydroxy, (ness.)alkyl or (ness.)alkoxy;

or N-oxides or tautomers;

or pharmaceutically acceptable salts of such compounds,

with the exception of the compounds of formula I where n is 1, R, R' means hydrogen, X is phenyl, a R2mean 3-triptoreline or 2-methoxyphenyl.

In the above definition of R2the wording "where each radical R2may be unsubstituted or mono - or polyamidine halogen" refers to the radical R2in which the substituents (ness.)alkyl, (ness.)alkenyl or (ness.)quinil within the above groups (cyclohexyl, phenyl, imidazolyl etc) in turn optionally are substituted halogenated way the definition includes, along with other radicals R2like triptoreline or bis(trifluoromethyl)phenyl.

Most preferably, a compound selected from the group of compounds including:

2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(2-methyl-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(6-methoxy-3-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[5-fluoro-3-triptoreline]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(TRANS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(4-n-butylphenyl)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(4-n-pentylphenol)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[4-(1-PROPYNYL)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(5-indazole)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide,

2-[(pyridine-6(1H)-one-3-yl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide and their pharmaceutically acceptable salts.

Additionally, most preferably the mi are compounds selected from the group of compounds including

hydrochloride 2-(phenylethylamine)-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[2-methyl-5-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-(CIS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(1-oxido-4-pyridyl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[3-[N-methylcarbamate)phenyl]methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(1-methylpyridin-2(1H)-one-5-yl)methylamino]-N-[3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridin Roxane,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(3-hydroxyphenyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-propyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-propyl-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[4-(n-propyl)-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(5-thiazolyl)-3-pyridinecarboxamide,

2-[(4-hydroxyphenyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide,

2-[(6-methoxy-3-pyridyl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide,

2-[(6-methoxy-3-pyridyl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(CIS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

<> 2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(TRANS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

2-[(1-oxido-4-pyridyl)methylamino]-N-[4-propyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-ethyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(1-methylpyridin-2(1H)-one-5-yl)methylamino]-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide and their pharmaceutically acceptable salts.

The connection according to the invention can be obtained by methods which, although so far not been used to obtain new compounds of the present invention, essentially known; first of all, this method is characterized by the fact that for the synthesis of compounds of formula I, where R1, R2, R3, R, R', X, W and n have the meanings specified for compounds of formula I, a derivative of pyridine of formula II

where W, R1and R2have the meanings specified for compounds of formula I, a Y represents a leaving group such as halogen, preferably chlorine, interacts with the amine of formula III

where n, R, R', R3and X have the meanings specified for compounds of formula I, optionally in the presence of a base and an appropriate catalyst, such as with the unity of copper(I), optionally in the presence of an inert solvent;

moreover, the above-mentioned starting compound II and III may also be present with protected functional groups, if necessary, and/or in the form of salts provided that such salt-forming group in the compound is present and the possible reaction in salt form;

moreover, any protective group in the protected compound of the formula I are removed;

and, if necessary, the obtained compound of the formula I is converted into another compound of formula I or its N-oxide, a free compound of formula I is transformed into salt obtained salt of a compound of the formula I is converted into the free compound or another salt, and/or a mixture of isomers of compounds of formula I is separated into the individual isomers.

In another embodiment, the compound according to the invention, where R'attached to the carbon atom connected to the nitrogen atom in the bridge group, mean hydrogen, can be obtained by a method in which aminopyridine of formula IV

where R1and R2have the meanings specified for compounds of formula I, interacts with the carbonyl-containing compound of the formula V

where X, n, R and R' have the meanings specified for compounds of formula I, in the presence of a reducing agent. Carbonyl-containing compound of the formula V m which may also be present in the form of a reactive derivative, however, the preferred free aldehyde or ketone. Reactive derivatives of compounds of formula V are, for example, the corresponding bisulfite adducts, or, above all, hemiacetals, acetals, policital or ketals of compounds of the formula V with alcohols, for example (ness.)the alkanols; or toataly or thioketal compounds of the formula V with mercaptans, for example (ness.)alkylsulfides.

Reductive alkylation is preferably carried out by hydrogenation in the presence of a catalyst, the first catalyst based on a noble metal such as platinum or primarily palladium, which is preferably associated with material media, such as coal, or catalyst on the basis of heavy metal such as Raney Nickel, at normal pressure or at a pressure of from 0.1 to 10 MPa (megapascals), or recover using complex hydrides, such as borhydride, primarily laborgerate alkali metal, such as laborgerate sodium, in the presence of an appropriate acid, preferably a relatively weak acids, such as (NISS.)alcancarao acid, especially acetic acid, or sulfonic acids such as para-toluensulfonate; in the usual solvents, for example alcohols, such as methanol or ethanol, or ethers, such as cyclizes the x esters, such as tetrahydrofuran, in the presence or in the absence of water.

Detailed description of the method

Unless otherwise stated below in the detailed description of the method R1, R2, R3, R, R', X, W and n have the meanings specified for compounds of formula I.

The interaction of the compounds of formulas II and III is preferably carried out in a polar solvent, such as alcohols, for example ethanol, isopropanol, butanol, 3-ethyl-3-pentanol, dimethylacetamide, dimethylformamide or N-organic, and preferably in an atmosphere of inert gas, such as nitrogen or argon. The base used in the reaction may be selected from conventional bases, such as potassium carbonate, cesium carbonate, or organic base such as a tertiary amine, such as ethyldiethanolamine, or an aromatic amine such as pyridine, or the reaction is carried out in the presence of an excess of the reagent of formula III. Satisfactory results are obtained when using potassium carbonate. The reaction is carried out in the presence of a catalyst based on copper ion or Nickel salts. As a catalyst the preferred copper oxide(I) or iodide copper(II). The reaction time is preferably from 0.5 h to 24 h, for example, 120 min, the reaction temperature is from room temperature to the boiling temperature of the solvent. If the solvent is sportsouth dimethylformamide, the reaction temperature preferably ranges from 80°C to the boiling point of the solvent.

Protective groups

If in the compounds of formulas II, III and/or IV should or need to protect one or more other functional groups, for example carboxy, hydroxy, amino or mercapto not involved in the reaction, then using these groups, which are usually used in the synthesis of peptides, and also of cephalosporins and penicillins, derivatives of nucleic acids and sugars.

The protective groups may already be present in the precursors and must protect the respective functional group from undesired side reactions, such as acylation, the formation of esters and ethers, oxidation, solvolysis and similar reactions. Protective groups characteristic that they can be easily removed, i.e. without undesired side reactions, usually solvolysis, recovery, photolysis, as well as using enzymes, for example, in conditions similar to physiological conditions, and it is characteristic that these groups are absent in the final product. For professionals it is obvious, or it can easily determine which protective groups are acceptable in above - and below reactions.

The protection of such functional groups such protective groups are themselves protective group and the reaction ekudaleni described, for example, in a number of books, such as J.F.W.McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York (1973), .W.Greene, "Protective Groups in Organic Synthesis", Wiley, New York (1981), "The Peptides"; Volume 3 (ed. E.Gross and J.Meienhofer), Academic Press, London and New York (1981), "Methods der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th edition. Volume 15/I, Georg Thieme Verlag, Stuttgart (1974), H.-D.Jakubke and H.Jescheit, "Aminosäuren, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel (1982), and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart (1974).

In one of the preferred embodiments of the invention from the compounds of formula I, including the radical 2-methoxypyridine receive compound of formula I, including the radical 2-hydroxypyridine, processing trimethylsilylimidazole for about 20 hours to 35 hours at a temperature of from 45°C to 70°With in an appropriate solvent, i.e. halogenated alkane, for example, in chloroform, optionally followed by treatment with methanol.

