Anthranilic acid and thioanthranilic acid n-arylamides

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

 

The invention relates to new benzamide derivatives, processes for their preparation, their use in a method of treatment of a human or animal, for their use individually or in combination with one or more other pharmaceutically active compounds, especially for the treatment of neoplastic diseases, such as neoplastic disease, retinopathy and age related macular degeneration; to a method of treatment of such diseases in animals, especially humans, and to the use of such compounds, individually or in combination with one or more other pharmaceutically active compounds for the preparation of pharmaceutical compositions (drug), intended in particular for the treatment of neoplastic diseases, retinopathy and age-related macular degeneration.

It is known that certain diseases are associated with dysregulation of angiogenesis, such as diseases associated with neovascularization of the eye, such as retinopathy (including diabetic retinopathy), age related macular degeneration; psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as rheumatoid or rheumatic inflammatory disease, especially arthritis, for example rheumatoid arthritis, or other chronic is a mini-inflammatory diseases, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and especially neoplastic diseases, for example so-called solid tumors and tumors of liquid tissue (such as leukemia).

Modern research has established that the basis of the mechanism regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth, as well as in numerous pathological anomalies and diseases, lies angiogenic factor known as vascular endothelial growth factor" ("Vascular Endothelial Growth Factor") (VEGF)and its cellular receptors (see Breier G. and other Trends in Cell Biology 6, 454-456 [1996] and references cited in this work).

VEGF is a dimeric linked by a disulfide bridge glycoprotein with a molecular mass of 46 kDa, and he belongs to the group of "platelet-derived growth factors" ("Platellet-Derived Growth Factor") (PDGF). It is produced by normal cell lines and lines of tumor cells, is a mitogen specific for endothelial cells, shows angiogenic activity in experimental systems in vivo (for example, in the cornea of rabbits), is chemotactic in respect of endothelial cells and monocytes and induces plasminogen activators in the endothelial cells that participate in proteol the political degradation of the extracellular matrix during the formation of capillaries. Known for a number of isoforms of VGEF, which have similar biological activity, but differ in the type of secreting their cells and their heparinase activity. In addition, there are other members of the VEGF family, such as placental growth factor" ("Placenta Growth Factor") (PLGF) and VEGF-C.

The VEGF receptors are transmembrane tyrosinekinase receptors. They are characterized by an extracellular domain with seven immunoglobulinlike domains and intracellular tyrosinekinase domain. There are various types of VEGF receptors, such as VEGFR-1, VGEFR-2 and VGEFR-3.

A large number of human tumors, particularly gliomas and carcinomas, Express high levels of VEGF and its receptors. This led to the hypothesis that VEGF produced by tumor cells can paracrine manner to stimulate the growth of blood capillaries and the proliferation of the endothelium of the tumor and, thus, due to increased blood flow can 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 factor in tumor angiogenesis in vivo was obtained on the basis of studies that inhibited the expression of VEGF or VEGF activity. This was achieved by using antibodies inhibiting VEGF activity using a dominant-negativnyh mutant VEGFR-2, inhibiting signal transduction, or using the methods of antisense VEGF RNA. All approaches lead to a decrease in the growth lines of glioma or other lines of tumor cells in vivo due to inhibited tumor angiogenesis.

It is believed that angiogenesis is essential for tumor maximum diameter in excess of about 1-2 mm; up to this limit oxygen and other nutrients can be delivered to tumor cells by diffusion. Thus, the growth of any tumor, regardless of its origin and calling her reason, depends on angiogenesis after reaching a certain size.

Three main mechanisms play an important role in the antitumor activity of angiogenesis inhibitors: 1) inhibition of the growth of vessels, especially capillaries, into avascular tumors that are at rest, resulting in the absence of tumor growth due to the achieved balance between apoptosis and proliferation; 2) prevention of the migration of tumor cells due to the absence of blood flow to the tumor and from them; 3) inhibition of proliferation of endothelial cells, which eliminates paracrine growth stimulating effect exerted on the surrounding tissue endothelial cells that normally line the vessels.

When POPs is assured of the invention is unexpectedly set, as described below benzamidine derivatives of the formula I represent a new class of compounds which have valuable pharmacological properties and inhibit, for example, the activity tyrosinekinase VEGF receptors, tumor growth, and dependent on VEGF cell proliferation, or can be used to treat mainly inflammatory rheumatic or rheumatoid diseases such as rheumatoid arthritis and/or pain, or other diseases that are listed above and below.

The compounds of formula I allow, for example, to implement an unexpected new therapeutic approach, particularly in relation to diseases, for treatment, and to prevent which inhibition of angiogenesis and/or tyrosinekinase VEGF receptor has a beneficial effect.

Detailed description of the invention

The invention relates to the use of compounds of formula I

where W represents O or S;

X represents NR8;

Y represents CR9R10-(CH2)nwhere R9and R10independently of one another denote hydrogen or (ness.)alkyl, and

n denotes an integer from 0 inclusive and up to 3, inclusive; or

Y denotes SO2;

R1denotes aryl;

R2denotes a mono - or bicyclic heteroaryl group comprising one renesola ring nitrogen atoms, provided what R2cannot denote 2-phthalimide, and in the case where Y denotes SO2cannot identify 2,1,3-benzothiadiazole-4-yl;

any of the radicals R3, R4, R5and R6independently of each other denotes H or Deputy, other than hydrogen, and

R7and R8independently of one another denote hydrogen or (ness.)alkyl;

or its N-oxide or pharmaceutically acceptable salt for a pharmaceutical product intended for the treatment of neoplastic diseases, which is facilitated by inhibition of the activity tyrosinekinase VEGF receptor.

General concepts that are used above and below in the present description, preferably have the following meanings, unless otherwise indicated:

Console "(ness.)" denotes a radical having up to 7 carbon atoms, especially up to 4 carbon atoms, these radicals can be either linear or branched and may have one or more branches.

If for compounds, salts, etc. used the plural form, it should be understood that it refers to a separate compound, salt or other

Any asymmetric carbon atoms (for example, in compounds of formula I in which R9means (ness.)alkyl), can be present in the (R)-, (S)- or (RS)-configuration, preferably in the (R)-or (S)- configuration. Thus, the compounds can be in the form of mixtures of isomers or as pure isomers, preferably in the form of enantiomerically pure diastereomers.

The invention also relates to the possible tautomers of the compounds of formula I.

(Ness.)alkyl preferably denotes alkyl having from 1 inclusive and up to 7 inclusive, preferably from 1 inclusive and up to 4, inclusive, carbon atoms and may be linear or branched; preferably (ness.)alkyl denotes butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or preferably methyl.

The index n is preferably 0 or 1, particularly preferably 0.

Y preferably represents a methylene (-CH2-) or ethylene (-CH2-CH2-), most preferably methylene.

"Aryl" means an aromatic radical which is attached to the molecule through a link located on the carbon atom of the aromatic ring radical. According to a preferred variant implementation aryl denotes an aromatic radical having 6-14 carbon atoms, in particular phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrene, and may be unsubstituted or substituted by one or more, preferably up to three, in particular one or two, substituents, in particular selected from a number of the, including amino, mono - or disubstituted by an amino group, halogen, alkyl, substituted alkyl, hydroxy, esterified to simple or complex ester hydroxy-, nitro-, cyano-, carboxy, esterified to complex air carboxypropyl, alkanoyl, benzoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino-, guanidino, ureido-, mercapto-, sulfo-, (ness.)allylthiourea, phenyl, phenoxy, phenylthio-, phenyl(ness.)alkylthio, alkylenedioxy, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl (ness.)alkylsulfonyl, alkylresorcinol, (ness.)alkanesulfonyl, phenylsulfonyl, phenyl (ness.)alkylsulfonyl, alkylphenolates, (ness.)alkenyl, (ness.)alkanoyl, halogen(ness.)allylmercaptan, halogen(ness.)alkylsulfonyl, in particular, such as trifloromethyl, dihydroxybis [In(OH)2], heterocyclyl and (ness.)alkylenedioxy attached to adjacent ring carbon atoms, such as methylendioxy; aryl preferably denotes phenyl or naphthyl, each of which may be either unsubstituted or independently substituted by one or two substituents selected from the series comprising halogen, in particular fluorine, chlorine or bromine; hydroxy-group; a hydroxy-group, esterified to simple ester using (ness.)of alkyl, for example methyl, or halogen(ness.)of alkyl, for example triforma the sludge; esterified to complex air carboxypropyl, preferably (ness.)alkoxycarbonyl, such as methoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl; N-monosubstituted carbarnoyl, in particular carbarnoyl, monosubstituted (ness.)the alkyl, such as stands, n-propylene or isopropyl; (ness.)alkyl, preferably methyl, ethyl or propyl; substituted alkyl, preferably (ness.)alkyl, for example methyl or ethyl, substituted (ness.)alkoxycarbonyl, such as methoxycarbonyl or etoxycarbonyl; halogen(ness.)alkyl, preferably trifluoromethyl; (ness.)alkylsulfonyl, such as methylsulfonyl, and (ness.)alkanesulfonyl, such as methanesulfonyl. Aryl preferably represents 3 - or 4-chlorophenyl, 3-bromophenyl, 4-phenoxyphenyl, 2-, 3 - or 4-were, 4-methoxyphenyl: 3-or 4-tert-butylphenyl, 4-n-propylphenyl, 4-triptoreline, 3-triptoreline, 3-trifloromethyl, 3,4-(trifluoromethyl)phenyl, 3-fluoro-4-were, 3-chloro-4-were, 4-chloro-3-triptoreline, 3-chloro-5-triptoreline, 4-methylsulfinylphenyl, 4-methanesulfonyl, 4-biphenyl, naphthyl, 2-naphthyl; tetrahydronaphthyl, in particular 5,6,7,8-tetrahydronaphthyl; hydroxynaphthyl, in particular 7-hydroxynaphthyl, 8-hydroxynaphthyl or 8-hydroxy-2-naphthyl; methoxyethyl, in particular 4-methoxy-2-naphthyl; aloneftis, in particular 4-chloronaphthyl or 3-bromo-2-naphthyl.

Mono is whether disubstituted amino group preferably denotes an amino group, substituted by one or two radicals independently of one another selected from the series comprising (ness.)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 preferably substituted by one or more, preferably one or two substituents selected from the series comprising nitro, amino, halogen, N-(ness.)alkylamino-, N,N-di(ness.)alkylamino-, hydroxy-, cyano-, carboxypropyl, (ness.)alkoxycarbonyl, (ness.)alkanoyl and carbarnoyl; and phenyl(ness.)alkoxycarbonyl, in which the phenyl radical is unsubstituted or preferably substituted by one or more, preferably one or two substituents selected from the series comprising nitro, amino, halogen, N-(ness.)alkylamino-, N,N-di(ness.)alkylamino-, hydroxy-, cyano-, carboxypropyl, (ness.)alkoxycarbonyl, (ness.)alkanoyl and carbarnoyl; and preferably denotes N-(ness.)alkylamino, such as N-methylaminopropyl, 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-di(ness.)alkylenediamine-, (ness.)alkanolamines, such as acetylamino, or to cover up the fir-tree, selected from a range that includes benzoylamine and phenyl(ness.)alkoxycarbonylmethyl, in which the phenyl radical in each case is unsubstituted or preferably substituted by nitro or amino, or also by halogen, amino, N-(ness.)alkylamino-, N,N-di(ness.)alkylamino-, hydroxy-, cyano-, carboxypropyl, (ness.)alkoxycarbonyl, (ness.)alkanoyl, carbamoyl or aminocarbonylmethyl.

Halogen preferably represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

In a preferred embodiment, the alkyl has a maximum of 12 carbon atoms and preferably denotes (ness.)alkyl, preferably methyl or also ethyl, n-propyl, isopropyl or tert-butyl.

Substituted alkyl refers to alkyl as shown in the last paragraph, preferably (ness.)alkyl, preferably methyl; in which may be one or more, preferably up to three substituents, especially selected from the series comprising halogen, preferably fluorine, and amino, N-(ness.)alkylamino-, N,N-di(ness.)alkylamino-, N-(ness.)alkanolamine-, hydroxy-, cyano-, carboxypropyl, (ness.)alkoxycarbonyl and phenyl(ness.)alkoxycarbonyl. Especially preferred is trifluoromethyl.

Esterified to a simple ester of the hydroxy-group is preferably sobeys 8-C20alkyloxy, such as n-dellarciprete, (ness.)alkoxygroup, preferably such as methoxy, ethoxy, isopropoxy - or n-pentyloxy, phenyl(ness.)alkoxygroup, such as benzyloxy or fenoxaprop, or as alternatives or additions to the previously specified C8-C20alkyloxy, such a group as n-dellarciprete, halogen(ness.)alkoxygroup, such as cryptometrics - or 1,1,2,2-tetrafluoroethoxy.

Esterified to complex ester of the hydroxy-group is preferably a (ness.)alkanoyloxy-, benzoyloxy-, (ness.)alkoxycarbonyl, such as tert-butoxycarbonylamino, or phenyl(ness.)alkoxycarbonylmethyl, such as benzyloxycarbonyloxy.

Esterified to complex air carboxypropyl preferably represents (ness.)alkoxycarbonyl, such as tert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or etoxycarbonyl, phenyl (ness.)alkoxycarbonyl or phenoxycarbonyl.

Alkanoyl represents, above all, alkylsulphonyl, preferably (ness.)alkanoyl, for example acetyl.

N-mono - or N,N-disubstituted carbarnoyl preferably substituted on the terminal nitrogen atom by one or two substituents selected from the series comprising (ness.)alkyl, phenyl(ness.)Ala is l and hydroxy(ness.)alkyl.

Alkylphenolic preferably represents (ness.)alkyl-phenylthiourea.

Alkylphenolates preferably represents (ness.)alkyl-phenylsulfonyl.

Alkylresorcinol preferably represents (ness.)alkyl-phenylsulfinyl.

Heterocyclyl preferably represents 5 - or 6-membered heterocyclic system with 1 or 2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated and may be unsubstituted or substituted preferably (ness.)the alkyl, such as methyl; preferred is a radical chosen from the series, including 2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolane-2-yl, 1H-pyrazole-3-yl and 1-methylpyrazole-3-yl.

Aryl in the form of phenyl, which substituted (ness.)alkylenedioxy associated with two adjacent carbon atoms, such as methylendioxy, preferably represents a 3,4-methylenedioxyphenyl.

Heteroaryl denotes a heterocyclic fragment, which is unsaturated in the ring, which links the heteroaryl radical to the rest of the molecule of formula I, and preferably is a mono-, bi - or tricyclic, preferably mono - or bicyclic; and at least in the linking ring, but not necessarily in Liu the om unattached ring, each one or more, preferably 1-4, most preferably 3 or 4 carbon atoms substituted by a heteroatom selected from the group comprising nitrogen, oxygen and sulfur; and connecting the ring preferably has 5 to 12, more preferably 5 to 7 ring atoms and may be unsubstituted or be substituted by one or more, preferably 1 or 2, substituents selected from the group mentioned above as substituents of aryl, most preferably (ness.)the alkyl, such as methyl; preferably heteroaryl choose from a range that includes thienyl, furyl, pyranyl, thianthrene, isobenzofuran, benzofuranyl, bromanil 2N-pyrrolyl, pyrrolyl, substituted (ness.)the alkyl of imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazoles, triazoles, tetrazoles, purinol, 4H-hemolysins, ethanolic, hinely, phthalazine, naphthyridine, Minoxidil, hintline, cinnoline, pteridine, carbazole, phenanthridine, acridine, pyrimidinyl, phenanthrolines and furutani; more preferably selected from a range that includes triazolyl, preferably 1,2,4-triazolyl, 1,2,3-triazole or 1,3,4-triazolyl, pyridyl, preferably 2-, 3 - or 4-pyridyl, indolyl, preferably 3-indolyl, (ness.)alkylthio is alil, preferably 2-(4-methylthiazolyl), pyrrolyl, preferably 1-pyrrolyl, (ness.)alkylimidazole, preferably 4-(1-methylimidazole), 4-(2-methylimidazole) or 4-(5-methylimidazole), benzimidazolyl, such as 1-benzimidazolyl, or tetrazolyl, such as 5-(1,2,3,4-tetrazolyl).