Additional stages of the method

Additional stages of the method, if necessary, functional groups of the parent compounds, not participating in the reaction, may be present in unprotected form or may be protected, for example, one or more groups described above as the "protective group". Then the protective groups are completely or partially remove one of these ways is impressive.

Salts of the compounds of formula I with salt-forming group can be obtained in a known manner. Thus, the acid additive salts of compounds of formula I can be obtained by the interaction with an acid or with a corresponding anion exchange reagent. Salt with two acid molecules (for example, dihalogenide the compounds of formula (I) can also be converted into a salt with one acid molecule (for example, in monohalogen); this stage can be accomplished by heating the melt, or for example by heating the solids in a high vacuum at elevated temperature, for example at a temperature of from 130°170°from the molecules of the compounds of formula I removed one molecule of acid.

Salts can be converted into the free compounds, for example, processing the respective basic agents, such as carbonates, alkali metal bicarbonates of alkali metals or hydroxides of alkali metals, typically potassium carbonate or sodium hydroxide.

Stereoisomeric mixtures, for example mixtures of diastereomers, can be separated into the respective isomers in a known manner using conventional separation methods. For example, diastereomer mixture can be separated into the individual diastereomers by fractional crystallization, chromatography, distribution in R is storytale etc. This separation can be performed at the level of the parent compound or final compounds of formula I. the Enantiomers can be separated using the diastereoisomeric salts, for example, by salt formation with enantiomerically pure chiral acid, or by chromatography, for example, IHVR, using chromatographic sorbents with chiral ligands.

The compound of formula I, where W denotes Oh, can be converted into the corresponding compound where W means S, for example, by using an appropriate sulfur compounds, for example, by reaction with a reagent of Lawesson (2,4-bis-(4-methoxyphenyl)-2,4-ditions-1,2,3,4-dithiophosphate) in a halogenated hydrocarbon, such as dichloromethane, or in an aprotic solvent such as toluene or xylene, at a temperature of from about 30°C to the boiling point of the solvent.

The compound of formula I, where R1means hydrogen, can be converted into the corresponding compound where R1means (ness.)alkyl, by reaction with, for example, diazo(ness.)the alkyl, first of all, diazomethane, in an inert solvent, preferably in the presence of a catalyst based on a noble metal, especially in dispersed form, for example copper, or salt of a noble metal, such as copper chloride(I) or copper sulfate(II). In addition, the possible reaction with (ness.)alkyla what agendae, or (ness.)alkanes containing other leaving group, for example, (ness.)alkyl alcohols, esterified with a strong organic sulfonic acid, such as (ness.)alkanesulphonic acid (optionally substituted with halogen, such as fluorine), an aromatic sulfonic acid, for example unsubstituted or substituted benzosulfimide acid, in which the substituents are preferably selected from the range (ness.)alkyl, for example methyl, halogen, such as bromine, and/or nitro, for example esterified methane sulfonic acid, for example trimethylsulfonium acid or para-toluensulfonate acid. The alkylation is conducted primarily in the aqueous solution and/or in the presence of polar solvents, typically alcohols, such as methanol, ethanol, isopropanol or ethylene glycol, ethers, typically dioxane, amides, typically DMF (dimethylformamide), or phenols, usually phenol, and in the absence of water in nonpolar solvents, usually in benzene and toluene, or in emulsions of the water/benzene, and, if possible, in the presence of acidic or basic catalysts, for example alkali, usually sodium hydroxide solution, or in the presence of solid catalysts, typically aluminum oxide, with grafted with hydrazine, in ethers, for example diethyl ether, typically at a temperature of from about 0°to pace atory boiling point of the reaction mixture, preferably from 20°C to the boiling point (solvent), optionally at elevated pressure, for example, in a sealed ampoule, it is also possible at temperatures above the boiling point (solvent), and/or in the atmosphere of inert gas, usually nitrogen or argon.

It should be emphasized that reactions similar to those described in this section can also be performed, with the corresponding intermediate compounds.

General conditions of implementation of the method

All the following stages of the method can be carried out in known conditions, preferably those mentioned above, in the absence of or usually in the presence of solvents or diluents, preferably inert to the reagents and dissolve them, in the absence or in the presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically kationoobmennikom, for example, N+form, depending on the type of reaction and/or reactants at reduced, normal or elevated temperature, for example in the range from -100°With up to approximately 190°C, preferably from approximately -80°With up to approximately 150°With, for example, from -80°C to -60°With, at room temperature, -20°C to 40°With, or at the boiling temperature of the solvent, atmospheric pressure or in a closed vessel, if is possible under pressure, and/or in an inert atmosphere, for example in an atmosphere of argon or nitrogen.

All initial and intermediate compounds containing soleobrazutaya group may be present as salts. Salt may also be present during the reactions, which take such compounds, provided that the presence of a salt form does not prevent the passage of reaction.

At all stages of the synthesis, the resulting mixtures of isomers can be separated into the individual isomers, for example diastereoisomers or enantiomers or any mixture of isomers, for example racemates or mixtures of diastereoisomers, usually, as described in the section "Additional stage of the way."

In some cases, usually when the hydrogenation, it is possible to carry out stereoselective reactions, which provide, for example, more than simple separation of individual isomers.

If the description method not stated otherwise, the solvents from which to choose acceptable for carrying out the above reactions include, for example, water, esters, typically (ness.)alkyl(ness.)alkanoate, such as ethyl acetate, ethers, typically aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically methanol, ethanol or 1 - or 2-propanol, NITRILES, typically acetonitrile, halogenated carbohydrate is childbirth, typically dichloromethane, amides, acids, typically dimethylformamide, bases, typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically (ness.)alcancarao acid, for example acetic acid, anhydrides of carboxylic acids, usually anhydrides (ness.)alkenylboronic acids, for example acetic anhydride, cyclic, linear or branched hydrocarbons, typically cyclohexane, hexane or isopentane, or mixtures of these solvents, e.g. aqueous solutions. Such mixtures of solvents can also be used in method (invention), for example, by chromatography or distribution.

The invention relates also to those forms of the way in which the synthesis begins with the compounds obtained in any other stage as an intermediate connection, hold the stage, not achieved the goal, or interrupt method at any stage, or get a starting material under the reaction conditions, or use referred to the source material in the form of a reactive derivative or salt, or get a connection method according to the invention and process the said compound in situ. In a preferred embodiment of the invention, the synthesis begins with such raw materials, which allow to obtain the compounds described above as preferred, especially preferred, Naib is more preferred and/or most preferred.

In a preferred embodiment of the invention the compound of formula I get the methods and stages of the method described in the examples or similar.

The compounds of formula I, including their salts, can also be obtained in the form of hydrates, or their crystals can include for example the solvent used for crystallization (MES).

Pharmaceutical preparations, methods for their preparation and use.

The present invention relates also to a method of treatment of neoplastic diseases, which are sensitive to inhibition of the activity of VEGF-receptor tyrosine kinase, which includes the introduction of the compounds of formula I or its N-oxide or pharmaceutically acceptable salt, where the radicals and symbols have the meanings specified for formula I, in an amount effective against the said diseases, to a warm-blooded animal in need of such treatment.

In another embodiment, the invention relates to a method of treating retinopathy or age-related macular degeneration, which includes the introduction of the compounds of formula I or its N-oxide or pharmaceutically acceptable salt, where the radicals and symbols have the meanings specified for formula I, in an amount effective against the said diseases, to a warm-blooded animal in need of such treatment.

The present invention relates also to F. rmaceuticals songs comprising the compound of formula I or its N-oxide as the active ingredient, which can be used primarily in the treatment of diseases mentioned in the beginning of the description of the application. Above all, preferred compositions for enteral administration, such as nasal, transbukkalno, rectal or, especially, oral administration and parenteral administration such as intravenous, intramuscular or subcutaneous injection, warm-blooded animals, especially humans. The compositions comprise the active ingredient alone or, preferably, in a mixture with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the disease to be treated, the species of animal, its age, weight and condition, individual pharmacokinetic data and method of administration.

The present invention relates, primarily, to pharmaceutical compositions comprising a compound of formula I, tautomer, N-oxide or pharmaceutically acceptable salt, or hydrate, or MES and at least one pharmaceutically acceptable carrier.

The invention relates also to pharmaceutical compositions for use in the method of prevention or primarily therapeutic treatment of the human or animal, to the way they are received (primarily in the form of compositions DL the treatment of tumors) and to a method of treatment of cancer, first of all, mentioned above.

The invention relates also to methods of preparation and use of compounds of the formula I or their N-oxides in a method of producing pharmaceutical preparations which comprise compounds of the formula I or their N-oxides as active component (active ingredient).

In a preferred embodiment of the invention the pharmaceutical preparation is suitable for introduction warm-blooded animal, especially humans or commercially mammal suffering from a disease sensitive to inhibition of angiogenesis or VEGF-receptor tyrosine kinase, such as psoriasis or, especially, cancer, and includes a number of compounds of formula I or its N-oxide, is effective in inhibiting angiogenesis or VEGF-receptor tyrosine kinase, or its pharmaceutically acceptable salt, if it contains soleobrazutaya group, and at least one pharmaceutically acceptable carrier.

Similarly, the preferred pharmaceutical composition for the prevention or primarily for therapeutic treatment of cancer and other proliferative diseases in a warm-blooded animal, especially humans or commercially mammal in need of such treatment, primarily suffering from such disease, VK is causa as active ingredient new compound of formula I or its N-oxide in a quantity which actively in preventive or primarily therapeutic relationship, in the above-mentioned diseases.

The pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, and in the preferred embodiment of the invention forms a single injection include from about 20% to about 90% active ingredient, and forms for repeated use in the preferred embodiment of the invention include from about 5% to about 20% of the active ingredient. Forms containing standard doses are, for example, tablets, coated and uncoated, ampoules, vials, suppositories or capsules. Other dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc. examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.

The pharmaceutical compositions of the present invention receive by known methods, for example using conventional mixing, granulating, coating, dissolving or lyophilization.

It is preferable to use the active ingredient in solution and in the form of suspensions or dispersions, especially in the form of an isotonic aqueous solutions, dispersions or suspensions which, e.g. the measures in the case of lyophilized compositions comprising the active ingredient alone or in a mixture with a carrier, for example mannitol, can be prepared immediately before use. The pharmaceutical compositions can be sterile and/or may include excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilizing agents, salts for regulating osmotic pressure and/or buffer substances, and can be prepared by known methods, such as conventional dissolution and lyophilization. The said solutions or suspensions may include thickeners, usually the sodium salt of carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin, or solubilizing agents, such as tween 80 (monooleate polyoxyethylene(20)sorbitan brand company ICI Americas, USA).

Suspensions in oil include as an oil component, vegetable, synthetic or semi-synthetic oils used for injection. In this regard, mention should be made of the liquid esters of fatty acids, which contain as the acid components of long-chain fatty acids having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridesilon acid, myristic acid, pentadecylic acid, palmitic is islote, margaric acid, stearic acid, arachidonic acid, beenbuy acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassicicola acid or linoleic acid, if necessary with the addition of antioxidants, such as vitamin E, β-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters contains up to 6 carbon atoms inclusive and is monatomic or polynuclear, such as mono-, di - or trivalent alcohol such as methanol, ethanol, propanol, butanol or pentanol or their isomers, but, first of all, the glycol or glycerol. Therefore, as esters of fatty acids should be mentioned the following: etiloleat, isopropylmyristate, isopropyl, "Labrafil M 2375" (trioleate of polyoxyethyleneglycol, the company Gattefosse, Paris),

"Labrafil M 1944 CS" (unsaturated poliglecaprone glycerides obtained by alcoholysis of peach oil containing glycerides and esters of polyethylene glycol, the company Gattefosse, France), "Labrasol" (saturated poliglecaprone glycerides obtained by alcoholysis of FCM and including glycerides and esters of polyethylene glycol, the company Gattefosse, France), and/or "Miglyol 812" (triglyceride of saturated fatty acids with chain length from C8to C12the firm Hulls AG, Germany the project), but first of all vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and, more preferably, peanut butter.

Injecting drugs is usually prepared in sterile conditions, for example, poured into ampoules or vials and sealed.

Pharmaceutical compositions for oral administration can be obtained by mixing the active ingredient with one or more solid carrier, optionally granulating the resulting mixture and processing the mixture or granules, if desired or necessary for inclusion of additional excipients, into tablets or cores tablets.

Acceptable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations of cellulose and/or calcium phosphates, for example tricalcium phosphate or calcium phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hypromellose, sodium salt of carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, optionally, disintegrators, such as the above-mentioned starches, and also carboximetilkrahmal, crosslinked polyvinylpyrrolidone, alginic acid and its salts, such as sodium alginate. Add the elegance of the excipients are, first of all, liquid air and oil, such as silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol or its derivatives.

Core tablets can be covered with optional intersolubility coating using, along with other materials concentrated solutions of sugar, which may include the Arabian gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or solutions to cover in appropriate organic solvents or mixtures of solvents, or to obtain intersolubility coating solutions of the respective preparations of cellulose such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. In tablets or coated tablets can be added dyes or pigments, for example, to identify or define the different doses of active ingredient.

Pharmaceutical compositions for oral administration include solid capsule containing gelatin, and also soft, sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules can contain the active ingredient in the form of granules, for example, in a mixture with fillers, such as corn starch, binding agents, and/or samalut the representatives, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in a liquid excipients, such as non-volatile oils, paraffin oil or liquid polyethylene glycols or fatty acid esters or ethylene or propylene glycol, to which may be added stabilizers and surfactants, such as fatty acid ester with polyoxyethylenesorbitan.

Pharmaceutical compositions suitable for rectal, represents, for example, suppositories, which contain a mixture of active ingredient with the base of the suppository. Suitable bases suppositories are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration, first of all, acceptable aqueous solutions of the active ingredient in water-soluble form, for example, water-soluble salt, or injectable suspension in water, which contain thickeners such as sodium carboxymethyl cellulose, sorbitol and/or dextran, and, if necessary, stabilizers. The active ingredient, optionally together with excipients, can also be present in the form of a lyophilized drug, and can be prepared in the form of a solution by adding appropriate rest is ritala immediately prior to parenteral administration.

The solutions used, for example, for parenteral administration, can also be used as solutions for injection.

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or a bactericidal agent such as sorbic or benzoic acid.

The invention also relates to a method or the method of treating one of the above pathological conditions, primarily disease sensitive to inhibition of VEGF-receptor tyrosine kinase or inhibition of angiogenesis, primarily corresponding to cancer or psoriasis. The compounds of formula I or their N-oxides can be introduced as such or, primarily in the form of pharmaceutical compositions for prophylactic or therapeutic purposes, preferably in a quantity effective against the mentioned diseases in warm-blooded animal, such as man, in need of such treatment. For a patient weighing 70 kg, a daily dose of from about 0.05 g to about 5 g, preferably from about 0.25 g to about 1.5 g of the compound of the present invention.