Mono - or bicyclic heteroaryl group comprising one or more ring nitrogen atoms, preferably represents a heteroaryl group as defined above for heteroaryl, provided that preferably at least one nitrogen atom is present in the form of an annular heteroatoms in the linking ring (which means the ring, from which begins the connection between heteroaryl fragment with the rest of the molecule), and provided that R2cannot denote 2-phthalimide, and in the case where Y denotes SO2cannot identify 2,1,3-benzothiadiazole-4-yl. Preferably heteroaryl denotes imidazolyl, particularly preferably imidazol-4-yl, hinely, preferably 3-, 4-, 5-chinolin, naphthyridine, preferably 3-(1,8-naphthyridine) or 4-(1,8-naphthyridine) or particularly preferably a fragment of formula Ib or Ic

where

r is 0-2;

A, b, D and E independently of one another denote N or CH, provided that no more than two of these radicals represent N; preferred is entrusted each of A, B, D and E represents CH; and Q denotes (ness.)alkyl, preferably methyl, hydroxy-, (ness.)alkoxy, preferably a methoxy group, (ness.)thioalkyl, preferably metalcorp, or halogen, preferably fluorine, chlorine or bromine.

Particularly preferably R2denotes 3-pyridyl, 4-pyridyl, 4-chinoline or 5-chinoline. Most preferably R2represents 4-pyridyl.

Deputy other than hydrogen, preferably selected from a range that includes amino, mono - or disubstituted by an amino group, halogen, alkyl, substituted alkyl, hydroxy, esterified to simple or complex ester hydroxy-, nitro-, cyano-, carboxy, esterified to complex air carboxypropyl, alkanoyl, carbarnoyl, N-mono - or N,N-disubstituted carbarnoyl, amidino-, guanidino-, mercapto-, sulfo-, (ness.)allylthiourea, phenylthio-, phenyl(ness.)alkylthio, alkylenedioxy, (ness.)alkylsulfonyl, phenylsulfonyl, phenyl (ness.)alkylsulfonyl, alkylresorcinol, (ness.)alkanesulfonyl, phenylsulfonyl, phenyl (ness.)alkylsulfonyl, alkylphenolates, (ness.)alkenyl, (ness.)alkanoyl, halogen (ness.)alkyl-mercaptopropyl, halogen (ness.)alkylsulfonyl, in particular such as trifloromethyl, and heterocyclyl. Two substituent other than hydrogen attached to adjacent ring carbon atoms, can also about the mean (ness.)alkylenedioxy, such as methylenedioxy, atlantoxerus. Preferably different from hydrogen Deputy denotes (ness.)alkyl or halogen, preferably methyl, chlorine or fluorine.

Preferably R7and R8denote hydrogen, and each R3, R4, R5and R6independently of one another denotes hydrogen, chlorine or fluorine.

Salts preferably are pharmaceutically acceptable salts of compounds of formula I.

Such salts, preferably pharmaceutically acceptable salts, receive, for example, in the form of an acid additive salts, preferably salts of the compounds of formula I with a basic nitrogen atom with organic or inorganic acids. Acceptable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Acceptable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, cekanova acid, dodekanisa acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, Emelyanova acid, subernova acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid is or aspartic acid, maleic acid, hydroxymaleimide acid, methylmaleimide acid, cyclohexanecarbonyl acid, adamantanecarbonyl acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane - or econsultancy acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonate acid, benzolsulfonat acid, 2-naphthalenesulfonate acid, 1,5-naphthalenedisulfonic acid, 2-, 3 - or 4-methylbenzenesulfonic acid, mmelserna acid, atisara acid, modellerna acid, N-cyclohexylsulfamic acid, N-methyl-N-ethyl - or N-propylsulfonyl acid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy - or alphagraph can also be obtained salts with bases, for example metal salts or ammonium, such as salts of alkaline metal or alkaline earth metal, for example sodium, potassium, magnesium or calcium, or ammonium salt-based ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or three(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethylpiperidine or N, N'-dimethylpiperazine.

If the same molecule is present in the basic group and an acidic group, the compound of the formula I can also form internal salts.

For the purposes of selection or purification it is also possible to use pharmaceutically unacceptable salts, for example the picrate or perchlorate. For therapeutic applications can only be used therapeutically acceptable salts or free compounds (optionally in the form of pharmaceutical compositions), and they are preferred.

Due to the close 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 new compounds, it should be understood that any reference to the free connection above or below in the present description, refers also to the corresponding salts, when it is necessary and appropriate.

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

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

The test for determining activity against tyrosinekinase VEGF receptor. The test is carried out using tyrosinekinase VEGF receptor (Flt-1). In more detail a method with the her as follows: 30 ál of kinase solution (10 ng of kinase domain of Flt-1, Shibuya and others, Oncogen 5, 519-524 [1990]) in 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 of polyethylene glycol (PEG) 20000, 1 mm dithiothreitol and 30 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 to be checked connections incubated together for 10 min at room temperature. Then the reaction stopped by adding 10 μl of 0,25M of ethylenediaminetetraacetate (EDTA), pH 7. Using a multichannel dispenser (firm LAB SYSTEMS, USA) add an aliquot of 20 μl of the membrane type Immobilon P of PVDF (polyvinyldifluoride) (firm Millipore, USA), which includes microtiter filtration device type Millipore, and attached to a vacuum unit. After complete removal of the liquid membrane sequentially washed 4 times in a bath containing 0.5%phosphoric acid (H3RHO4), and once washed with ethanol, incubated each time for 10 min with shaking, and then placed in a device of the type Hewlett Packard TopCount Manifold and measure the radioactivity after addition of 10 μl of Microscint®(scintillation fluid for counting β-radiation). The values of the IC50determined using linear regression analysis of percent inhibition using three concentrations of each link is (usually of 0.01, 0.1 and 1 Microm). The values of the IC50that could be defined for compounds of formula I, are in the range from 0.01 to 100 μm, preferably in the range of from 0.01 to 50 microns.

Antitumor activity of the compounds according to the invention can be demonstrated in experiments in vivo as follows.

Activity in vivo using as models Nude mice subjected to xenotransplantation: female Nude mice of BALB/c mice (aged 8-12 weeks), Novartis Animal Farm, Sissein, Switzerland) is kept in a sterile environment, giving them food and water ad libitum (without limitation). Tumors induce in mice either by subcutaneous injection of tumor cells (e.g., cell line carcinoma of the prostate Du 145 (registration number ATSS NTV 81; see Cancer Research 37. 4049-4058 (1978)), or by implantation of tumor fragments (approximately 25 mg) subcutaneously in the left flank of the animals using a trocar-needle 13-th size under anesthesia using Forene®(firm Abbott, Switzerland). Processing the test connection starts when the mean tumor volume reached 100 mm3. Tumor growth is assessed by two-three times per week and 24 hours after the last treatment, determining the length of the two orthogonal directions. The tumor volumes calculated according to published methods (see Evans and others, Brit. J. Cancer 45. 466-468 [1982]). Protivo the Holevo activity is determined by the average increase in tumors in the treated animals, divided by the mean volume of tumors in untreated animals (control)and after multiplying by 100 expressed as T/C %. The reduction of tumors (given in %) is defined as the ratio of the lowest average tumor volume to the average tumor volume at the beginning of processing. The test compound is administered daily by stomach tube.

Alternatively, in a similar manner can also be applied to other cell lines, for example:

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

- line cells of mammary adenocarcinoma (MDA-MB 468 (ATSS No. NTV 132; see also In Vitro 14, 911-915 [1978]);

- line cells of mammary adenocarcinoma (MDA-MB 231 (ATSS No. NTV 26; see also J. Natl. Cancer Inst. (Bethesda) 53, 661-674 [1974]);

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

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

- line cell carcinoma of the prostate DU145 (ATSS No. NTV 81; see also Cancer Res.31, 4049-4058 [1978]); and

- line cell carcinoma of the prostate PC-3 (ATSC No. CRL 1435; see also Cancer Res.40, 524-534 [1980]).

The inhibition induced VEGF autophosphorylation KDR-receptor can be confirmed by additional in vitro experiments on cells: transfection SNO-tile and, permanently Express human VEGF receptor (KDR), are seeded in complete culture medium (supplemented with 10% fetal calf serum (FCS) in 6-well plates to culture cells and incubated at 37°C in an atmosphere of 5% CO2to achieve about 80%confluently. Then be tested compounds diluted with culture medium (without FCS, but with the addition of 0.1% bovine serum albumin) and added to cells. Control options include medium without test compounds). After incubation for 2 h at 37°add recombinant VEGF; the final concentration of VEGF 20 ng/ml After an additional five-minute incubation at 37°With cells washed twice chilled on ice SFR (phosphate buffered saline) and immediately are lysed using 100 μl of buffer for lysis in the hole. Then the lysates centrifuged to remove cell nuclei and the concentration of protein supernatant determined using having to sell the set for the analysis of proteins (firm BIORAD). Then the lysate was either immediately used for experiments or stored at -20°C.

To assess the phosphorylation of the receptor KDR perform enzyme-linked immunosorbent assay (ELISA) using immunogenic as follows: monoclonal antibody is KDR (for example, Mat 1495.12.14 obtained from N. Towbin) immobilized on black tablets for ELISA (type OptiPlate™ HTRF-96 Packard company). Then the tablets are washed and the remaining available proteinsathome sites saturated with 1% BSA in SFR. Then in these tablets, cell lysates (20 μg protein per well) incubated over night at 4°With antibody to phosphotyrosine made with alkaline phosphatase (AF) (RU:AF firm Transduction Laboratories). Tablets are again washed and then detect the binding of antibodies to phosphotyrosine with catching phosphorylated receptor using fluorescent AF-substrate (type CDP-Star, ready-to-use, with Emerald II; firm TROPIX). Luminescence is assessed through a scintillation counter type Packard Top Count Microplate Scintillation Counter (Top Count). The difference between the signal of the positive control (stimulated VEGF) and the signal of the negative control (not stimulated VEGF) corresponds induced phosphorylation of VEGF KDR receptor (=100%). The activity of test compounds is calculated as inhibition (%) induced phosphorylation of VEGF KDR-receptor, the concentration of a substance that produces half maximal inhibition, known as ED50(dose causing 50%inhibition). The values of the ED50for compounds of formula I are preferably in the range from 0.001 μm d is 6 μm, preferably in the range of 0.005 to 0.5 μm.

The compound of formula I or its N-oxide also inhibits in varying degrees, other tyrosine kinase involved in signal transduction that is mediated by trophic factors, for example the AbI kinase, a kinase of the Src-family, preferably c-Src kinase, Lck, and Fyn; and kinases of the EGF family, for example-rb2-kinase (HER-2)-rb3-kinase, C-rb4-kinase; kinase receptor insulinogenic growth factor (IGF-1 kinase), primarily members of the family tyrosinekinase PDGF receptors such as kinase to the PDGF receptor, kinase receptor CSF-1, kinase receptor Kit kinase and VEGF receptor; and serine/trionychinae, they all play a role in growth regulation and transformation in mammalian cells, including human cells.

Inhibition of C-rb2-tyrosine kinase (HER-2) can be estimated, for example, similar to determine the inhibition of protein kinase EGF-R (see Hause and others, Europ. J. Biochem. 140, 363-367 [1984]). The allocation of C-erbB2 kinase and identification of its activity can be carried out using well known methods (see T. Akiyama and others, Science 232, 1644 [1986]).

On the basis of these studies found that the compound of the formula I according to the invention has therapeutic efficacy, particularly in relation to disease-dependent protein kinase, especially proliferative diseases.

The possibility of using the compounds of formula I for the treatment of arthritis as an example of an inflammatory rheumatic or rheumatoid disease can be demonstrated as follows.

To determine antiaritmicheskoi activity of compounds of the formula I or their salts use a well-known model induced by adjuvant arthritis in rats (Pearson, Proc. Soc. Exp. Biol., 91, 95-101 [1956]). Caused by the adjuvant arthritis can be treated using two different dosing schemes: either (I)since immunization adjuvant (preventive treatment): or (II), beginning with the 15th day, when artecasa response is already evident (therapeutic treatment). Preferably used therapeutic regimen dosing. For comparison, a separate group treated with inhibitor of cyclooxygenase-2, such as 5-bromo-2-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]thiophene or diclofenac.

In more detail, the method consists in the following: the male Wistar rats (5 animals weighing approximately 200 g on the group, supplied by the company Credo, France) injected VK (intradermally) in the base of the tail with 0.1 ml of mineral oil containing 0.6 mg of freeze-dried killed by thermal treatment of Mycobacterium tuberculosis. Rats treated with the test compound (3, 10 or 30 mg/kg orally, once daily) or vehicle (water)by processing from 15 to 22 day (therapeutic CX is mA dosing). At the end of the experiment, the swelling of the paws appreciate using microcircula. Inhibition of swelling of the legs (in %) calculated by comparison with the swelling of the paws suffering from arthritis treated with carrier animals (inhibition of 0%) and normal processed by carrier animals (inhibition of 100%).

The activity of compounds of the formula I as painkillers can be demonstrated with the following models of nociception (pain). According to this model hyperalgesia induced by injection of the sole of a suspension of yeast, evaluate, acting on the leg elevated pressure up until the animals start to signal voice or to withdraw the paw from the feed pressure pad. This model allows to identify inhibitors SOH, therefore, as a control, it uses diclofenac at a concentration of 3 mg/kg

Method: Determine the background pressure necessary to cause the voice signals or OTDELENIE paws for male rats Sprague Dawley (weighing about 180 g, supplied by the firm Iffa Credo, France) (for 2 h before treatment), and then are injected into the sole of the hind legs 100 ál of 20%suspension of yeast in the water. After 2 h (time 0 h) rats treated orally (r.o.) test compound (3, 10 or 30 mg/kg), diclofenac (3 mg/kg) or vehicle (saline), and experience in the deystviy pressure should be repeated after 1 and 2 h after treatment. Using standard devices supplied by the company Ugo Basile, Italy, the pressure required to cause the voice signal or OTDELENIE paws of the treated compound in rats, these points in time are compared with the pressure required to produce a specified response in the treated carrier animals.

Based on these studies unexpectedly found that the compound of the formula I according to the invention can be used for the treatment of inflammatory (preferably rheumatic or rheumatoid) disease and/or pain. The compounds of formula I, especially of formulae IA or N-oxide) according to the invention also have therapeutic efficacy, particularly in relation to other diseases dependent protein kinase, especially proliferative diseases.