First of all, the present invention relates also to the use of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salt, before su is th, the compounds of formula I, referred to as preferred, or its pharmaceutically acceptable salts, as such or in the form of a pharmaceutical product in a mixture with at least one pharmaceutically acceptable carrier for therapeutic and prophylactic treatment of one or more of the above diseases, preferably of the disease sensitive to inhibition of VEGF-receptor tyrosine kinase or angiogenesis, first of all, the appropriate oncological disease or also psoriasis, more preferably, if

the mentioned disease sensitive to inhibition of VEGF-receptor tyrosine kinase or angiogenesis.

The preferred dosage of the composition(s) and obtaining pharmaceutical products (medicines)that you should use in each case described above.

Raw materials

The object of the invention are also new raw materials and/or intermediate compounds and methods for their preparation. In a preferred embodiment of the invention using such raw materials and choose the conditions of the reactions, which provide the preferred compounds.

Starting materials of formulas II and III are known, are commercial products or can be synthesized analogously or according to the methods known vannoy engineering.

For example, a derivative of pyridine of the formula II can be obtained by the reaction of compounds of formula VI

where W has the meanings specified for formula I, Y represents halogen, preferably chloro, and Y' is a leaving group, for example, alkylthio, azide or preferably halogen, for example chlorine, with a compound of formula VII

where the radicals R1and R2have the meanings specified for formula I. In the process, the reaction temperature preferably is strictly controlled by cooling or dilution of the reaction mixture and maintained within the range of 0°C to room temperature. Not necessarily the solution is added an aqueous solution of alkali to neutralize the protonated leaving group, for example, HCl. For example, the reaction is carried out by adding the amine of formula VII in an inert solvent, such as ethyl acetate, ethanol, dimethylformamide or tetrahydrofuran, to aqueous alkali solution such as aqueous solution of sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium carbonate, optionally containing a catalytic amount of 4-(dimethylamino)pyridine, and then added dropwise to the alkaline solution of amine VII, the compounds of formula VI in the same or a different inert solvent.

All other starting materials are known, m which may be obtained by known methods or are commercial products; first of all, they can be obtained by methods described in the examples.

Upon receipt of source materials available functional groups that should not participate in the reaction, if necessary, must be protected. Preferred protective groups, methods for their introduction and removal are described in "Protective groups or examples.

The invention is illustrated by the following examples without limiting its scope.

Unless otherwise specified, the reaction was performed at room temperature.

A. Obtaining intermediates

Intermediate compound 1A

2-Chloro-N-(3-formationl)-3-pyridinecarboxamide

A solution of 3-aminobenzotrifluoride (company Fluka, Buchs, Switzerland; 2.5 ml, 2,90 g, 18 mmol) in ethyl acetate (40 ml) was added at room temperature to a stirred aqueous solution of sodium hydroxide (40 ml of 1 M solution). The obtained mixed solution was treated dropwise over 30 min a solution of 2-chloronicotinamide (firm Lancaster Synthesis, Lancashire, England; 3,52 g, 20 mmol) in dry ethyl acetate (25 ml) and the resulting mixture was stirred at ambient temperature for 2 hours Then the mixture was extracted with ethyl acetate (3×100 ml) and the combined extracts are then washed with water (2×100 ml), hydrochloric acid (2×100 ml of 2 M solution), water (2×100 ml), feast upon the authorized aqueous solution of sodium bicarbonate (2× 100 ml), saturated aqueous sodium chloride (1×100 ml), dried (Na2SO4), filtered and the solvent evaporated under reduced pressure, it was obtained the crude product, which was purified by recrystallization from ethyl acetate/hexane to obtain specified in the title compound as a colourless crystalline solid, tpl.117-118°C.

The following compounds were obtained in the same way as described above, using the appropriate amine (firm Fluka or Aldrich, Buchs, Switzerland, or the firm indicated in parentheses).

Intermediate compound 1B, 2-chloro-N-(4-bromo-3-triptoreline)-3-pyridinecarboxamide, tpl.173-174°received using 4-bromo-3-triptorelin.

Intermediate compound 1B, 2-chloro-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.167-169°received with use of 3,4-bis(trifluoromethyl)aniline (firm Fluorochem, Derbyshire, England).

Intermediate compound 1G, 2-chloro-N-(3-fluoro-5-triptoreline)-3-pyridinecarboxamide, was obtained using 3-fluoro-5-(trifluoromethyl)aniline (firm Fluorochem, Derbyshire, England).

Intermediate compound 1D, 2-chloro-N-(TRANS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide, tpl.135-136°C, obtained using TRANS-4-tert-butylcyclohexylamine (firm Lancaster Synthesis, Lancashire, England).

Intermediate compound 1E, 2-chloro-N-(CIS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide, tpl.171-173°received using CIS-4-tert-butylcyclohexylamine (firm Lancaster Synthesis, Lancashire, England).

Intermediate compound 1G, 2-chloro-N-(4-propylphenyl)-3-pyridinecarboxamide, tpl.107-110°received using 4-n-propylaniline.

Intermediate compound 1Z, 2-chloro-N-(4-butylphenyl)-3-pyridinecarboxamide, tpl.96-98°received using 4-n-butylaniline.

Intermediate compound 1i, 2-chloro-N-(4-pentylphenol)-3-pyridinecarboxamide, tpl.94-96°C, was obtained using 4-n-pentylaniline.

Intermediate compound 1K, 2-chloro-N-(5-indazole)-3-pyridinecarboxamide, tpl.233-255°received using 5-aminoindazole.

The intermediate connection 1l, 2-chloro-N-(3-ethenolysis)-3-pyridinecarboxamide, tpl.180°received using 3-aminoisoquinoline (firm Maybridge Chemical Co. Ltd., England).

Intermediate compound 1m, 2-chloro-N-(4-fluoro-3-triptoreline)-3-pyridinecarboxamide, tpl.140-141°received using 4-fluoro-3-(trifluoromethyl)aniline.

Intermediate compound 1H, 2-chloro-N-[4-(1,1-dimethylethyl)phenyl]-3-pyridinecarboxamide, tpl.74-76°received using 4-tert-butylaniline.

Intermediate compound 1o, 2-chloro-N-[3-(1,1-di is eilati)phenyl]-3-pyridinecarboxamide, was obtained using 3-tert-butylaniline (firm Maybridge Chemical Co. Ltd., England).

Intermediate compound 1H, 2-chloro-N-(2-fluoro-3-triptoreline)-3-pyridinecarboxamide, tpl.104-105°received using 2-fluoro-3-triptorelin.

Intermediate compound 1R, 2-chloro-N-(2-methyl-3-triptoreline)-3-pyridinecarboxamide, tpl.142-143°received using 2-methyl-3-triptorelin (firm Fluorochem, Derbyshire, England).

Intermediate compound 1C, 2-chloro-N-(2-methyl-5-triptoreline)-3-pyridinecarboxamide, tpl.182-183°received using 2-methyl-5-triptorelin (firm Fluorochem, Derbyshire, England).

Intermediate compound 2

2-Chloro-N-[4-(1-PROPYNYL)phenyl]-3-pyridinecarboxamide

Through stir a solution of 4-bromoaniline (0,86 g, 5.0 mmol) in dry toluene (50 ml) was purged argon for 10 minutes Then add tributyl-1-propenylidene (2.5 g, 6.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g) and the resulting mixture was heated at 100°C in argon atmosphere for 10 hours Then the mixture was cooled, filtered and evaporated under reduced pressure, it was obtained the crude 4-(1-PROPYNYL)benzolamide in the form of oil. The oil was dissolved in ethyl acetate (15 ml) was added to a mixed aqueous solution of sodium hydroxide (12 ml of 1 M solution) at room temperature. According to the scientists mixed the solution was treated dropwise over 30 min a solution of 2-chloronicotinamide (firm Lancaster Synthesis, Lancashire, England; 1.06 g, 6 mmol) in dry ethyl acetate (20 ml) and the resulting mixture was stirred for 2 h at ambient temperature. Then the mixture was extracted with ethyl acetate (3×50 ml) and the combined extracts are then washed with water (2×40 ml), saturated aqueous sodium hydrogen carbonate (2×40 ml), saturated aqueous sodium chloride (1×40 ml), dried (Na2SO4), filtered and the solvent evaporated under reduced pressure, it was obtained the crude product, which was purified by chromatography on a column of silica gel with elution by ethyl acetate solution (50%) in hexane and recrystallized from ether/hexane to obtain specified in the connection header in the form of a crystalline solid beige color, tpl.136-138°C.

B. Examples

Example 1

2-[[2-(4-Pyridyl)ethyl]amino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

4-Pyridinediamine (firm Maybridge Chemical Co., Cornwall, England; 0.31 g, 2.5 mmole) was added to a stirred mixture of 2-chloro-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (intermediate compound 1A, 0,90 g, 3 mmole), powdered potassium carbonate (0.35 g, 2.5 mmole) and copper iodide(I) (0,48 g, 2.5 mmole) in dimethylformamide (10 ml). The resulting mixture was purged with argon and then heated at 100°C in argon atmosphere for 2 hours. The mixture is then about what was lagali, was treated with water (100 ml) and was extracted with ethyl acetate (3×80 ml). The combined extracts were washed with an aqueous solution of ammonia (2×50 ml of 10%aqueous solution), dried (Na2SO4), filtered and the solvent evaporated under reduced pressure, it was obtained the crude product, which was purified by chromatography on a column of silica gel with elution by ethyl acetate and recrystallized from ethyl acetate/hexane to obtain specified in the title compound as a colourless crystalline solid, tpl.128-138°C.

Example 2

2-[(4-Pyridyl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

A mixture of intermediate compound 1A (6,00 g, 20 mmol) and 4-pyridylmethylamine (30 ml) was stirred at 150°C for 16 h in an argon atmosphere. The cooled mixture was diluted with ethyl acetate (100 ml) and was extracted with saturated aqueous sodium hydrogen carbonate (100 ml), water (4×50 ml) and saturated aqueous sodium chloride (50 ml). The ethyl acetate solution was dried (Na2SO4), filtered and the solvent evaporated under reduced pressure, it was obtained the crude product, which was purified by chromatography on a column of silica gel with elution by ethyl acetate and recrystallized from 2-propanol/isopropyl ether to obtain specified in the header soy is inane in the form of a colorless crystalline solid, tpl.152-153°C.

The compounds described in examples 3-16, obtained similarly as described in examples 1 and 2, using the appropriate amines and optionally using other known methods (for example, demethylation using trimethylsilylmethyl).

Example 3

2-[(2-Methyl-4-pyridyl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.144-142°C.

Example 4

(a) 2-[(6-Methoxyphenyl-3-yl)methylamino]-N-[3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide, tpl.89-90°C.

(b) the Dihydrochloride of 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide, tpl.85°C.

Example 5

2-[(3-Methoxyphenyl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide.

Example 6

2-[(4-Pyridyl)methylamino]-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.194-196°C.

Example 7

2-[(4-Pyridyl)methylamino]-N-[3-fluoro-5-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide, tpl.195-196°C.

Example 8

2-[(4-Pyridyl)methylamino]-N-(TRANS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide, tpl.165-167°C.

Example 9

2-[(4-Pyridyl)methylamino]-N-[4-(n-propyl)phenyl]-3-pyridinecarboxamide, tpl.147-149°C.

Example 10

2-[(4-Pyridyl)methylamino]-N-[4-(n-butyl)phenyl]-3-pyridinecarboxamide, tpl.107-108°C.

Example 11

2-[(4-Pyridyl)mate the amino]-N-[4-(n-pentyl)phenyl]-3-pyridinecarboxamide, tpl.106-107°C.

Example 12

2-[(4-Pyridyl)methylamino]-N-[4-(1-PROPYNYL)phenyl]-3-pyridinecarboxamide, tpl.216-221°C.

Example 13

2-[(4-Pyridyl)methylamino]-N-(5-indazole)-3-pyridinecarboxamide, tpl.225-230°C.

Example 14

2-[(4-Pyridyl)methylamino]-N-(3-ethenolysis)-3-pyridinecarboxamide, tpl.191-195°C.

Example 15

Hydrochloride 2-(phenylethylamine)-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.203-207°C.

Example 16

2-[(4-Pyridyl)methylamino]-N-[4-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.172-173°C.

Example 17

2-[(4-Pyridyl)methylamino]-N-[4-(tert-butyl)phenyl]-3-pyridinecarboxamide, tpl.186-187°C.

Example 18

2-[(4-Pyridyl)methylamino]-N-[4-((tert-butylether)phenyl]-3-pyridinecarboxamide, tpl.162-163°C.

Example 19

2-[(4-Pyridyl)methylamino]-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.137-140°C.

Example 20

2-[(4-Pyridyl)methylamino]-N-[4-bromo-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide, tpl.164-165°C.

Example 21

2-[(4-Pyridyl)methylamino]-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.146-147°C.

Example 22

2-[(4-Pyridyl)methylamino]-N-[2-methyl-5-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.155-156°C.

Example 23

2-[(4-Pyridyl)methylamino]-N-(CIS-4-tert-butylcyclohexyl)-3-pyrid carboxamid, tpl.103-106°C.

Example 24

2-[(6-Methoxyphenyl-3-yl)methylamino]-N-[4-bromo-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide, tpl.124-125°C.

Example 25

2-[(6-Methoxyphenyl-3-yl)methylamino]-N-[2-fluoro-3-(trifluoromethyl)-

phenyl]-3-pyridinecarboxamide, tpl.107-108°C.

Example 26

2-[(6-Methoxyphenyl-3-yl)methylamino]-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.144-146°C.

Example 27

2-[(1-Oxo-4-pyridyl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.169-171°C.

Example 28

2-[3-(N-Methylcarbamate)phenyl]methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide.

A mixture of 2-amino-N-(3-triptoreline)-3-pyridinecarboxamide (0.56 g, 2.0 mmole), 3-formyl-N-methylbenzamide (0.50 g, 2.4 mmole) and acetic acid (0.5 ml) in methanol (50 ml) was stirred at 25°C in argon atmosphere for 12 hours Then portions over 30 min was added Lamborghini sodium (0.40 g 90%-aqueous solution of 5.75 mmole), the mixture was stirred for 8 h, diluted with dichloromethane (100 ml and was treated with saturated aqueous sodium hydrogen carbonate (50 ml). Then the mixture was stirred for 5 min and filtered, it was obtained the crude product, which was purified by crystallization from isopropanol to obtain specified in the title compound as a colourless crystalline solid ve is esta, tpl.208-210°C.

Example 29

2-[(1-Methylpyridin-2(1H)-one-5-yl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

2-[(6-Methoxyphenyl-3-yl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide was heated at 140°C for 18 h, it was obtained the crude product, which was purified by chromatography on a column of silica gel with elution with a solution of ethanol (10%) in dichloromethane and recrystallized from ethyl acetate to obtain specified in the connection header in the form of a crystalline solid beige color, tpl.224-225°C.