Due to their effectiveness as inhibitors of the activity tyrosinekinase VEGF receptor the compounds of formula I primarily inhibit the growth of blood vessels, and therefore they are effective, for example, for many of the diseases associated with impaired angiogenesis, particularly diseases associated with neovascularization of the eye, preferably retinopathy, such as diabetic retinopathy, or age related macular degeneration, psoriasis, haemangioblastoma, such as hemangioma, proliferative disorders of mesangial the cells, such as chronic or acute kidney disease, such as diabetic nephropathy, malignant nephrosclerosis, syndromes, thrombotic microangiopathy, or transplant rejection, or especially inflammatory kidney disease, such as glomerulonephritis, especially mesangiocapillary glomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, fibrotic disease (e.g., cirrhosis), diabetes, endometriosis, chronic asthma, arterial arteriosclerosis or atherosclerosis, which occurs following transplantation, neurodegenerative diseases and, above all, a disease associated with neoplasia (solid tumor, as well as leukemia and other tumors liquid fabrics, especially those that Express c-kit, KDR or fit-1), first of all, such as breast cancer, cancer of the colon, lung cancer (especially small cell lung cancer), cancer of the prostate or Kaposi's sarcoma. The compound of formula I (or its N-oxide) inhibits tumor growth and, above all, can be used to prevent the metastatic spread of tumors and the growth of metastases.

The compound of formula I may be introduced individually or in combination with one or more other therapeutic the ski agents, for combination therapy, and can be used in fixed combination, or may be used consistent or independent from each other, the introduction of the compounds according to the invention and one or more other therapeutic agents, or can be used combined introduction of fixed combinations and one or more other therapeutic agents. The compound of the formula I, in particular, in the treatment of tumors can be used in addition to chemotherapy, radiotherapy, immunotherapy, surgical intervention, or in addition to, or in conjunction with them. From the point of view of other modes of treatment prolonged therapy equally can be seen as supportive therapy in combination with other therapeutic interventions, as described above. Other possible modes of treatment represent a therapy designed to maintain the condition of the patient after reduction of the tumor, or even chemopreventive therapy, for example, for patients at risk.

As therapeutic agents in combination with the compounds according to the invention, in particular, can be used one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or more compounds selected from the group comprising an inhibitor of the biosynthesis of the floor of the amines, inhibitor of protein kinase, particularly serine/threonine-protein kinase, such as protein kinase C or tyrosine-protein kinase, such as tyrosinekinase the receptor for epidermal growth factor, a cytokine, a negative growth regulator, such as TGF-β or IFN-β, aromatase inhibitor, classical cytotoxic agent and inhibitor interaction S2 domain with a phosphorylated protein.

The connection according to the invention is intended not only to treat people (preventive and preferably therapeutic), but also for the treatment of other warm-blooded animals, such as commercially important animals, such as rodents, such as mice, rabbits, or rats, or Guinea pigs. This connection can also be used as a standard in the above-described testing systems for comparison with other compounds.

In General, the invention also suggested the use of the compounds of formula I or N-oxide for inhibiting the activity tyrosinekinase receptor VEGF both in vitro and in vivo.

The compound of formula I or its N-oxide may also be used for diagnostic purposes, for example for the diagnosis of tumors derived from a warm-blooded animal hosts, and, in particular, people, and implanted mice to determine, if they decrease their growth after treatment in this connection, in order to IP ledout their sensitivity to the specified connection and, thus, to facilitate the identification of possible therapeutic treatments of neoplastic diseases of the original owner.

In groups the following preferred compounds of formula I of the General list of the above signs, it is advisable to use certain substituents, for example, to replace more General more specific designations designations, or, in particular, designations, which are preferred.

In addition, the invention relates to the use of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salts, in which the radicals and symbols have the above significance, for the preparation of a pharmaceutical product for the treatment of retinopathy or age-related macular degeneration.

The invention also relates to a method of treatment of a neoplastic disease, which is facilitated by inhibition of the activity tyrosinekinase receptor of VEGF, providing for the introduction of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salts, in which the radicals and symbols have the above significance, in an amount effective against the specified diseases of warm-blooded animal that is in need of such treatment.

In addition, the invention relates to a method of treating retinopathy or age-related de is enerali yellow spots, providing for the introduction of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salts, in which the radicals and symbols have the above significance, in an amount effective against the specified diseases of warm-blooded animal that is in need of such treatment.

In particular, the invention relates to a compound of formula I, in which

W represents O or S;

X represents NR8;

Y represents CR9R10-(CH2)nwhere

R9and R10independently of one another denote hydrogen or (ness.)alkyl and

n denotes an integer from 0 inclusive and up to 3, inclusive; or

Y denotes SO2;

R1denotes aryl;

R2denotes a mono - or bicyclic heteroaryl group,

includes one or more ring nitrogen atoms, provided that R2cannot denote 2-phthalimide, and in the case where Y denotes SO2cannot identify 2,1,3-benzothiadiazole-4-yl; any of the radicals R3, R4, R5and R6independently of each other denotes H or Deputy, other than hydrogen, and

R7and R8independently of one another denote hydrogen or (ness.)alkyl; with the exception of the compounds of formula I in which W represents O; X represents NR8; Y represents CH2; R1oboznachaet is 4-chlorophenyl; R2represents 2-pyridyl; R3, R4, R5, R7and R8each represents H, and R6denotes chlorine;

or its N-oxide, or pharmaceutically acceptable salt.

Preferred are the compounds of formula I, in which

W represents O or S;

X represents NR8;

Y denotes CHR9-(CH2)nwhere

R9denotes hydrogen or (ness.)alkyl and

n denotes an integer from 0 inclusive and up to 3, inclusive; or

Y denotes SO2;

R1denotes aryl;

R2denotes a mono - or bicyclic heteroaryl group,

includes one or more ring nitrogen atoms, provided that R2cannot denote 2-phthalimide, and in the case where Y denotes SO2cannot identify 2,1,3-benzothiadiazole-4-yl;

any of the radicals R3, R4, R5and R6independently of each other denotes H or Deputy, other than hydrogen, and

R7and R8independently of one another denote hydrogen or (ness.)alkyl; with the exception of the compounds of formula I in which W represents O; X represents NR8; Y represents CH2; R1represents 4-chlorophenyl; R2represents 2-pyridyl; R3, R4, R5, R7and R8each represents H and R6denotes chlorine;

or their salts.

W represents O or S;

X represents NR8;

Y denotes CHR9-(CH2)nwhere

R9denotes hydrogen or (ness.)alkyl and

n is 0-3; or

Y denotes SO2;

R1denotes phenyl which may be unsubstituted or substituted by 1-3 substituents, independently of one another selected from the series consisting of amino, mono - or disubstituted by an amino group, where the substituents independently of one another selected from the series comprising (ness.)alkyl, hydroxy(ness.)alkyl, phenyl (ness.)alkyl, (ness.)alkanoyl, benzoyl and substituted benzoyl in which the phenyl radical is substituted by one or two substituents selected from the series comprising nitro, amino, halogen, N-(ness.)alkylamino-, N,N-di(ness.)alkylamino-, hydroxy-, cyano-, carboxypropyl, (ness.)alkoxycarbonyl, (ness.)alkanoyl and carbarnoyl; and phenyl (ness.)alkoxycarbonyl, in which the phenyl radical is substituted by one or two substituents selected from the series comprising nitro, amino, halogen, N-(ness.)alkylamino-, N,N-di(ness.)alkylamino-, hydroxy-, cyano-, carboxypropyl, (ness.)alkoxycarbonyl, (ness.)alkanoyl and carbarnoyl; (ness.)alkyl; substituted (ness.)alkyl which contains up to three substituents, independently of one another selected from the series comprising halogen, N-(n is ZS.)alkylamino-, N,N-di(ness.)alkylamino-, N-(ness.)alkanolamine-, hydroxy-, cyano-, carboxypropyl, (ness.)alkoxycarbonyl and phenyl(ness.)alkoxycarbonyl; hydroxy; (ness.)alkoxy; phenyl (ness.)alkoxy; phenyloxy; halogen(ness.)alkoxy; (ness.)alkanoyloxy; benzyloxy; (ness.)alkoxycarbonyl; phenyl (ness.)alkoxycarbonyl; nitro; cyano; carboxy; (ness.)alkoxycarbonyl; phenyl(ness.)alkoxycarbonyl; phenoxycarbonyl; (ness.)alkylsulphonyl; carbarnoyl; N-mono - or N,N-disubstituted carbarnoyl, which is substituted on the terminal nitrogen atom by one or two substituents, independently of one another selected from the series comprising (ness.)alkyl, phenyl (ness.)alkyl and hydroxy(ness.)alkyl; amidino-; guanidino-; mercapto-; sulfo-; (ness.)alkylthio-; phenylthio-; phenyl (ness.)alkylthio-; (ness.)alkylenedioxy; (ness.)alkylsulfonyl; phenylsulfonyl; phenyl(ness.)alkylsulfonyl; (ness.)alkylresorcinol; (ness.)alkanesulfonyl; phenylsulfonyl; phenyl(ness.)alkylsulfonyl; (ness.)alkylphenolates; (ness.)alkenyl; (ness.)alkanoyl; halogen (ness.)allylmercaptan; halogen (ness.)alkylsulfonyl; dihydroxybis (-B(OH)2); and (ness.)alkylen-vaxigrip attached to adjacent ring carbon atoms;

R2indicates imidazolyl, hinely, naphthyridine or fragment of formula Ib or Ic

where

r equally is 0-2;

A, b, D and E independently of one another denote N or CH, provided that no more than two of these radicals represent N; preferably; and

Q denotes (ness.)alkyl, hydroxy, (ness.)alkoxy, (ness.)thioalkyl or halogen;

any of the radicals R3, R4, R5and R6independently from each other represents H, fluorine or (ness.)alkyl; and

R7and R8independently of one another denote H or (ness.)alkyl; or N-oxides or pharmaceutically acceptable salt.

More specifically preferred compound of formula I, in which

W represents O;

X represents NR8;

Y denotes CHR9-(CH2)nwhere

R9denotes H or methyl and

n is 0;

or Y denotes SO2;

R1denotes phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl, which in each case may be unsubstituted or, independently of one another substituted by one or two substituents selected from the series comprising halogen; (ness.)alkyl; (ness.)alkoxy -, hydroxy-group; phenyl; phenoxy-; halogen (ness.)alkoxygroup; halogen(ness.)alkyl; (ness.)alkoxycarbonyl; N-(ness.)allylcarbamate; (ness.)alkylsulfonyl; (ness.)alkanesulfonyl and (ness.)alkoxycarbonyl-(ness.)alkyl;

R2indicates imidazolyl, hinely, naphthyridine, 2-methylpyridin-4-yl, 3-pyridyl or 4-pyridyl;

have any of radikale the R 3, R4, R5and R6independently of each other denotes H, methyl or chlorine;

R3and R4together form methylenedioxy and R5and R6independently from each other represents H, methyl or chlorine;

R7and R8independently from each other represents H, fluorine or methyl;

or its N-oxide, or pharmaceutically acceptable salt.

Even more preferred is a compound of formula I, in which

W represents O;

X represents NR8;

Y denotes CHR9-(CH2)nwhere

R9denotes H or methyl and

n is 0;

or Y denotes SO2;

R1denotes phenyl, which may be either unsubstituted, or substituted by one or two substituents selected from the series comprising halogen; (ness.)alkyl; halogen (ness.)alkyl; (ness.)alkylsulfonyl; and (ness.)alkanesulfonyl;

R2indicates imidazolyl, hinely, naphthyridine, 2-methylpyridin-4-yl, 3-pyridyl or 4-pyridyl;

any of the radicals R3, R4, R5and R6independently of each other denotes H or methyl; and

R7and R8independently of one another denote H or methyl;

or its N-oxide, or pharmaceutically acceptable salt.

Most preferred are the compounds of formula I, in which

W represents O;

X represents NR8;

Y about who appoints CHR 9-(CH2)nwhere

R9denotes H or methyl and

n is 0;

or Y denotes SO2;

R1denotes phenyl, which may be either unsubstituted, or substituted by one or two substituents selected from the series comprising halogen; (ness.)alkyl; halogen (ness.)alkyl; (ness.)alkylsulfonyl and (ness.) alkanesulfonyl;

R2indicates imidazolyl, hinely, 2-methylpyridin-4-yl or 4-pyridyl; any of the radicals R3, R4, R5and R6independently of each other denotes H or methyl; and

R7and R8independently of one another denote H or methyl;

or their salts.

Most preferred are the compounds of formula I, in which

W represents O;

X represents NR8;

Y denotes CH2;

R1denotes phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl, which in each case may be unsubstituted or, independently of one another substituted by one or two substituents selected from the series comprising halogen; (ness.)alkyl; (ness.)alkoxy -, hydroxy-group; phenyl; phenoxy-; halogen (ness.)alkoxygroup; (ness.)alkoxycarbonyl; N-(ness.)allylcarbamate and (ness.)alkoxycarbonyl)-(ness.)alkyl;

R2represents 4-pyridyl;

any of the radicals R3, R4, R5and R6independently of each other denotes H, methyl or chlorine; or

Rsub> 3and R4together form methylenedioxy and R5and R6independently of one another denote H, methyl or chlorine; and

R7and R8denote H;

or N-oxides or pharmaceutically acceptable salt.

Especially preferred is the compound of formula I, which are given below in the examples, or its pharmaceutically acceptable salt, in particular a compound of formula I, specifically noted in the examples, or its salt.

Most preferred are compounds selected from the group including:

2-[(4-pyridyl)methyl]amino-N-(4-triptoreline)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-fluoro-4-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-chloro-3-triptoreline)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-chloro-5-triptoreline)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-were)-6-methylbenzamide; and

2-[(4-chinolin)methyl]amino-N-(4-chlorophenyl)benzamide;

or their pharmaceutically acceptable salts.

In addition, the most preferred are compounds selected from the group including:

2-[(4-pyridyl)methyl]amino-N-[3-fluoro-(4-trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-phenylbenzene;

2-[(4-pyridyl)methyl]amino-N-[4-fluoro-(3-trifluoromethyl)phenyl]Bentham is d;

2-[(4-pyridyl)methyl]amino-N-[3-fluoro-(5-trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3,5-(bistritei)phenyl]benzamide;

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

2-[(4-pyridyl)methyl]amino-N-[3-methoxy-(5-trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(1,1-dimethylethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-tianfeng)benzamide;

2-[(4-pyridyl)methyl]amino-N-[(3-methylthio)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-acetylaminophenol)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-[(aminocarbonyl)amino]phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(dimethylamino)phenyl]benzamide;

5-methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

3-methyl-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

4,5-debtor-2-[(4-pyridyl)methyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N'-methyl-N'-[3-(trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[(3-methylsulphonyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[(3-methylsulfinyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(1,1-dimethylethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-chlorophenyl) benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-bromophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-were)benzamide;

2-[(4-who iridis)methyl]amino-N-(3-benzoylphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(aminocarbonyl)phenyl]benzamide;

2-[(3-pyridyl)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-chinoline)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(5-chinoline)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-(2-methyl)pyridyl)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-(1,2-dihydro-2-oxo)pyridyl)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-chinoline)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(2-imidazolyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[1-methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[(1-oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-chloronaphthyl)benzamide;

6-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

6-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

3,4-methylenedioxy-6-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

4,5-dimethyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(7-hydroxynaphthyl)benzamide;

2-[(4-pyridyl)IU is Il]amino-N-(8-hydroxy-2-naphthyl)benzamide;

4-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

5-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(5,6,7,8-tetrahydronaphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-biphenyl)benzamide;

5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(2-naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-methoxyphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(triptoreline)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-methoxy-2-naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-bromo-2-naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(isopropoxycarbonyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(triptoreline)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(isopropylcarbamate)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-chloro-4-were) benzamide;

2-[(4-pyridyl)methyl]amino-N-(2-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(methoxycarbonylmethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-phenoxyphenyl)benzamide;

or their pharmaceutically acceptable salts.

The connection according to the invention can be obtained by using methods which, although not previously used to obtain new compounds of the present invention, are well known, primarily through the process, the best of what the existing topics that

a) for the synthesis of compounds of formula I in which X represents NR8where R8represents hydrogen and Y represents CHR9-(CH2)nwhere the symbols have the meanings specified for formula I, and the rest of the characters R1, R2, R3, R4, R5and R6have the meanings specified for compounds of formula I, an aniline derivative of the formula II

where W, R1, R3, R4, R5, R6and R7have the meanings specified for compounds of formula I, is subjected to the interaction with the carbonyl derivative of formula III,

where n, R2and R9have the meanings specified for compounds of formula I, in the presence of a reducing agent;

b) for the synthesis of compounds of formula I in which Y denotes SO2a symbols R1, R2, R3, R4, R5, R6, R7, W and X have the meanings specified for compounds of formula I, an aniline derivative of the formula II, as described in variant a) method, is subjected to the interaction with the compound of the formula IVa

or its reactive derivative, or a compound of formula IVb

where Hal' represents chlorine, bromine or iodine; or

C) for the synthesis of compounds of formula I, in which X about the mean NR 8, Y represents CR9R10-(CH2)nand other symbols R1, R2, R3, R4, R5, R6, R7and R8have the meanings specified for compounds of formula I, a halogenated derivative of formula V

where Hal represents iodine, bromine or chlorine, and W, R1, R3, R4, R5, R6and R7have the meanings specified for compounds of formula I, is subjected to the interaction with the amine of formula VI

where n, R2, R8, R9and R10have the meanings specified for compounds of formula I, in the presence of a suitable catalyst such as a palladium catalyst, for example, obtained in situ from Tris(dibenzylideneacetone)diplegia(0) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in an inert solvent, such as toluene, in the presence of an aprotic base such as tert-piperonyl sodium or cesium carbonate, or Nickel catalyst, such as dibromo-bis(bipyridyl)Nickel(2) in a solvent such as isopropylmyristate, or copper catalyst, such as iodide, methide(I) in a solvent such as dimethylformamide;

g) for the synthesis of compounds of formula I in which X represents NR8, Y denotes CH2W represents Oh, R2represents 4-pyridyl, R7and R8each represents H and R 1, R3, R4, R5and R6have the meanings specified for compounds of formula I, the compound of formula VII

where R3, R4, R5and R6have the meanings specified for compounds of formula I, and R11means (ness.)alkyl, are subjected to interaction with the compound of the formula VIII

where R1has the values specified for the compounds of formula I, in the presence of trimethylaluminum in an inert solvent, for example toluene;

and source the products listed in sections a), b), C) and d)may also optionally have functional groups in protected form and/or be in the form of salts, provided that, if there is a salt-forming group and the possible reaction involving compounds in salt form;

remove any protective groups in a protected derivative of a compound of formula I;

and, if necessary, transform the obtained compound of the formula I into another compound of formula I or its N-oxide, turn the free compound of formula I in salt, turn obtained salt of a compound of formula I into the free compound or into another salt and/or divide a mixture of isomers of compounds of the formula I into the individual isomers.

Detailed description of the variants of the method of obtaining

The following more detailed description of the AI methods to obtain R 1, R2, R3, R4, R5, R6, R7, R8, R9, R10X, Y and W have the meanings specified for compounds of the formula I, unless otherwise indicated.

Variant a) method (reductive alkylation)

Carbonitrile compound of formula III may also be present in the form of a reactive derivative; however, preferred is a free aldehyde or ketone.

Reactive derivatives of compounds of formula III are, for example, corresponding bisulfite adducts or preferably hemiacetals, acetals, policital or ketals of compounds of formula III with alcohols, for example (ness.)the alkanols; or thioacetal or thioketal compounds of the formula III with mercaptans, for example (ness.)alkanolamide.

Reductive alkylation is preferably carried out by hydrogenation in the presence of a catalyst, particularly a catalyst of a noble metal, usually platinum or preferably palladium, which is preferably associated with a carrier, such as charcoal, or in the presence of a catalyst of hard metal, typically of Raney Nickel at normal pressure or at a pressure of from 0.1 to 10 megapascals (MPa), or repair is carried out using complex hydrides, as a rule borohydride, preferably of laboraryrio school is full metal, for example lamborginid sodium, in the presence acceptable acid, preferably a relatively weak acids, such as (ness.)alcancarao acid, preferably acetic acid, or sulfonic acids such as para-toluensulfonate acid; in the conventional solvents, for example alcohols, such as methanol or ethanol, or ethers, for example cyclic ethers, such as tetrahydrofuran, in the presence of water or without water.

Variant b) method (condensation)

According to this variant of the method, reagents, which carry out the introduction of the radical R2Y contain either free alphagroup (formula IVa), or are in the form of its reactive derivative, for example in the form received from the activated complex ester or reactive anhydride, either in the form of a reactive cyclic amide, or contain alphagroup in the form of a sulfonic acid halide (formula IVb). Reactive derivatives can also be formed in situ.

In the formula IVb Hal' preferably denotes chlorine or bromine. The reaction is carried out in an acceptable solvent, for example dichloromethane, for example, at room temperature or at the temperature of reflux distilled solvent, in the presence of a suitable amine, for example N-ethyldiethanolamine, and optional 4-dimethyl is inoperative.

The amino compounds of the formula II, which takes part in the reaction, is preferably in free form, preferably, when it is subjected to interaction sulfonyloxy group, it is present in reactive form; however, it can itself be derivatisation, for example, the interaction with postitem, such as diethylphosphate, 1,2-phenylenecarbonyl, ethyldichlorosilane, ativanklonopin or tetraethylpyrophosphate. A derivative of such compounds having the amino group, is also, for example, a halide or isocyanate, carbamino acid, amino group, which participates in the reaction, can be replaced by halogenocarboxylic, such as chlorocarbonyl, or modified with the formation of the isocyanate groups, respectively.

Condensation of activated esters, reactive anhydrides or reactive cyclic amides to the corresponding amines is usually carried out in the presence of inorganic bases such as bicarbonate of an alkali metal, or preferably an organic base, for example a simple three(ness.)the bonds alkylamines, for example triethylamine or tributylamine, or one of the above organic bases. If necessary use a condensing agent, for example, as described for free is Urbanovich acids.

The condensation is preferably carried out in an inert, aprotic, preferably non-aqueous solvent, or solvent mixture, usually in amide carboxylic acids, such as formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic simple ether, for example tetrahydrofuran or dioxane, in a complex ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, optionally at reduced or elevated temperature, for example in the temperature range from approximately -40° up to approximately +100°C, preferably from approximately -10° up to approximately +70°and from about +100° to +200°when using complex arylsulfonate esters, in particular at temperatures from 10 to 30°With, if necessary, in the atmosphere of inert gas, such as nitrogen or argon.

It is also possible to use the water, usually an alcohol, for example ethanol, or aromatic solvents such as benzene or toluene. When the bases are the hydroxides of alkali metals, if necessary, may be added acetone.

Variant b) method (amination)

The amination process of predpochtitel the exercise but using the interaction of the Ullman reaction in the presence of a copper catalyst, such as compounds of copper(0) or copper(I), for example of oxide copper(I)bromide copper(0) or copper iodide(I), in the presence of reasonable grounds (such as a metal carbonate, for example potassium carbonate) to neutralize the acid formed in the reaction. Details of this reaction are summarized in Hoyben-Weyl "Methods der Organischen Chemie", volume 11/1, p.32-33, 1958; Organic Reactions, volume 14, p.19-24, 1965 and J. Lindley, (1984) Tetrahedron, volume 40, str-1456, 1984. The amount of catalyst generally is in the range from 1 to 20 mol.%. The reaction is carried out in an inert aprotic solvent, such as a simple ether (for example, dimethoxyethane or dioxane) or amide (for example, dimethylformamide or N-organic) in the atmosphere of inert gas at a temperature of from 60 to 180°C.

Alternative amination process includes the application of elements of group VIII, when the metallic core of the catalyst should be a transition metal with zero valency, such as palladium or Nickel, which has the ability to perform the addition of oxygen to the relationship aryl-halogen. State of the metal, characterized by a zero valence, can be obtained in situ from the state of M(II). Catalytic complexes can include chelating ligands such as alkyl, aryl or heteroaryl derivatives of phosphines or beforenov, Iminov or arsinami. Suppose the equipment catalysts contain palladium or Nickel. Examples of such catalysts include palladium(II)chloride, palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0) and Nickel acetylacetonate(II). The metal catalyst is typically present in an amount of from 0.1 to 10 mol.%. Chelating ligands can be either "odnosima", as, for example, trialkylphosphine, such as tributylphosphine, triarylphosphine, such as tri(ortho-tolyl)phosphine, and triethanolamine, such as tri-2-furifosmin; or they can be "two-pronged", as, for example, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,2-bis(diphenylphosphino)ethane, 1,1'-bis(diphenylphosphino)ferrocene and 1-(N,N-dimethylamino)-1'-(DICYCLOHEXYL-phosphino)the biphenyl. Supporting ligand may be added so as to form a complex with the metal center in the form of complex metal prior to introduction into the reaction mixture, or can be added to the reaction mixture in the form of individual compounds. Supporting ligand, typically present in amounts of from 0.01 to 20 mol.%. It is often necessary to add to the reaction mixture is acceptable base, such as trialkylamine (for example, diisopropylethylamine or 1,5-diazabicyclo[5,4,0]undec-5-ene), an alkoxide of an alkali metal of group I (e.g., tert-piperonyl potassium) or a carbonate (e.g., cesium carbonate or potassium phosphate. The reaction is usually carried out in inert aprotic solvent, such as just the ether (for example, dimethoxyethane or dioxane), or in amide (for example, dimethylformamide or N-organic) in the atmosphere of inert gas at a temperature of from 60 to 180°C.

Amination is preferably carried out in inert aprotic, preferably non-aqueous, solvent or solvent mixture, usually in amide carboxylic acids, such as formamide or dimethylformamide, cyclic simple ether, for example tetrahydrofuran or dioxane, or a nitrile, for example acetonitrile, or in mixtures thereof, optionally at reduced or at an acceptable temperature, for example in the temperature range from about 40° up to approximately 180°and, if necessary, in the atmosphere of inert gas, such as nitrogen or argon.

Option g) way (amidation)

According to this variant of the method first amide dimethylaluminum receive in situ from Me3Al and the corresponding amine. Then add esters, which are to be processed, and the reaction is carried out at a temperature of from 20°to 150°C, preferably at a temperature of 100°to 120°With, for example, when 110°C, depending on the reactivity of the amide and ether complex, in an inert solvent like benzene, toluene, xylene, tetrahydrofuran,6-C10alkanes or mixtures thereof.

N-oxides can be obtained f the m method by reacting the compounds of formula I with hydrogen peroxide or perezida, for example 3-chloroperoxybenzoic acid, in an inert solvent, for example dichloromethane, at a temperature of from -10°C to +35°With, for example at temperatures from 0°to room.

Protective groups

If in the compound of formula II, III and/or IV are present one or more other functional groups, for example carboxy-, hydroxy-, amino - or mercaptopropyl, or they must be protected, as they should not participate in the reaction, these groups represent a group that is usually used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as derivatives of nucleic acids and sugars.

Protective groups can also be present in the precursors and should protect the functional group from undesired secondary reactions, such as acylation, the formation of esters and ethers, oxidation, solvolysis and other similar reactions. A characteristic feature of the protective groups is that they are easy to remove, i.e. amenable to removal without undesired secondary reactions, as a rule, by solvolysis, recovery, photolysis or by enzymatic activity, for example, in conditions similar to physiological conditions, so that they are not present in the final products. The specialist should be clear, or it could easily install and remove the IC, what protective group suitable for above and below reactions.

The protection of such functional groups such protective groups are themselves protective group and the reaction of their removal are described, for example, a conventional reference manuals, such as J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides", volume 3 (edited E.Gross and J.Meienhofer) Academic Press, London and New York 1981, in "Methods der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th ed., volume 15/1, Georg Thieme Verlag, Stuttgart 1974, H.-D.Jakubke and H.Jescheit, "Aminosauren, Peptide, Protein (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.

Additional stages of the process

In the advanced stages of the ways in which conduct, if necessary, functional groups in the original connection, which should not participate in the reaction, may be present in unprotected form or may be protected, for example, one or more protective groups mentioned above in the section "Protective group". Then the protective groups are completely or partially removed according to one of the described methods.

Salts of the compounds of formula I with salt-forming group can be obtained by well known methods. For example, an acid additive salt is connected to the th formula I can be obtained by treatment with an acid or acceptable 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 per compound (for example, in monohalogen); this can be done by heating to a molten state or, for example, by heating the compound in the form of a solid substance in a high vacuum at elevated temperature, for example at a temperature of from 130 to 170°With one molecule of the acid is replaced by one molecule of the compounds of formula I.

Typically, the salts can be converted into the free compounds, for example, processing acceptable alkaline 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 are well known method using a suitable separation methods. Diastereomer mixture, for example, can be separated into the individual diastereomers by using fractionated crystallization, chromatography, distribution in solvents and similar methods. This separation can be done either at the level of the parent compound or the compounds of formula I. the Enantiomers can be separated with the help of obtaining on asterionella salts, for example, when obtaining salt with enantiomerically pure chiral acid, or by means of chromatography, for example GHUR, using chromatographic substrates with chiral ligands.

The compound of the formula I, in which W represents Oh may be converted into the corresponding compound in which W represents S, for example, by using the appropriate serosoderjaschei connection, for example, through reaction using a reagent of Lawesson (2,4-bis(4-methoxyphenyl)-2,4-dicicco-1,2,3,4-dithiophosphate) hydrate halogenated carbon such as dichloromethane, in an aprotic solvent such as toluene or xylene, at temperatures from about 30°to the temperature of reflux distilled.

The compound of formula I in which any of the radicals R7and R9or both represent hydrogen and which is a part sulfonamidnuyu connection (Y denotes SO2), can be converted into the corresponding compound in which R7and/or R9means (ness.)alkyl, by reacting, for example, diazo(ness.)alkyl compound, preferably diazomethane, in an inert solvent, preferably in the presence of a catalyst of a noble metal, preferably in dispersible form, for example copper, or salt of a noble metal, such as copper chloride(I) or copper sulfate (II).

That the same may interact with (ness.)alkylhalogenide or other (ness.)alkanes, bearing a leaving group, for example, (ness.)alkylmercury, esterified to complex ester 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 benzene sulfonic acid, where the substituents are preferably selected from a range including (ness.)alkyl, such as methyl, halogen, such as bromine, and/or nitro-group, for example, using esterified methane sulfonic acid, trimethylsulfonium acid or para-toluensulfonate acid.

In addition, the alkylation of compounds of formula I in which R8represents hydrogen and Y represents CR9R10-(CH2)ncan be made with such alkylating agents.