Example 30

2-[(6-Methoxyphenyl-3-yl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide

Mix a solution of 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (see example 24, 0.96 g, 2.0 mmole) in dry toluene (50 ml) was purged with argon at 40°C for 20 minutes Then added tributyl-1-propenylidene (1.0 g, 2.4 mmole) and tetrakis(triphenylphosphine)palladium(0) (60 mg) and the resulting mixture was heated at 100°C in argon atmosphere for 30 hours the Mixture was cooled, treated with an aqueous solution of sodium hydroxide (20 ml, 0.1 M solution)was purged with air for 2 h and the resulting mixture was diluted with ethyl acetate (200 ml). The organic phase is then washed with water (2×40 ml), saturated aqueous solution of the m sodium chloride (1× 40 ml), dried (Na2SO4), filtered and the solvent evaporated under reduced pressure, it was obtained the crude product, which was purified by chromatography on a column of silica gel with elution by ethyl acetate solution (50%) in hexane and recrystallized from ether/hexane to obtain specified in the connection header in the form of a crystalline solid of light yellow color, tpl.109-111°C.

The compounds described in examples 31-32, obtained similarly as described in example 30, using the corresponding arilbred.

Example 31

2-[(4-Pyridyl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.213-217°received using 2-[(4-pyridyl)methylamino]-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (see example 20).

Example 32

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-PROPYNYL-3-trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.211-218°received using 2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide(see example 35).

Example 33

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[3-trifluoromethyl)phenyl]-3-pyridinecarboxamide.

A mixture of 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (see example 4; 1.4 g, 3.5 mmole) and trimethacrylate (company Fluka, Buchs, Switzerland; 1,4ml, 10.3 mmole) in chloroform (30 ml) was stirred at 60°within 10 minutes the Cooled mixture was treated with methanol (2 ml) and stirred at room temperature for 10 minutes the Solvent is evaporated under reduced pressure, the residue was treated with aqueous ammonia solution (100 ml of 10%aqueous solution) and was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with a saturated solution of sodium chloride (50 ml), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure, it was obtained the crude product, which was purified by recrystallization from hot ethyl acetate to obtain specified in the title compound as a colourless crystalline solid, tpl.200-202°C.

The compounds described in examples 34-38, obtained similarly as described in example 33, using the corresponding methoxypyridine.

Example 34

2-[(3-Hydroxyphenyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.143-146°received using 2-[(3-methoxyphenyl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (see example 5).

Example 35

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.202-205 are°C, was obtained using 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-bromo-3-(cryptomite is)phenyl]-3-pyridinecarboxamide (see example 24).

Example 36

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.219-222°C, was obtained using 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (see example 25).

Example 37

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[2-methyl-3-trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.196-201°received using 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (see example 26).

Example 38

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-propyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.220-224°received using 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-propyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide(see example 39).

Example 39

2-[(6-Methoxyphenyl-3-yl)methylamino]-N-[4-propyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide.

A solution of 2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide (see example 30; 1,87 g, 4.25 mmole) in methanol (100 ml) was first made at atmospheric pressure in the presence of platinum catalyst on coal (5%Pt/C (0.4 g) at 22°C. the Calculated amount of hydrogen was absorbed for 13 hours Then the mixture was filtered, the solvent evaporated under reduced pressure, thus was obtained the crude product, which was purified re what kristallizatsiei from dichloromethane/hexane to obtain specified in the title compound as a colourless crystalline solid connections, tpl.51-61°C.

Example 40

2-[(4-Pyridyl)methyl]amino-N-[4-(n-propyl)-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide, tpl.147-149°received in the same way as described in example 39, using 2-[(4-pyridyl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (see example 31).

Example 41

The following compounds can be obtained similarly as described above.

Example 41A

2-[(4-Pyridyl)methyl]amino-N-(5-thiazolyl)-3-pyridinecarboxamide.

Example 41B

2-[(4-Hydroxyphenyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide.

Example 41C

2-(4-Pyridyl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide.

Example 41G

2-[(6-Methoxy-3-pyridyl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide.

Example d

2-[(6-Methoxy-3-pyridyl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide.

Example a

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide.

Example I

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide.

Example s

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-(CIS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide.

Example I

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-(TRANS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide.

Example 41k

2-[(1-Oxido-4-pyridyl)methylamino]-N-[4-propyl-3-(trifluoromethyl)-phenyl]-pyridinecarboxamide.

Example l

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-ethyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide.

Example 41m

2-[(Pyridine-2(1H)-one-5-yl)methyl]amino-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide.

Example n

2-[(1-Methylpyridin-2(1H)-one-5-yl)methylamino]-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide.

Example 42

Soft capsules

5000 soft gelatin capsules, each of which comprises as active ingredient 0.05 g of one of the compounds of formula I mentioned in the previous examples, was prepared as follows:

The composition of

The active ingredient250 g
Neuroglial2 l

Method of delivery:

powdered active ingredient is suspended in europiccola (propylene glycol laurate, the company Gattefosse S.A., Saint Priest, France) and were crushed with a wet pulverizer to obtain a particle size of from 1 to 3 μm. Then the mixture portions on 0,419 g was filled in soft capsules made of gelatin using a device for filling capsules.

1. A method of inhibiting the activity of endothelial growth factor vascular (VEGF) receptor tyrosine kinase, including the introduction of the compounds of formula I

where

n is from 1 to vluchteling;

W means Of;

R1and R3independently from each other and each means hydrogen, C1-C7alkyl or C1-C7acyl;

R2means the group cycloalkyl, unsubstituted, mono - or politeley aryl, unsubstituted, mono - or politeley mono - or bicyclic heteroaryl containing one or two nitrogen atom;

R and R' independently from each other and each means hydrogen or C1-C7alkyl;

X means a group cycloalkyl, unsubstituted, mono - or politeley aryl, polyamidine, unsubstituted, mono - or politeley mono - or bicyclic heteroaryl containing one or two nitrogen atom, or pharmaceutically acceptable salts of such compounds, in an amount effective for inhibition of VEGF-receptor tyrosine kinase

2. The compound of the formula I

where

n is from 1 to 6, inclusive;

W means Of;

R1and R3independently from each other and each means hydrogen, C1-C7alkyl or C1-C7acyl;

R2means the group cycloalkyl, unsubstituted, mono - or politeley aryl, unsubstituted, mono - or politeley mono - or bicyclic heteroaryl containing one or two nitrogen atom;

R and R' independently from each other will cardionet hydrogen or C 1-C7alkyl;

X means a group cycloalkyl, unsubstituted, mono - or politeley aryl, unsubstituted, mono - or politeley mono - or bicyclic heteroaryl containing one or two nitrogen atom;

or pharmaceutically acceptable salt of such a compound,

with the exception of the compounds of formula I where n is 1, W denotes O, R1, R3, R, R' means hydrogen, X is phenyl, and R2mean 3-triptoreline or 2-methoxyphenyl or 2-chloro-3-pyridyl, or X is 4-methoxyphenyl, a R2means of 2-chloro-3-pyridyl, or X is 4-pyridyl, a R2means 4-[3-(3-pyridyl)-5-cryptomaterial-1-yl]phenyl, and compounds of formula I where n is 1, W denotes O, R3, R, R' means hydrogen, R1means methyl, R2means of 2-chloro-3-pyridyl, and X is phenyl.