In both cases, the alkylation is preferably carried out in 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, typically phenol, as well as in an anhydrous environment in non-polar solvents, typically benzene or toluene, or in emulsions benzene/water, optionally in the presence of acidic or alkaline ka is alization, for example liquor, usually in sodium hydroxide solution, or in the presence of solid catalysts, typically of aluminum oxide with an additive of hydrazine, in ethers, such as diethyl ether, typically at a temperature of from 0°C to the boiling temperature of the corresponding reaction mixture, preferably at temperatures from 20°to the temperature of reflux distilled, if necessary, at elevated pressure, for example, in a sealed tube, it is also possible at temperatures exceeding the boiling point, and/or in the atmosphere of inert gas, usually nitrogen or argon.

It should be obvious that the reactions are similar to those described in this section, the reactions of transformation can also be carried out at the level of the respective intermediate products.

General conditions ways to get

All stages are presented in this description of the method can be carried out in known reaction conditions, preferably in specially specified conditions, without solvents or diluents or usually in the presence of solvents or diluents which are inert to the reagents, but is capable of dissolving, in the absence of catalysts, condensing agents or neutralizing agents or in the presence of catalysts, condensing agents or neutralizing AG is now, for example ion exchangers, typically cation exchangers, for example, N+form, depending on the type of reaction and/or reactants at reduced, normal or elevated temperature, for example at a temperature in the range from -100°With up to approximately 190°C, preferably from approximately -80°With up to approximately 150°With, for example, at temperatures from -80 to -60°With, at room temperature, at a temperature of from -20 to 40°or at the boiling point of the used solvent, at normal atmospheric pressure or in a closed vessel, optionally under pressure and/or in the atmosphere of inert gas, for example argon or nitrogen.

Salt can be present in all initial and intermediate products, if they contain soleobrazutaya group. Salt may also be present in the process of interaction of these compounds, provided that it is not contrary to the response.

At all stages of the reactions present isomeric mixtures can be separated into their individual isomers, for example diastereoisomers or enantiomers or any mixture of isomers, for example racemates or diastereomeric mixture, generally according to the methods described in the section "Additional stages of the process."

In certain cases, usually in the process of hydrogenation can be conducted stereoselective reactions, that is you, for example, to facilitate the recovery of the individual isomers.

Solvents which may be selected such, are suitable for representing the interest of the reactions include, for example, water, esters, typically (ness.)alkyl-(ness.)alkanoate, such as diethylacetal, ethers, typically aliphatic ethers, for example diethyl ether, or a simple 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 hydrocarbons, 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, typically anhydrides (ness.)alkanovykh acids, for example acetic anhydride, cyclic, linear or branched hydrocarbons, typically cyclohexane, hexane or isopentane, or mixtures of these solvents, e.g. aqueous solutions, if method is not specified. Such mixtures of solvents can also be used in the process, for example by chromatography or distribution.

The invention also suggested that such ia ianti way where as the original product is using the connection obtained at any stage as an intermediate product, and are missing the stage, or in which the process is discontinued at any stage, or in which the initial product formed in the reaction conditions, or in which the original product is used in the form of its reactive derivative or salt, or to obtain a connection using the method according to the invention and processing compounds in situ. In a preferred embodiment, the method begins with such original products, which provide connections that are indicated above as preferred, in particular as particularly preferred, most preferred and/or most preferred.

In a preferred embodiment, the compound of formula I get according to the processes and stages of the processes described in the examples.

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

Pharmaceutical compositions, methods for their preparation and use

The present invention also proposed pharmaceutical compositions that include a compound of formula I or the th N-oxide as the active substance and which can be used, in particular, for the treatment of the above diseases. Compositions for enteral administration, such as nasal, buccal, rectal, or preferably oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous injection, warm-blooded animals, especially humans, are especially preferred. Compositions include the active substance individually or preferably in combination with a pharmaceutically acceptable carrier. The dose of active ingredient depends on the disease to be treated, and the patient's age, weight and individual condition, individual pharmacokinetic parameters and route of administration.

The invention also relates to pharmaceutical compositions intended for use according to the method according to the invention for the prophylactic or mainly for therapeutic treatment of the human or animal, the method of their preparation (in particular, in the form of compositions intended for the treatment of cancers and treatment method associated with the formation of tumor diseases, in particular diseases listed above.

The invention also proposed methods and the use of compounds of the formula I or their N-oxides for the preparation of pharmaceutical compositions comprising the compounds of formula I or their N-hydroxy who s as active component (active ingredient).

In a preferred embodiment, the pharmaceutical composition is suitable for administration warm-blooded animal, preferably people or important from an economic point of view mammal suffering from a disease that is facilitated by inhibition of angiogenesis or tyrosinekinase VEGF receptor, such as psoriasis, or preferably from neoplastic disease, and it contains a number of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salt, if salt-forming group, effective for inhibiting angiogenesis or tyrosinekinase receptor VEGF, in combination with at least one pharmaceutically acceptable carrier.

Also preferred is a pharmaceutical composition for prophylactic or mainly for therapeutic treatment of neoplastic and other proliferative diseases of warm-blooded animals, mainly man or important from an economic point of view of a mammal in need of such treatment, which suffers from such a disease, comprising as active substance a new compound of formula I or its N-oxide in a quantity prophylactically or mainly therapeutically active against such diseases.

The pharmaceutical compositions contain from around the about 1% to about 95% active ingredient, forms for administration as a single dose in a preferred embodiment, contain from about 20% to about 90% of the active substance and form, by type of introduction is not related to a single dose, in a preferred embodiment, contain from approximately 5% to approximately 20% active ingredient. Standard dosage forms are, for example, tablets, coated or 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 substance.

The pharmaceutical compositions of the present invention are prepared in the usual well known methods, for example using accepted processes of mixing, granulating, coating, dissolving or lyophilization.

Preferred is the use of solutions of active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example, in the case of lyophilised compositions contain the active substance one or in combination with a carrier, for example mannitol, can be prepared by predetremined. The pharmaceutical compositions can be sterile and/or may include excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, soljubilizatory, salts for regulating osmotic pressure and/or buffers, and they are made well-known methods, for example using conventional dissolution and lyophilization. These solutions or suspensions can include agents that increase the viscosity, typically the sodium carboxymethyl cellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin, or soljubilizatory, for example tween 80 [polyoxyethylene(20)servicemanual; trademark of ICI Americas Inc., The US].

Oil suspensions, typically intended for injection include as component sizing vegetable, synthetic or semi-synthetic oils. Among them are especially noteworthy liquid fatty acid esters that contain as the acid component of the fatty acid with a chain length from 8 to 22, especially from 12 to 22 carbon atoms, for example lauric acid, tridesilon acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidonoyl acid, beenbuy acid or corresponding unsaturated acids, for example oleic acid, elaidic is islote, erucic acid, brussilov acid or linoleic acid, if necessary in the composition to add antioxidants, such as vitamin E, β-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and represents a monovalent or polyvalent, such as one-, di - or trivalent alcohol such as methanol, ethanol, propanol, butanol or pentanol or its isomers, but mainly glycol and glycerin. Thus, as esters of fatty acids specially note: etiloleat, isopropylmyristate, isopropyl, "Labrafil M 2375" (trioleate of polyoxyethyleneglycol, firm Gattefossé, Paris), "Labrafil M 1944 CS" (unsaturated poliglecaprone glycerides obtained by alcoholysis of oils from apricot pits and consisting of glycerides and polietilenglikoli ether; the company Gattefosse, France), "Labrasol" (saturated poliglecaprone glycerides obtained by alcoholysis of FCM and consisting of glycerides and polietilenglikoli ether; the company Gattefosse, France), and/or "Miglyol 812" (triglyceride of saturated fatty acids with a chain length of C8-C12the company Hüls AG, Germany), and preferably a vegetable oil such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and most of predpochtitel is but peanut butter.

The manufacture of injectable compositions usually carried out under sterile conditions, while they fill, for example, ampoules or vials and sealed containers.

Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active substance with one or more solid carriers, optionally granulating the resulting mixture and, if desired or if necessary, processing the mixture or granules, by incorporating additional excipients to obtain tablets or cores tablets.

Acceptable carriers are, in particular, fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations of cellulose and/or calcium phosphates, for example, the average calcium phosphate or secondary acidic calcium phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hypromellose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or, if necessary, leavening agents, such as the abovementioned starches, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or its salt, such as sodium alginate. Additional excipients are, in particular, regulators yield and oil, for example credit is newww acid, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol or its derivatives.

Core tablets can be coated with an acceptable optional intersolubility coatings, for which inter alia can be used in concentrated sugar solutions, which may include gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or covering solutions in suitable organic solvents or mixtures of solvents, or for cooking intersolubility coatings can be used solutions are suitable preparations of cellulose such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. Dyes or pigments can be added to the tablets or coating of tablets, for example for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for oral administration also include capsules of hard surface consisting of gelatin, as well as a sealed capsule with a soft coating consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules with solid coating can contain the active substance in the form of granules, for example, in a mixture with fillers, such as corn starch, binders and/or lubricating substances is involved, such as talc or magnesium stearate, and optionally a stabiliser. Capsules, soft coated active substance is preferably dissolved or suspended in an acceptable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters and ethylene or propylene glycols, which can also be added stabilizers or surfactants, for example, ether type of polyoxyethylenesorbitan and fatty acids.

Pharmaceutical compositions suitable for rectal administration, are, for example, suppositories, which consist of a combination of the active substance and basis of the suppository. Acceptable bases suppositories are, for example, natural or synthetic triglycerides, saturated hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration are especially suitable are aqueous solutions of the active ingredient in water-soluble form, for example in the form of a water-soluble salt, or aqueous suspension for injection, which contain substances that increase the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally stabilizers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilisate and can the t to be prepared with a solution prior to parenteral introduction by adding acceptable solvents.

Solutions, for example, are suitable for parenteral administration can also be applied in the form of solutions for infusion.

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

The invention is also a method or the method of treating one of the above pathological conditions, in particular diseases that may be alleviated when the inhibition tyrosinekinase VEGF receptor or inhibition of angiogenesis, in particular, the corresponding neoplastic disease or also psoriasis. The compounds of formula I or their N-oxides can be entered individually or preferably in the form of pharmaceutical compositions for prophylactic or therapeutic purposes, preferably in a quantity effective against the said diseases, to a warm-blooded animal, such as man, in need of such treatment. In the case of an individual with a body weight of approximately 70 kg, administered daily dose of the compounds according to the invention is from approximately 0.1 g to approximately 5 g, preferably from approximately 0.5 g to about 2 g

The present invention also preferably relates to the use of compounds of formula I or its pharmaceutically acceptable with the and, in particular the compounds of formula I or its N-oxide, which is preferred, or its pharmaceutically acceptable salt, individually or in the form of a pharmaceutical composition with at least one pharmaceutically acceptable carrier for therapeutic or prophylactic treatment of one or more of the above diseases, in particular neoplastic disease or also psoriasis, more preferably a disease that can be facilitated with the inhibition of angiogenesis or inhibition tyrosinekinase VEGF receptor.

The present invention also preferably relates to the use of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salts, in particular the compounds of formula I, which is preferred, or its pharmaceutically acceptable salt, individually or in the form of a pharmaceutical composition with at least one pharmaceutically acceptable carrier for therapeutic or prophylactic treatment of one or more of the above disease, preferably a disease that can be facilitated when the inhibition tyrosinekinase VEGF receptor or inhibition of angiogenesis, in particular, neoplastic disease or also psoriasis, more preferably a disease that can be facilitated the ri inhibition tyrosinekinase VEGF receptor or angiogenesis.

The present invention also preferably relates to the use of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salts, in particular the compounds of formula I, which is preferred, or its pharmaceutically acceptable salts, for the preparation of pharmaceutical compositions for therapeutic or prophylactic treatment of one or more of the above diseases, in particular neoplastic disease or also psoriasis, more preferably a disease that can be facilitated when the inhibition tyrosinekinase VEGF receptor or angiogenesis.

The above-described preferred dosage quantities, composition and method of preparation of pharmaceutical products (medicines)that may apply in each case.

Original products

New original and/or intermediate products and ways of obtaining them are also the subject of the present invention. In a preferred embodiment, use of such products and choose reaction conditions, to be able to get the preferred connection.

Starting materials of formulas II, III, IVa, IVb, V, VI, VII and VIII are known or can be synthesized by known methods, or go on sale.

For example, aniline of the formula II mo the et can be obtained from nitro compounds of formula IX

where R1, R3-R7and W have the meanings indicated for formula I.

Recovery is preferably carried out in the presence of a suitable reducing agent such as tin chloride (II) or hydrogen, in the presence of an appropriate catalyst, such as Raney-Nickel (preferably using hydrogen under pressure, for example, from 2 to 20 bar) or PtO2, in a suitable solvent, for example, alcohol such as methanol. The reaction temperature is preferably in the range from 0 to 80°C, preferably from 15 to 30°C.

Nitrosoaniline formula IX can be obtained by the interaction of the acid of formula X

where W denotes an oxygen, and R3-R6have the above values,

or its activated derivative with an amine of the formula XI

where R1and R7have the meanings specified for formula I, for example, in the presence of binders, such as dicyclohexylcarbodiimide, at a temperature of from 0°C to 50°C, preferably at room temperature.

If necessary, the radical W, which represents Oh may be replaced by the radical W, which stands for S, using a reagent of Lawesson, according to the method described above for a similar transformation with the unity of formula I, in which W represents Oh, a compound in which W represents s

It is also possible first to carry out the restoration of the nitro compounds of formula X to obtain the corresponding aniline derivative in the reaction conditions are similar to those described for the recovery of nitro compounds of formula IX, followed by the interaction of the resulting aniline derivative with an amine of the formula XI in conditions similar to those described above. However, then it may be necessary to protect the amino group of aniline.

Derivative of Anthranilic acid of the formula VII can be obtained by reductive amination of compounds of formula XII

where

R3, R4, R5and R6have the meanings specified for formula I, and R11means (ness.)alkyl or aryl, first by reacting the compounds of formula XII with 4-pyridylcarbonyl, and then with a reducing agent, such as centripetalism sodium, in the form of a one-stage process (ness.)alcohol, for example methanol, ethanol or propanol, at a temperature of from 0°C to 50°C, preferably at room temperature.

The sequence reaction, which initially receive Imin, using as the source of the product amine of formula XII, and then carry out the restoration can also be accomplished on time the ranks stages of the reaction. Reagents that can be used for introduction of hydrogen in the imine double bond include borane in tetrahydrofuran, LiAlH4, NaBH4sodium in ethanol and hydrogen in the presence of a catalyst.

All other starting materials are known, can be obtained by known methods or go on sale; in particular, they can be obtained using the processes described in the examples.

Upon receipt of the original products the existing functionally active groups, which should not participate in the reaction, must be protected. Preferred protective groups, their introduction and their removal are described in "Protective groups or examples.

Examples

The following examples serve to illustrate the invention and do not limit the scope of the invention.

Temperatures are given in degrees Celsius. If not specified, the reaction was performed at room temperature.

The production of intermediate products:

1. The intermediate product 1A: 2-Nitro-N-(triptoreline)benzamid

A solution containing 2-nitrobenzoate (company Fluka, Buchs, Switzerland) (1.97 ml, 15 mmol) and 4-dimethylaminopyridine (company Fluka, Buchs, Switzerland) (10 mg) in dichloromethane (10 ml)and added under stirring to a mixture of 4-aminobenzotrifluoride (company Fluka, Buchs, Switzerland) (2.66 g, of 16.5 mmole) and triethylamine (1.90 g, 18,8 is mole) in dichloromethane (100 ml) in an argon atmosphere and the mixture is stirred for 16 h at 25° C. the mixture is Then treated with stirring, saturated aqueous sodium bicarbonate (50 ml) and then extracted with dichloromethane (2×50 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent a gradient from 10 to 50% ethyl acetate in hexane, getting mentioned in the title compound as a colourless solid crystalline substance.

The intermediate product 1b: 2-Nitro-N-[3-fluoro(4-trifluoromethyl)phenyl]benzamide

A solution of 4-amino-2-fermentatively (firm Fluorochem, Derbyshire, UK; 14.4 g, 75 mmol) in ethyl acetate (150 ml) is added at room temperature with stirring to a solution of sodium hydroxide (3,30 g, 82,5 mmole) in water. Then to this solution with stirring is added dropwise over 30 min a solution of 2-nitrobenzotrifluoride (11,0 ml, 82,5 mmole) in anhydrous ethyl acetate (110 ml). Then the resulting mixture is stirred over night at ambient temperature. The mixture is extracted with ethyl acetate (3×100 ml). The combined extracts washed sequentially with water (2×100 ml), hydrochloric acid (2×100 ml, 2M solution), water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml) and saturated the one solution of sodium chloride (1× 100 ml), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by recrystallization from ethyl acetate-hexane, obtaining mentioned in the title compound as a colourless solid crystalline substances, tPL185-189°C.

These compounds have a similar way, using the appropriate amine (suppliers which are, for example, the company Fluka or Aldrich, both located in the town of Buchs, Switzerland, or other providers listed in parentheses):

(1C) 2-nitro-N-(4-chlorophenyl)benzamide using 4-Chloroaniline,

(1d) 2-nitro-N-(4-were)benzamide using 4-methylaniline,

(1E) 2-nitro-N-(3-fluoro-4-were)benzamide, using 3-fluoro-4-methylaniline (firm Riedel-de Haen, Silz, Germany)

(1f) 2-nitro-N-[4-chloro(3-trifluoromethyl)phenyl]benzamide using 4-chloro-3-(trifluoromethyl)benzolamide,

(1g) 2-nitro-N-[3-chloro(5-trifluoromethyl)phenyl]benzamide using 3-amino-5-chlorobenzotrifluoride obtained from 4-amino-3-chloro-5-nitrobenzotrifluoride (firm Maybridge Chemical Co. Ltd.), as described in the application for the European patent EP 0516297),

(1h) 2-nitro-N-[4-fluoro-(3-trifluoromethyl)phenyl]benzamide, using 4-fluoro-3-(trifluoromethyl)benzolamide,

(1i) 2-nitro-N-[3-fluoro-(3-trifluoromethyl)phenyl]benzamide, using 3-fluoro-5-(trifluoromethyl)benzamid (firm Fluorochem, Derbyshire, Velikov the power supply),

(1j) 2-nitro-N-[3,5-(bistritei)phenyl]benzamide using 3,5-(bistritei)benzolamide,

(1k) 2-nitro-N-[3,4-(bistritei)phenyl]benzamide using 3,4-(bistritei)Benjamin,

(1l) 2-nitro-N-[3-methoxy-(5-trifluoromethyl)phenyl]benzamide, using 3-methoxy-5-(trifluoromethyl)benzolamide,

(1m) 2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide, using 3-(trifluoromethyl)benzolamide,

(1n) 2-nitro-N-[3-(1,1-dimethyl)ethyl)phenyl]benzamide, using 3-tert-butylaniline,

(1o) 2-nitro-N-(3-tianfeng)benzamide using 3-canbeseen,

(1P) 2-nitro-N-(3-methylthiophenyl)benzamide using 3-methylcobalamin,

(1q) 2-nitro-N-[3-[(1-oxoethyl)amino]phenyl]benzamide using 3-methylcobalamin (firm Pfaltz and Bauer Inc., Connecticut, USA)

(1r) 2-nitro-N-[3-[(aminocarbonyl)amino]phenyl]benzamide using 3-aminophenylamino (Bayer Organica, Leverkusen, Germany),

(1s) 2-nitro-N-[3-(dimethylamino)phenyl]benzamide using the dihydrochloride of N,N-dimethyl-1,3-benzydamine (firm Lancaster Synthesis, Lancashire, UK)

(1t) 5-methoxy-2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide, using 5-methoxy-2-nitrobenzoate (which can be obtained according to the method described by Sami Khan and LaMontagne, J. Med. Chem., 22: 1005-1008, 1979; 5-methoxy-2-nitrobenzoic acid) and 3-(trifluoromethyl)benzenamine,

(1u) 3-methyl-2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide, using 3-methyl-2-nitro is benzoylchloride (which can be obtained according to the method described by Edge and others, J. Chem. Soc. Perkin Trans, 1, 1701-1714, 1982; 3-methyl-2-nitrobenzoic acid) and 3-(trifluoromethyl)benzenamine,

(1v) 4,5-debtor-2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide using 4,5-debtor-2-nitrobenzoate obtained from 4,5-debtor-2-nitrobenzoic acid according to the method described in the German patent application DE 3717904,

(1w) 2-nitro-N-methyl-N-[3-(trifluoromethyl)phenyl]benzamide using N-methyl-3-(trifluoromethyl)benzolamide obtained according to the method described in Berbalk, etc., Monatshefte Chemie, 107: 401-404, 1976; from 3-(trifluoromethyl)benzenamine,

(1x), 2-bromo-N-[3-(trifluoromethyl)phenyl]benzamide using 2-bromobenzoyl-chloride instead of (in lieu) 2-nitrobenzaldehyde and 3-(trifluoromethyl)benzenamine.

The intermediate product 1y: 2-Nitro-N-[3-(methylsulphonyl)phenyl]benzamide

3-Chloroperoxybenzoic acid (71,8 g of a 55%aqueous solution, 229 mmol) is added under stirring to a mixture of 2-nitro-N-(3-methylthiophenyl)benzamide (intermediate 1; 22,0 g, 76,3 mmole) in dichloromethane (1 l) at 0°C. Then the resulting mixture was stirred at 35°C for 70 hours, the mixture is washed successively with an aqueous solution of sodium hydroxide (2×100 ml) and aqueous sodium thiosulfate solution (20×50 ml 10%solution). The organic phase is dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent 50%ethyl acetate in hexane, and after recrystallization from diisopropyl ether get mentioned in the title compound as a colourless solid crystalline substances, tPL172-173°C.

2. The intermediate product 2A: 2-Amino-N-(4-triptoreline)benzamid

A solution of intermediate 1A (1.92 g, to 6.19 mmole) in methanol (200 ml) hydronaut at a pressure of 5 bar in the presence of Raney Nickel (400 mg) at 21°C. for 1 h dissolving the calculated amount of hydrogen. The mixture is then filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by recrystallization from dichloromethane-hexane, obtaining mentioned in the title compound as a colourless solid crystalline substances, tPL160-161°C.

These compounds have a similar way, using the appropriate amine:

(2b) 2-amino-N-[3-fluoro-4-(trifluoromethyl)phenyl]benzamide, tPL135-137°using intermediate product 1b

(2s) 2-amino-N-(4-chlorophenyl)benzamide, tPL156-173°C, in the form of hydrochloride, using intermediate product 1C

(2d) 2-amino-N-(4-were)benzamide using intermediate product Id

(2E) 2-amino-N-(3-fluoro-4-were)benzamid, tPL149-151°C using intermediate 1E,

(2f) 2-amino-N-[4-chloro-3-(trif ormetal)phenyl]benzamide, tPL148-150°using intermediate 1f,

(2g) 2-amino-N-[3-chloro-5-(trifluoromethyl)phenyl]benzamide, tPL174-175°using intermediate product 1g,

(2h) 2-amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide, tPL159-162°using intermediate product 1h,

(2i) 2-amino-N-[3-fluoro-5-(trifluoromethyl)phenyl]benzamide, tPL142-144°using intermediate product 1i,

(2j) 2-amino-N-[3,5-(bistritei)phenyl]benzamide, tPL192-193°using intermediate product 1j,

(2k) 2-amino-N-[3,4-(bistritei)phenyl]benzamide using intermediate product 1k

(2l) 2-amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide, tPL125-126°using intermediate product 1l,

(2m) 2-amino-N-[3-(trifluoromethyl)phenyl]benzamide, tPL131-133°C using intermediate product 1m,

(2n) 2-amino-N-[3-(1,1-dimethyl)ethyl)phenyl]benzamide, tPL84-86°using intermediate product 1n,

(2O) 2-amino-N-(3-tianfeng)benzamid, tPL161-163°using intermediate product 1o,

(2P) 2-amino-N-(3-methylthiophenyl)benzamid, tPL88-90°using intermediate product 1P,

(2q) 2-amino-N-[3-[(1-oxoethyl)amino]phenyl]benzamide, tPL132-134°using intermediate product 1q,

(2r) 2-amino-N-[3-[(aminocarbonyl)amino]phenyl]benzamide, tPL187-189°using intermediate products is 1r,

(2s) 2-amino-N-[3-(dimethylamino)phenyl]benzamide, tPL109-110°using intermediate product 1s

(2t) 2-amino-5-methoxy-N-[3-(trifluoromethyl)phenyl]benzamide, tPL98-99°using intermediate product 1t,

(2u) 2-amino-3-methyl-N-[3-(trifluoromethyl)phenyl)benzamide, tPL103-108°using intermediate product 1u,

(2v) 2-amino-4,5-debtor-N-[3-(trifluoromethyl)phenyl]benzamide, tPL198-200°using intermediate product 1v,

(2w) 2-amino-N'-methyl-N'-[3-(trifluoromethyl)phenyl]benzamide, tPL61-64°using intermediate product 1w.

The intermediate product 2: 2-Amino-N-[3-(methylsulphonyl)phenyl]benzamide

A solution of intermediate 1y (22,0 g, 68.7 mmole) in methanol (1500 ml) hydronaut at a pressure of 7 bar in the presence of 10%palladium on coal (1 g) at 22°C. for 1 h dissolving the calculated amount of hydrogen. The mixture is then filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using ethyl acetate as eluent, and recrystallization from simple diisopropyl ether-hexane, obtaining mentioned in the title compound as a colourless solid crystalline substances, tPL190-193°C.

The intermediate product 2y: 2-Amino-N-[3-(methylsulfinyl)phenyl]benzamide

Solution ol the interstitial product 2P (2.58 g, 10 mmol) in methanol (100 ml) is added dropwise during 30 minutes under stirring to a solution of metaperiodate sodium (2.25 g, 10.5 mmole)is mixed with the solvent (100 ml ethanol and 100 ml of N2O) at 0°C. the Mixture was stirred at 5°C for 17 h and then diluted with water (600 ml) and extracted with dichloromethane (3×150 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent ethyl acetate in hexane and recrystallization from isopropanol-simple diisopropyl ether, getting mentioned in the title compound as a colourless solid crystalline substances, tPL117-121°C.

The intermediate product 2z: 2-Amino-N-[4-(1,1-dimethyl)ethyl)phenyl]benzamide

A solution of 4-tert-butylaniline (9.00 g, 60,3 mmole) in dimethylformamide (20 ml) is added with stirring to a solution of stoynova anhydride (9.75 g, 60 mmol) in dimethylformamide (80 ml) at 100°C. the Mixture was stirred at 100°C for 4 h and Then the solvent is evaporated under reduced pressure, obtaining a residue which is dissolved in ethyl acetate (300 ml) and washed with saturated aqueous ammonium chloride. The solution is dried (Na2SO4), filtered and the solvent is evaporated at Pont the leaders introduce pressure, receiving the crude product which is purified by chromatography on columns on silica gel, using as eluent 10%ethyl acetate in hexane and recrystallization from methyl tert-butyl ether-cyclohexane, getting mentioned in the title compound as a colourless solid crystalline substances, tPL132-134°C.

These compounds have a similar way, using the appropriate amine:

(2A) 2-amino-N-(3-chlorophenyl)benzamide, tPL136-137°C, using 3-Chloroaniline;

(2b) 2-amino-N-(3-bromophenyl)benzamide, tPL150-153°C, using 3-bromaniline;

(2 ° C) 2-amino-N-(3-were)benzamid, tPL115-117°using 3-methylaniline;

(2ad) 2-amino-N-(3-benzoylphenyl)benzamide in the form of a yellow oil using (3-AMINOPHENYL)phenylmethane;

(AE) 2-amino-N-[(3-aminocarbonyl)phenyl]benzamide using 3-aminobenzamide.

The intermediate product yingfa y-n.2af: 2-Amino-N-(4-were)-6-methylbenzamide

(I) 2-{[(1,1-Dimethylmethoxy)carbonyl]amino}-6-methylbenzoic acid

A solution containing 2-amino-6-methylbenzoic acid (9,90 g, 65,5 mmole), triethylamine (12,4 ml, 9.00 g, 89,10 mmole) in anhydrous dimethylformamide (300 ml), treated with stirring in an argon atmosphere di-tert-BUTYLCARBAMATE (19,44 g, 89,1 mmole) and stirring is continued at 18°C for 18 hours the Solvent is evaporated when s is low pressure, receiving the remainder, which is treated with an aqueous solution of citric acid (100 ml of 10%aqueous solution) and extracted with dichloromethane (2×100 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent 5%methanol in dichloromethane and recrystallization from methyl tert-butyl ether-cyclohexane, getting mentioned in the title compound as a colourless solid crystalline substance.

(II) N-(4-Were)-2-{[(1,1-dimethylmethoxy)carbonyl]amino}-6-methylbenzamide

To a mixture of 2-{[(1,1-dimethylmethoxy)carbonyl]amino}-6-methylbenzoic acid (ceiling of 5.60 g, 22.3 mmole) and para-toluidine (4,78 g, 44,6 mmole) in anhydrous dimethylformamide (110 ml) is added under stirring in an argon atmosphere first N-methylmorpholin (x 6.15 ml, 5,64 g, 55.8 mmole), and then hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (10,15 g, and 26.8 mmole) and stirring is continued at 18°C for 16 hours the Solvent is evaporated under reduced pressure, obtaining a residue, which is treated with an aqueous sodium bicarbonate solution (200 ml of 10%aqueous solution) and extracted with dichloromethane (3×100 ml). The combined extracts are washed with aqueous citric acid solution (100 ml of 10%aqueous solution), dried(Na 2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent 20%methanol in dichloromethane and recrystallization from methyl tert-butyl ether-hexane, obtaining mentioned in the title compound as a colourless solid crystalline substances, tPL250°C.

(III) Hydrochloride 2-amino-N-(4-were) -6-methylbenzamide

Under stirring in an argon atmosphere is treated with a solution of N-(4-were)-2-{[(1,1-dimethylmethoxy)carbonyl]amino}-6-methylbenzamide (1,67 g, 4,90 mmole) in methanol (4 ml) saturated aqueous solution of hydrogen chloride in dioxane (30 ml) and stirring is continued at 18°C for 210 minutes the Solvent is evaporated under reduced pressure, obtaining the crude product which is purified by recrystallization from methanol - simple diisopropyl ether, getting mentioned in the title compound as a colourless crystalline solid substances, tPL217 to 220°C.