3. The compound of formula I according to claim 2, where n is from 1 to 6 inclusive; W means On; R1and R3independently from each other and each means hydrogen, C1-C7alkyl or C1-C7acyl;

R2means the group cycloalkyl, an aryl group or a mono - or bicyclic group heteroaryl containing one or two nitrogen atom, with the latter two groups in each case are unsubstituted or have up to three substituents selected from a range of amino, mono - or disubstituted amino, halo is Yong, C1-C7alkyl, substituted alkyl, C1-C7alkenyl, C1-C7quinil, C1-C7alkanoyl, hydroxy, simple or ester of the hydroxy-group, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, C1-C7alkylthio, phenyl, phenoxy, phenylthio, phenyl C1-C7alkylthio, alkalinity, C1-C7alkylsulfonyl, phenylsulfonyl, phenyl C1-C7alkylsulfonyl, alkylresorcinol, C1-C7alkanesulfonyl, phenylsulfonyl, phenyl C1-C7alkylsulfonyl, alkylphenolates, halogen, C1-C7allylmercaptan, Halogens1-C7alkylsulfonyl, dihydroxybis(-B(OH)2), heterocyclyl and C1-C7alkylenedioxy associated with the adjacent carbon atoms in the cycle;

R and R' independently from each other and each means hydrogen or C1-C7alkyl;

X means an aryl group or a mono - or bicyclic group heteroaryl containing one or two nitrogen atom, where the term "mono - or bicyclic heteroaryl group" includes, but is not limited to, radical (1H)2-he-pyridinyl, and groups in each case are unsubstituted or may contain up to three substituents, wybran the x number of amino, mono - or disubstituted amino, halogen, C1-C7alkyl, substituted alkyl, C1-C7alkenyl, C1-C7quinil, C1-C7alkanoyl, hydroxy, simple or ester of the hydroxy-group, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino, guanidino, ureido, mercapto, sulfo, C1-C7alkylthio, phenyl, phenoxy, phenylthio, phenyl C1-C7alkylthio, alkalinity, C1-C7alkylsulfonyl, phenylsulfonyl, phenyl C1-C7alkylsulfonyl, alkylresorcinol, C1-C7alkanesulfonyl, phenylsulfonyl, phenyl C1-C7alkylsulfonyl, alkylphenolates, halogen, C1-C7allylmercaptan, halogen, C1-C7alkylsulfonyl, dihydroxybis(-B(OH)2), heterocyclyl and C1-C7alkylenedioxy associated with the adjacent carbon atoms in the cycle;

or pharmaceutically acceptable salt of such a compound,

with the exception of the compounds of formula I where n is 1, W means Of,

R1, R3, R, R' means hydrogen, X is phenyl, a R2mean 3-triptoreline, 2-methoxyphenyl or 2-chloro-3-pyridyl, or X is 4-pyridyl, a R2means phenyl, substituted in position 4 unsubstituted or substituted group 1-pyrazolyl, and Conn is of formula I, where n is 1, W denotes O, R3, R, R' means hydrogen, R1means methyl, R2means of 2-chloro-3-pyridyl, and X is phenyl.

4. The compound of formula I according to claim 2, where n is from 1 to 3 inclusive; W means On; R1and R3independently from each other and each means hydrogen, C1-C7alkyl or C1-C7acyl;

R2means cyclohexyl, phenyl, indazoles, thiazolyl, benzo[d]thiazolyl,

benzo[d]pyrazolyl or ethenolysis, which in each case is unsubstituted or mono - or disubstituted by C1-C7the alkyl, C1-C7alkenyl or C1-C7the quinil;

where each radical R2may be unsubstituted or mono - or polyamidine halogen;

R and R' independently from each other and each means hydrogen or C1-C7alkyl;

X is phenyl, pyridyl, pyrimidyl or chenail, which in each case is unsubstituted or mono - or polyamidine group of oxo, hydroxy, C1-C7alkyl, C1-C7alkoxy or N - C1-C7allylcarbamate;

or pharmaceutically acceptable salt of such a compound,

with the exception of the compounds of formula I where n is 1, W means Of,

R1, R3, R, R' means hydrogen, X is phenyl, a R2mean 3-triptoreline or 2-meth is xifei.

5. The compound of formula I according to claim 2, where

n is 1 or 2;

W means Of;

R1and R3mean hydrogen;

R2means cyclohexyl, phenyl, indazoles, thiazolyl or ethenolysis, which in each case is unsubstituted or mono - or disubstituted by C1-C7the alkyl

or C1-C7the quinil;

where each radical R2may be unsubstituted or mono - or polyamidine halogen;

R and R' independently from each other and each means hydrogen or C1-C7alkyl;

X is phenyl, pyridyl, pyrimidyl or chenail, which in each case is unsubstituted or mono - or polyamidine group of oxo, hydroxy, C1-C7alkyl, C1-C7alkoxy or C1-C7allylcarbamate;

or pharmaceutically acceptable salt of such a compound,

with the exception of the compounds of formula I where n is 1, R, R' means hydrogen, X is phenyl, a R2mean 3-triptoreline or 2-methoxyphenyl.

6. The compound of formula I according to claim 2, selected from the group of compounds including

2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(2-methyl-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]3-pyridinecarboxamide,

2-[(6-methoxy-3-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[5-fluoro-3-triptoreline]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(TRANS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(4-n-butylphenyl)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(4-n-pentylphenol)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[4-(1-PROPYNYL)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(5-indazole)-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide,

2-[(pyridine-6(1H)-one-3-yl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide and their pharmaceutically acceptable salts.

7. The compound of formula I according to claim 2, selected from the group of compounds comprising the hydrochloride of 2-(phenylethylamine)-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

p num="514"> 2-[(4-pyridyl)methylamino]-N-[2-methyl-5-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-(CIS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-bromo-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[2-fluoro-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[2-methyl-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(1-oxido-4-pyridyl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[3-(N-methylcarbamate)phenyl]methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(1-methylpyridin-2(1H)-one-5-yl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methylamino]-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-PROPYNYL-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(3-hydroxyphenyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)IU is Il]amino-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino]-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-propyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(6-methoxyphenyl-3-yl)methylamino]-N-[4-propyl-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-[4-(n-propyl)-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(5-thiazolyl)-3-pyridinecarboxamide,

2-[(4-hydroxyphenyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(4-pyridyl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide,

2-[(6-methoxy-3-pyridyl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide,

2-[(6-methoxy-3-pyridyl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(3-ethenolysis)-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(benzo[d]pyrazole-5-yl)-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(CIS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-(TRANS-4-tert-butylcyclohexyl)-3-pyridinecarboxamide,

2-[(1-oxido-4-pyridyl)methylamino]-N-[4-propyl-3-(trifluoromethyl)-phenyl]-3-pyridinecarboxamide,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[4-ethyl-3-(trifluoromethyl)phenyl]-3-pyridine boxlid,

2-[(pyridine-2(1H)-one-5-yl)methyl]amino-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide,

2-[(1-methylpyridin-2(1H)-one-5-yl)methylamino]-N-[3,4-bis(trifluoromethyl)phenyl]-3-pyridinecarboxamide and their pharmaceutically acceptable salts.

8. The pharmaceutical composition inhibiting activity endothelial growth factor vascular receptor tyrosine kinase, comprising the compound of formula I according to any one of claim 2 to 7 or its pharmaceutically acceptable salt in an effective inhibiting amount, and at least one pharmaceutically acceptable carrier.