Examples

Example 1: 2-[(4-Pyridyl)methyl]amino-N-[(4-trifluoromethyl)phenyl]benzamide

Lambrogini sodium (0,80 g of 90%aqueous solution, 11.5 mmole) is added in portions during 30 minutes under stirring to a mixture containing acetic acid (0.15 ml), 4-pyridinecarboxamide (1,00 g of 3.57 mmole) of the intermediate product 2A (1,00 g, of 3.57 mmole) in methanol (15 ml) at 25°C in argon atmosphere. The mixture is stirred for 16 h, diluted with dichloromethane (100 ml) and treated with saturated aqueous sodium bicarbonate (50 ml). The mixture is stirred for another 5 min and then extracted with dichloromethane (3×50 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent 33%ethyl acetate in hexane and recrystallization from 2-propanol-hexane, obtaining mentioned in the title compound as a colourless solid crystalline substances, tPL171-175°, which has the following physical characteristics:1H-NMR (DMSO-d6d of 4.49 (d, J=6,l Hz, 2H), 6,56 (d, J=8,4 Hz, 1H), 6,66 (t, J=8.5 Hz, 1H), 7,26 (t, J=8,4 Hz, 1H), 7,33 (d, J=5,9 Hz, 2H), 7,71 (d, J=8.5 Hz, 2H), 7,72 (m, 1H), of 7.90 (t, J=6,1 Hz, 1H), of 7.96 (d, J=8.5 Hz, 2H), 8,49 (d, J=5,9 Hz, 2H) and 10,46 (s, 1H).

These compounds have a similar way, using the appropriate amine:

Example 2: 2-[(4-Pyridyl)methyl]amino-N-[3-fluoro-(4-trifluoromethyl)phenyl]benzamide, tPL162-164°using intermediate product 2b.

Example 3: 2-[(4-Pyridyl)methyl]amino-N-phenylbenzene, tPL160-161°using 2-aminobenzamide.

Example 4: 2-[(4-Pyridyl)methyl]amino-N-(4-chlorophenyl)benzo the Ministry of foreign Affairs, tPL134-139°using intermediate product 2C.

Example 5: 2-[(4-Pyridyl)methyl]amino-N-(4-were)benzamide using intermediate product 2d.

Example 6: 2-[(4-Pyridyl)methyl]amino-N-(3-fluoro-4-were)benzamid get using intermediate 2A. After purification by chromatography (silica gel, eluent: 33% ethyl acetate in hexane) base is dissolved in ethyl acetate and treated with a solution of hydrogen chloride in dichloromethane. Osadovskaya the product is filtered and recrystallized from dichloromethane-hexane, getting dihydrochloride, tPL116-124°C.

Example 7: 2-[(4-Pyridyl)methyl]amino-N-[4-chloro-3-(trifluoromethyl)phenyl]benzamide, tPL162-172°using intermediate product 2f.

Example 8: 2-[(4-Pyridyl)methyl]amino-N-[3-chloro-5-(trifluoromethyl)phenyl]benzamide, tPL190-194°using intermediate product 2g.

Example 9: 2-[(4-Pyridyl)methyl]amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide, tPL183-185°using intermediate product 2h.

Example 10: 2-[(4-Pyridyl)methyl]amino-N-[3-fluoro-5-(trifluoromethyl)phenyl]benzamide, tPL196-197°using intermediate product 2i.

Example 11: 2-[(4-Pyridyl)methyl]amino-N-[3,5-(bistritei)phenyl]benzamide, tPL180-185°using intermediate product 2j.

Example 12: 2-[(4-Pyridyl)methyl]amino-N-[3,4-(bistritei)phenyl]Besame is, using intermediate product 2k.

Example 13: 2-[(4-Pyridyl)methyl]amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide, tPL134-136°using intermediate product 2l.

Example 14: 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide, tPL157-159°using intermediate product 2m.

Example 15: 2-[(4-Pyridyl)methyl]amino-N-[3-(1,1-dimethylethyl)phenyl]benzamide, tPL144-147°using intermediate product 2n.

Example 16: 2-[(4-Pyridyl)methyl]amino-N-(3-tianfeng)benzamid, tPL157-160°using intermediate product 2O.

Example 17: 2-[(4-Pyridyl)methyl]amino-N-[(3-methylthio)phenyl]benzamide, tPL138-142°using intermediate product 2P.

Example 18: 2-[(4-Pyridyl)methyl]amino-N-(3-acetylaminophenol)benzamid, tPL157-158°using intermediate product 2q.

Example 19: 2-[(4-Pyridyl)methyl]amino-N-[3-[(aminocarbonyl)amino] phenyl]benzamide, tPL200-202°using intermediate product 2r.

Example 20: 2-[(4-Pyridyl)methyl]amino-N-[3-(dimethylamino)phenyl]benzamide, tPL152-154°using intermediate product 2s.

Example 21: 5-Methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide, tPL175-178°C using intermediate product 2t.

Example 22: 3-Methyl-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide get using intermediate product 2u. P the following purification via chromatography (silica gel, eluent: 33% hexane in ethyl acetate) base is dissolved in ethyl acetate and treated with a solution of hydrogen chloride in dichloromethane. Osadovskaya the product is filtered and recrystallized from ethyl acetate, getting dihydrochloride, tPL94-98°C.

Example 23: 4,5-Debtor-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide, tPL175-178°C using intermediate product 2v.

Example 24: 2-[(4-Pyridyl)methyl]amino-N-methyl-N-[3-(trifluoromethyl)phenyl]benzamide, tPL127-128°using intermediate product 2w.

Example 25: 2-[(4-Pyridyl)methyl]amino-N-[(3-methylsulphonyl)phenyl]benzamide, tPL178-184°using the intermediate product 2.

Example 26: 2-[(4-Pyridyl)methyl]amino-N-[(3-methylsulfinyl)phenyl]benzamide, tPL175-178°C using intermediate product 2y.

Example 27: 2-[(4-Pyridyl)methyl]amino-N-[4-(1,1-dimethylethyl)phenyl]benzamide, tPL168-170°C using intermediate product 2z.

Example 28: 2-[(4-Pyridyl)methyl]amino-N-(3-chlorophenyl)benzamide, tPL131-133°using intermediate 2A.

Example 29: 2-((4-Pyridyl)methyl]amino-N-(3-bromophenyl)benzamide, tPL156-159°using intermediate product 2b.

Example 30: 2-[(4-Pyridyl)methyl]amino-N-(3-were)benzamid, tPL139-140°using the intermediate product 2 ° C.

Example 31: 2-[(4-Pyridyl)methyl]amino-N-(3-benzoyle the Il)benzamid, tPL168-169°using intermediate product 2ad.

Example 32: 2-[(4-Pyridyl)methyl]amino-N-[3-(aminocarbonyl)phenyl]benzamide, tPL195-203°using intermediate product e.

Example 33: 2-[(4-Pyridyl)methyl]amino-N-(were)-6-methylbenzamide, tPL162-163°using intermediate product yingfa y-n.2af.

The following connections will receive is similar to the process described in example 14, using the appropriate aldehyde.

Example 34: 2-[(3-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide, tPL140-142°using 3-pyridinecarboxamide.

Example 35: 2-[(4-Chinoline)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide, tPL191-193°C, using 4-chinainternational.

Example 36: 2-[(5-Chinoline)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide, tPL176-178°using 5-chinainternational obtained according to the method described by Wommack and others, J. Het. Chem., 6: 243-245, 1969, from 5-aminoquinoline.

Example 37: 2-[(4-(2-Methyl)pyridyl)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide, tPL146-147°using 2-methyl-4-pyridinecarboxamide obtained according to the method described by Boehm and others, J. Med. Chem., 39: 3929-3937, 1996, from 2-methyl-4-lepirudin, which in turn receive according to the method described in Ashimori, etc., Chem. Pharm. Bull., 38: 2446-2458, 1990, from 2-methylpyridine-1-oxide.

Example 38: 2-[(4-(1,2-Dihydro-2-oxo)pyridyl)methylamino-N-[3-(trifloromethyl)phenyl]benzamide, tPL183-185°C, using 1,2-dihydro-2-oxo-4-pyridinecarboxamide obtained according to the method described by Ren, Sakai and Nakanishi, J. Amer. Chem. Soc., 119: 3619-3620, 1997, from 2-hydroxy-4-methylpyridine.

Example 39: 2-[(4-Chinoline)methyl]amino-N-(4-chlorophenyl)benzamide, tPL178-209°receive according to the method described in example 4 using 4-chinainternational.

Example 40: 2-[(2-Imidazolyl)methyl]amino-N-(4-chlorophenyl)benzamide, tPL181-184°C, receive according to the method described in example 4, using 1H-imidazol-2-carboxaldehyde.

Example 41: 2-[2-(4-Pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide

4-Pyridinediamine (firm Maybridge Chemical Co. Ltd, Cornwall, UK; 0.31 g, 2.5 mmole) is added with stirring to a mixture containing 2-bromo-N-[3-(trifluoromethyl)phenyl]benzamide (intermediate 1×; 1,72 g, 5 mmol), powdered potassium carbonate (0.35 g, 2.5 mmole) and copper iodide (I) (the company Fluka, Buchs, Switzerland; of 0.48 g, 2.5 mmole) in dimethylformamide (10 ml). Then the resulting mixture is blown with argon, and then maintained at 160°C in argon atmosphere for 15 hours the Mixture is cooled, treated with water (100 ml) and extracted with ethyl acetate (3×80 ml). The combined extracts are washed with aqueous ammonia solution (2x10%), dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude p is oduct, which is purified by chromatography on columns on silica gel, using as eluent 50%ethyl acetate in hexane and recrystallization from ethyl acetate-hexane, obtaining mentioned in the title compound as a colourless solid crystalline substances, tPL151-152°C.

The following connections receive according to the method described in example 41, using the appropriate amine.

Example 42: 2-[2-(3-Pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide, tPL102-103°using 3-pyridinediamine (firm Maybridge Chemical Co. Ltd, Cornwall, UK).

Example 43: 2-[1-Methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide, using 1-(3-pyridyl)-2-Propylamine obtained according to the method described in I. Amer. Chem. Soc., 119: 3619-3620, 1997.

Example 44: 2-[(1-Oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide

3-Chloroperoxybenzoic acid (of 2.06 g of a 70%aqueous solution, 8.4 mmole) is added with stirring to a mixture containing 2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (example 14; 1.86 g, 5 mmol) in dichloromethane (50 ml) at 0°C. Then the resulting mixture was stirred at room temperature for 15 hours the Mixture is diluted with dichloromethane (100 ml) and sequentially washed with an aqueous solution of sodium hydroxide (CH ml), water a solution of thiosulfate (2×50 ml 10%solution).

Organic is ABC dried (Na 2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent 20%ethanol in ethyl acetate and recrystallization from ethyl acetate-hexane, obtaining mentioned in the title compound as a colourless solid crystalline substances, tPL181-184°C.

Example 45: 2-[(4-Pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benzamide

Lambrogini sodium (0.55 g, a 14.1 mmole) is added with stirring to a mixture containing paraformaldehyde (0,82 g, 27.3 mmole) and 2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (example 14; of 1.03 g, 2,78 mmole) in tetrahydrofuran (30 ml), at 20°C in argon atmosphere. Then the resulting mixture is treated dropwise triperoxonane acid (15 ml) and stirred at room temperature for 20 hours the Mixture is diluted with chilled on ice with an aqueous solution of sodium hydroxide (100 ml, 5M) and extracted with dichloromethane (3×100 ml). The organic phase is dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure, obtaining the crude product which is purified by chromatography on columns on silica gel, using as eluent ethyl acetate, getting mentioned in the title compound as a colourless crystalline solid is about substance.

Example 46: 2-[(4-Pyridyl)methyl]amino-N-(4-chloronaphthyl)benzamid

0.75 ml of trimethylaluminum (2M in toluene) are added to the suspension containing 266 mg of 4-chloro-1-naphtylamine in 1 ml of toluene. After 10 minutes add a cold solution containing 242 mg methyl-N-(4-pyridylmethyl)anthranilate in 2 ml of toluene. The mixture is stirred for 1 h at room temperature and for 1 h at the temperature of reflux distilled. After cooling to room temperature, add saturated NaHCO3and the mixture is extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride solution and concentrated. The residue is crystallized from ethyl acetate, getting mentioned in the title compound in the form of solids, tPL137°C.

Stage 1 of example 46: N-(4-pyridylmethyl)anthranilate

3 ml of acetic acid and 8.6 g of 4-pyridinecarboxamide added to a solution containing 7.5 g of methylanthranilate in 300 ml of methanol. The mixture is stirred for 12 h under nitrogen atmosphere at room temperature. Add 5.7 g of centripetality sodium (85%) and the mixture stirred for 3 h at room temperature. Add to 1.14 g centripetality sodium (85%) and the mixture stirred for 12 h at room temperature. Restoral is evaporated and the residue is dissolved in ethyl acetate and washed with saturated solution of NaHCO3and a saturated solution of chloride is the atrium. The organic extract was concentrated and purified on silica gel using hexane/ethyl acetate (1:1)to give methyl-N-(4-pyridylmethyl)anthranilate, tPL86°C.

Examples 47-72

Compounds of examples 47-72 get a similar manner using recovery amination followed by amidation using amine and trimethylaluminum according to the method described in example 46. Applied Anthranilic esters are commercially available or can be synthesized as described below.

The synthesis of the original product, for example, 47:

2-Methyl-6-nitrobenzoic acid is subjected to interaction with trimethylsilyldiazomethane, receiving methyl-2-methyl-6-nitrobenzoate, tPL44-45° (Chem. Pharm. Bull., vol. 29, 1475, 1981). Methyl-2-methyl-6-nitrobenzoate hydronaut at room temperature and atmospheric pressure in methanol in the presence of 10%palladium on powdered coal, receiving 2-methyl-6-aminobenzoate.

The synthesis of the original product, for example, 48:

2-Amino-6-chlorobenzoyl acid is subjected to interaction with trimethylsilyldiazomethane, receiving methyl-2-amino-6-chlorobenzoate (Chem. Pharm. Bull., 29, 1475, 1981).

The synthesis of the original product for example 49:

3,4-Methylenedioxy-6-nitrobenzaldehyde is transformed into methyl-3,4-dimethylaniline-6-nitrobenzoate in methanol in the presence of sodium cyanide manganese dioxide (Synthetic Commun., 27(7), 1281-1283, 199). Methyl-3,4-methylenedioxy-6-nitrobenzoate hydronaut in ethanol at room temperature and atmospheric pressure in the presence of 10%palladium on powdered coal, receiving 3,4-methylenedioxy-6-aminobenzoate.

The synthesis of the original product, for example, 50:

0,41 g of sodium nitrite in water is added to 1 g of 4,5-dimethyl-2-nitroaniline 3 ml conc. HCl and stirred for 1 h at +4°C. This solution is added to a mixture containing of 0.67 g of copper cyanide (I), and 0.98 g of sodium cyanide, 0.32 g of sodium carbonate, 25 ml of water and 3 ml of toluene. The mixture is stirred for 12 h at room temperature and treated, receiving 0.45 g of 4,5-dimethyl-2-nitrobenzonitrile. 4,5-Dimethyl-2-nitrobenzonitrile restore using iron powder in acetic acid, receiving 4,5-dimethyl-2-aminobenzonitrile. 4,5-Dimethyl-2-aminobenzonitrile maintained at a temperature of reflux distilled for 12 h in conc. HCl, receiving 4,5-dimethyl-2-aminobenzoic acid. 4,5-Dimethyl-2-aminobenzoic acid is subjected to interaction with trimethylsilyldiazomethane, receiving methyl-4,5-dimethyl-2-aminobenzoate (Chem. Pharm. Bull., 29, 1475, 1981).