9. The method of obtaining the compounds of formula I according to claim 2 or its N-oxide, or pharmaceutically acceptable salts, which is characterized by the fact that the pyridine derivative of the formula II

where W, R1and R2have the meanings specified for compounds of formula I, a Y means halogen, interacts with the amine of formula III

where n, R, R', R3and X have the meanings specified for compounds of formula I, in the presence of a base and compounds of copper(I), optionally in the presence of an inert solvent;

where the above-mentioned starting compound II and III, if necessary, may also be present with protected functional groups and/or in the form of salts, provided that this is olearacea group connection is present and the reaction in salt form is possible;

any protective groups in a protected derivative of a compound of the formula I are removed; and, if necessary, the obtained compound of the formula I is converted into another compound of formula I or salt obtained salt of a compound of the formula I is converted into the free compound or another salt.



 

Same patents:

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, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel tricyclic compounds, their pharmaceutically acceptable salts and solvates useful for inhibition of activity of farnesyl-protein-transferase. Invention describes compound of the formula (1.0): or its pharmaceutically acceptable salt or solvate wherein one among a, b, c and d means nitrogen atom (N) or -N+O-, and other a, b, c and d mean carbon atom and wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; or all a, b, c and d mean carbon atom wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; broken line (- - -) means optional binds; X means N or -CH when optional bond is absent, and it means carbon atom (C) when optional bond presents; when optional bond between carbon atom 5 and carbon atom 6 presents then only a single substitute A presents bound with carbon atom 5, and only a single substitute B presents bound with carbon atom 6, and A and B fifer from hydrogen atom (H); if optional bind between carbon atom 5 and carbon atom 6 is absent then two substitutes A present bound with carbon atom 5, and two substitutes B bound with carbon atom 6 wherein at least one of two substitutes A or one among two substitutes B mean H and wherein at least one of two substitutes A or one of two substitutes B has value distinct from H, and other radical are described in the invention claim. Also, invention disclosed a pharmaceutical composition comprising such compounds, a method for inhibition of anomalous growth of cells and methods for treatment of proliferative diseases as cancer.

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

52 cl, 2 tbl, 505 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel 1,2,4-trizole compound represented by the general formula (1): wherein R2 represents unsubstituted pyridyl or pyridyl substituted with cyano-group, and so on; R1 represents unsubstituted pyridyl, pyridyl substituted with halogen atom, and so on, or phenyl substituted with cyano-group and, so on; R3 represents hydrogen atom or pivaloyloxy-substituted lower alkyl wherein each is bound with one nitrogen atom that is a member of 1,2,4-triazole ring in the general formula (1). Compound is useful as a therapeutic agent against hyperuricemia and gout caused by hyperuricemia. Also, invention describes a medicinal agent designated for inhibition of activity of xanthine oxidase. Also, invention describes method for synthesis of compound of the formula (I).

EFFECT: valuable biochemical and medicinal properties of compounds, improved methods of synthesis.

8 cl, 2 tbl, 39 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 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, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivative of pyridine of the general formula (I): wherein each symbol has the following values: R1 and R2 mean hydrogen, halogen atoms, lower alkyl, lower alkoxy-group; R3 and R4 mean hydrogen atom, lower alkyl, halogen atom; R5 means hydrogen atom, lower alkyl; n = 0 or 1, or its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and intermediates substances used in synthesis. Compounds possess inhibitory effect on activity of phosphodiesterase of type 4.

EFFECT: valuable medicinal and biochemical properties of derivatives.

9 cl, 13 tbl, 147 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-thio-substituted derivatives of imidazole of the formula (I) , their optical isomers and physiologically acceptable salts wherein R1, R2, R3 and R4 have values given in claim 1 of the invention. Compounds possess immunomodulating and/or inhibitory effect on cytokine release and can be useful in treatment of diseases associated with the immune system disorder. Also, invention relates to a pharmaceutical agent inhibiting release of cytokines based on compounds of the formula (I) and using these compounds for preparing a pharmaceutical agent inhibiting release of cytokines for treatment of diseases associated with the immune system disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 1 tbl, 88 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of diphenylazethidinone of the formula (I): wherein R1 means hydrogen atom; R2 means -(CH2)0-1-NH-C(O)-(C3-C12)-alkylene-C(O)NH-L; R3 and R6 mean hydrogen atom; R4 and R5 mean atoms F, Cl, Br, J; L means compound of the formula: wherein Rx, Ry and Rz mean hydrogen atom (H), and to their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit cholesterol-declining activity and can be used in medicine.

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

4 cl, 9 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to N-[2-hydroxy-3-(1-pipeidinyl)-propoxy]pyridin-1-oxide-3-carboxamidine and its optically active enantiomers, i. e. (R)-(-)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridin-1-oxide-3-carboxamidine and (S)-(+)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridin-1-oxide-3-carboxamidine. Except for, invention relates to a method for preparing N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridin-1-oxide-3-carboximidoyl chloride that can be used as active component of medicinal preparations and for preparing optically active enantiomers of indicated compound with using compounds as intermediate substances.

EFFECT: improved conversion methods.

7 cl, 5 dwg, 7 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

The invention relates to new compounds derived from benzo(5,6)-cyclohepta-(1,2)-pyridine of the formula I, where R1means of groups a), b), C), d), e), f), i) k) l) m) n) o) p), r), s); R2and R3together form a bond when the value of R1- group a) or group m) or mean hydrogen for the other R1; R4the hydrogen for the other R1or bromine when the value of R1group o) or group f); R5the hydrogen for the other R1or bromine for R1group r or group s), and their pharmaceutically acceptable salts or solvate

The invention relates to organic chemistry, in particular to a method for producing compounds of formula I, which is known for its antibacterial and antifungal activity, where R1denotes a branched or unbranched alkyl with 1-17 carbon atoms, branched or nonbranched alkyl with 2-17 carbon atoms, cycloalkyl with 3-8 carbon atoms in the ring, and the specified cycloalkenyl the residue is not substituted or substituted with 1-3 alkyl residues each, depending on the circumstances, with 1-3 carbon atoms, phenyl, phenyloxy-(C1-C4)-alkyl or phenyl-(C1-C4)-alkyl, and phenyl, phenyloxy-(C1-C4)-alkyl, phenyl-(C1-C4)-alkyl residues are not substituted or substituted in the aromatic nucleus with 1-3 (C1-C6)-alkyl, benzyl, (C1-C6)-CNS, phenoxy or halide residues, and these cycloalkyl, phenyl, phenyloxy-(C1-C4)-alkyl residues directly or via a methylene or ethylene group associated with peritoneum ring; and R2denotes a hydrogen atom, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms or benzyl residue, by interacting Piron values, salt of hydroxylamine in the environment of a solvent and in the presence of a carbonate of an alkali metal and/or hydrogen carbonate of an alkali metal in an amount of 0.8 to 5 equivalents per salt hydroxylamine, and the interaction is carried out in the presence of organic acid or its salt

The invention relates to applicable in medicine new derived aminotriazole or its hydrate and its pharmaceutically acceptable salts

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of N-nicotinoyl-γ-aminobutyric acid. Method involves synthesis of mixed anhydride of nicotinic and pivalic acid by interaction of pivaloyl chloride with nicotinic acid in a solvent medium chosen from solvents of the 3-d toxicity class, for example, from acetone or butyl acetate in the presence of pyridine bases as catalyst followed by the acylation of reaction of γ-aminobutyric acid with prepared solution of mixed anhydride and the following isolation of the end substance from reaction mass. Invention provides increasing the yield of the end substance to 87.5% and substitution of high-toxic solvents for less toxic solvents.

EFFECT: improved method of synthesis.

3 cl, 2 ex

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