Table 1: Examples 47-72

The following compounds are compounds of the formula I, in which W represents O, X denotes NH, Y represents CH2, R2represents 4-pyridyl, R6and R7denote N.

N
ExampleR1R3R4R5tPLthat °
474-chlorophenylmethylNN190
484-chlorophenylchlorineHN183-185
494-chlorophenylN-O-CH2O-
504-chlorophenylNmethylmethyl
514-n-propylphenylNchlorineN
524-n-propylphenylNNN
537-hydroxynaphthylNNN
548-hydroxy-2-naphthylNNN235
554-chlorophenylNNchlorine186
564-chlorophenylNmethylN127
575,6,7,8-tetrahydronaphthylNNN116
584-biphenyl - NNN135-136
594-chlorophenylNchlorineN206-207
60naphthylNNN
612-naphthylNNN159-160
624-methoxyphenylNNN
633-trifloromethylNNN
644-methoxy-2-naphthylNNN152-154
653-bromo-2-naphthylNNN130-132
664-(isopropoxycarbonyl)phenylNNN70
674-trifloromethylNNN
684-(isopropylcarbamate)phenylNN79
693-chloro-4-wereNNN143
702-wereNNN143
713-(methoxycarbonylmethyl)phenylNNN
724-phenoxyphenylNNN

Example 73: Test to determine the activity against tyrosinekinase Fit-1-receptor VEGF

The test is carried out as described above using tyrosinekinase Flt-1 VEGF receptor. Defined in this test, the value of the IC50below the accuracy with which they could be obtained.

Table 2

The test for determining activity against tyrosinekinase Flt-1-Denenrooa VEGF
The connection specified in the header exampleIC50(µm)
40,18
50,26
70,56

Example 74: Capsules, soft coated

Batch of 5000 gelatin capsules, soft coated, each of which, to the operation of the active substance contains 0.05 g of one of the compounds of formula I, specified in the preceding examples, was prepared as follows:

Composition

The active ingredient250 g
Lauroglycol2 l

Preparation process: the Powdered active ingredient is suspended in Lauroglykol®(propylene glycol laurate, the company Gattefosse S.A., Saint-Prex, France) and grind when wet mill fine grinding, receiving particle size of about 1-3 microns. Using a machine for filling capsules in gelatin capsules, soft coated contribute a portion of the mixture on 0,419 g each.

1. Pharmaceutical product having inhibitory activity against tyrosinekinase Flt-1 VEGF receptor associated with neoplastic disease and angiogenesis, representing a compound of formula I

where W represents O;

X represents NR8where R8is hydrogen or lower alkyl;

Y denotes CH2(CH2)nwhere n is 1;

R1represents 4-chlorophenyl, 4-were, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl;

R2represents 4-pyridyl;

R3- R7denote hydrogen,

or its N-oxide, or pharmaceutically acceptable salt.

2. The way Le is placed neoplastic disease, which is facilitated by inhibition of the activity tyrosinekinase receptor of VEGF, providing for the introduction of compounds of formula I, or its N-oxide, or pharmaceutically acceptable salts, in which the radicals and symbols have the meanings indicated in claim 1, warm-blooded animal that is in need of such treatment in an amount effective for this disease.

3. The compound of the formula I

where W represents O;

Y represents CR9R10-(CH2)nwhere R9and R10independently of one another denote hydrogen or lower alkyl;

n denotes an integer from 0 to 3 inclusive, provided that n is 1 when R9and R10both represent hydrogen;

X represents NR8where R8is hydrogen or lower alkyl;

R1denotes aryl which may be substituted by 1-2 substituents selected from the series comprising halogen, trifluoromethyl, lower alkyl, lower alkoxy, hydroxy, phenyl, phenoxy, lower alkoxycarbonyl lowest allylcarbamate, cyano, methylthio, acetylamino, aminocarbonyl, methylsulphonyl, methylsulfonyl, benzoyl;

R2denotes a mono - or bicyclic nitrogen-containing group, provided that R2cannot denote 2-phthalimide or 2,1,3-benzothiadiazole-4-yl;

R3/sub> - R6independently of one another denote hydrogen or one or two of these substituents denote methyl, chlorine or-O-CH2Oh, and the other is hydrogen;

R7is hydrogen or lower alkyl, with the exception of the compounds of formula I, where W denotes O, X represents NR8where R8is hydrogen or lower alkyl;

Y denotes CH2(CH2)nwhere n is 1;

R1represents 4-chlorophenyl, 4-were, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl;

R2represents 4-pyridyl;

R3- R7denote hydrogen,

or its N-oxide, or pharmaceutically acceptable salt.

4. The compound of formula I according to claim 3, in which

W represents O;

X represents NR8where R8is hydrogen or lower alkyl;

Y denotes CHR9-(CH2)nwhere R9represents hydrogen, n represents an integer from 0 to 3 inclusive, provided that n is 1 when R9denotes hydrogen;

R1denotes aryl which may be substituted by 1-2 substituents selected from the series comprising halogen, trifluoromethyl, lower alkyl, lower alkoxy, hydroxy, phenyl, phenyloxy, lower alkoxycarbonyl lowest allylcarbamate, cyano, methylthio, acetylamino, aminocarbonyl, methylsulphonyl, methylsulfonyl, benzoyl;

R22cannot denote 2-phthalimide;

R3- R6independently of one another denote H or one or two of these substituents denote methyl, chlorine or-O-CH2Oh, and the other is hydrogen;

R7denotes hydrogen or (ness.)alkyl,

with the exception of the compounds of formula I, where W denotes O; X represents NR8;

Y denotes CH2; R1represents 4-chlorophenyl; R2represents 2-pyridyl; R3, R4, R5, R7and R8each represents H and R6denotes chlorine,

or its salt.

5. The compound of formula I according to claim 3, in which

W represents O;

X represents NR8where R8is hydrogen or lower alkyl;

Y denotes CHR9R10-(CH2)nwhere R9and R10independently of one another denote hydrogen or lower alkyl, n denotes an integer from 0-3, inclusive, provided that n is 1 when R9and R10both represent hydrogen;

R1denotes aryl which may be substituted by 1-2 substituents selected from the series comprising halogen, trifluoromethyl, lower alkyl, lower alkoxy, hydroxy, phenyl, phenyloxy, lower alkoxycarbonyl lowest allylcarbamate, cyano, methylthio, acetylamino, aminocarbonyl, methylsulphonyl, methylsulfonyl, benzoyl;

R2

where r is 0-2;

A, b, D and E independently of one another denote N or CH, provided that no more than two of these radicals represent preferably N; and

Q denotes lower alkyl or hydroxy;

any of the radicals R3, R4, R5and R6independently from each other represents H, fluorine or (ness.)alkyl; and

R7and R8independently of one another denote H or (ness.)alkyl;

or its N-oxide, or pharmaceutically acceptable salt.

6. The compound of formula I according to any one of p, 4 or 5, in which n is 0.

7. The compound of formula I according to claim 3, in which

W represents O;

X represents NR8where R8hydrogen or lower alkyl;

Y denotes CHR9-(CH2)nwhere R9denotes H or methyl and n is 0;

R1denotes aryl which may be substituted by 1-2 substituents selected from the series comprising halogen, trifluoromethyl, lower alkyl, lower alkoxy, hydroxy, phenyl, phenyloxy, lower alkoxycarbonyl lowest allylcarbamate, cyano, methylthio, acetylamino, aminocarbonyl, methylsulphonyl, methylsulfonyl, benzoyl;

R2denotes a mono - or bicyclic nitrogen-containing group, provided th the R 2cannot denote 2-phthalimide;

R3- R6independently from each other represents H or one or two of these substituents denote methyl, chlorine or-O-CH2Oh, and the other is hydrogen;

R7denotes hydrogen or lower alkyl,

with the exception of the compounds of formula I, where W denotes O; X represents NR8;

Y denotes CH2; R1represents 4-chlorophenyl; R2represents 2-pyridyl; R3, R4, R5, R7and R8each represents H and R6denotes chlorine;

or its salt.

8. The compound of formula I according to claim 3, in which

W represents O;

X represents NR8where R8is hydrogen or methyl;

Y denotes CHR9-(CH2)nwhere R9denotes H or methyl and

n is 0;

R1denotes phenyl which may be substituted by one or two substituents, independently of one another selected from the series comprising halogen, trifluoromethyl, lower alkyl, methylsulphonyl, methylsulfinyl;

R2indicates imidazolyl, hinely, naphthyridine, 2-methylpyridin-4-yl, 3-pyridyl or 4-pyridyl;

R3- R6independently of each other denotes H or methyl; and

R7denotes H or methyl,

or its N-oxide, or pharmaceutically acceptable salt.

9. The compound of formula I according to claim 3, in which

W represents O;

X represents NR8where R8is hydrogen or methyl;

Y denotes CHR9-(CH2)nwhere R9denotes H or methyl and

n is 0;

R1denotes phenyl which may be substituted by one or two substituents selected from the series comprising halogen; trifluoromethyl, (ness.)alkyl; methylsulfinyl methylsulphonyl;

R2indicates imidazolyl, hinely, 2-methylpyridin-4-yl or 4-pyridyl;

any of the radicals R3, R4, R5and R6independently of each other denotes H or methyl and

R7denotes H or methyl,

or its salt.

10. The compound of formula I according to any one of p-9, in which R2represents 4-pyridyl.

11. The compound of formula I according to claim 3, in which

W represents O;

X represents NR8;

Y denotes CH2;

R1denotes phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl, which in each case may be substituted by one or two substituents selected from the series comprising halogen; (ness.)alkyl; (ness.)alkoxy-; (ness.)alkoxycarbonyl; N-(ness.)allylcarbamate;

R2represents 4-pyridyl;

any of the radicals R3, R4, R5and R6independently of each convoy is achet N, methyl or chlorine, or

R7and R8denote H;

or its N-oxide, or pharmaceutically acceptable salt.

12. The compound of formula I according to claim 5, selected from the group including:

2-[(4-pyridyl)methyl]amino-N-(4-triptoreline)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-fluoro-4-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-chloro-3-triptoreline)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-chloro-5-triptoreline)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-were)-6-methylbenzamide; and

2-[(4-chinolin)methyl]amino-N-(4-chloromethylene)benzamid,

or its pharmaceutically acceptable salt.

13. The compound of formula I according to claim 5, selected from the group including:

2-[(4-pyridyl)methyl]amino-N-[3-fluoro-(4-trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-phenylbenzene;

2-[(4-pyridyl)methyl]amino-N-[4-fluoro-(3-trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-fluoro-(5-trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3,5-(bistritei)phenyl]benzamide;

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

2-[(4-pyridyl)methyl]amino-N-[3-methoxy-(5-trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(1,1-dimethylethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-tianfeng)benzamide;

2-[(4-pyridyl)methyl]amino-N-[(3-methylthio)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-acetylaminophenol)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-[(aminocarbonyl)amino]phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(dimethylamino)phenyl]benzamide;

5-methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

3-methyl-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

4,5-debtor-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N'-methyl-N'-[3-(trifluoromethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[(3-methylsulphonyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[(3-methylsulfinyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(1,1-dimethylethyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-chlorophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-bromophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-benzoylphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(aminocarbonyl)phenyl]benzamide;

2-[(3-pyridyl)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-chinoline)methyl]amino-N-[3-(trifloromethyl)FeNi is]benzamide;

2-[(5-chinoline)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-(2-methyl)pyridyl)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-(1,2-dihydro-2-oxo)pyridyl)methyl]amino-N-[3-(trifloromethyl)phenyl]benzamide;

2-[(4-chinoline)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(2-imidazolyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[1-methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;

2-[(1-oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide; and

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

or its pharmaceutically acceptable salt.

14. The compound of formula I according to claim 5, selected from the group including:

2-[(4-pyridyl)methyl]amino-N-(4-chloronaphthyl)benzamide;

6-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

6-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

3,4-methylenedioxy-6-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

4,5-dimethyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(7-hydroxine the Il)benzamide;

2-[(4-pyridyl)methyl]amino-N-(8-hydroxy-2-naphthyl)benzamide;

4-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

5-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(5,6,7,8-tetrahydronaphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-biphenyl)benzamide;

5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(2-naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-methoxyphenyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(trichromatic)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(4-methoxy-2-naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-bromo-2-naphthyl)benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(isopropoxycarbonyl)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(triptoreline)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-[4-(isopropylcarbamate)phenyl]benzamide;

2-[(4-pyridyl)methyl]amino-N-(3-chloro-4-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-(2-were)benzamide;

2-[(4-pyridyl)methyl]amino-N-[3-(methoxycarbonylmethyl)phenyl]benzamide; and

2-[(4-pyridyl)methyl]amino-N-(4-phenoxyphenyl)benzamide,

or its pharmaceutically acceptable salt.

15. The compound of formula I according to any one of p-14, or its N-oxide, is whether the pharmaceutically acceptable salt of such compounds, possessing inhibitory activity against tyrosinekinase Flt-1 VEGF receptor.

16. Pharmaceutical composition having inhibitory ability in relation to activity tyrosinekinase VEGF receptor intended for the treatment of neoplastic diseases, comprising the compound of formula I according to claim 1 and any of PP-14, or its N-oxide, or pharmaceutically acceptable salt, or hydrate, or MES and at least one pharmaceutically acceptable carrier.

17. The method of obtaining the compounds of formula I according to claim 3, or its N-oxide, or pharmaceutically acceptable salts, characterized in that

a) for the synthesis of compounds of formula I in which X represents NR8where R8represents hydrogen and Y represents CHR9-(CH2)nwhere the symbols have the meanings specified for compounds of formula I, and the rest of the characters R1, R2, R3, R4, R5and R6have the meanings specified for compounds of formula I, an aniline derivative of the formula II

where W, R1, R3, R4, R5, R6and R7have the meanings specified for compounds of formula I, is subjected to the interaction with the carbonyl derivative of formula III

where n, R2and R9have the meanings specified the s for the compounds of formula I,

in the presence of a reducing agent; or

b) for the synthesis of compounds of formula I in which X represents NR8, Y represents CR9R10-(CH2)nand other symbols R1, R2, R3, R4, R5, R6, R7and R8have the meanings specified for compounds of formula I, a halogenated derivative of formula V

where Hal represents iodine, bromine or chlorine, and W, R1, R3, R4, R5, R6and R7have the meanings specified for compounds of formula I,

subjected to interaction with the amine of formula VI

where n, R2, R8, R9and R10have the meanings specified for compounds of formula I,

in the presence of a suitable catalyst in an inert solvent in the presence of an aprotic base; and source the products listed in the methods a) or b), can also optionally have functional groups in protected form and/or be in the form of salts, provided, if there is a salt-forming group and the possible reaction involving compounds in salt form;

remove any protective groups in a protected derivative of a compound of formula I, and optionally convert the compound obtained of the formula I into another connected to the e of the formula I or its N-oxide, make a free compound of formula I in salt, turn obtained salt of a compound of formula I into the free compound or into another salt and/or divide a mixture of isomers of compounds of the formula I into the individual isomers.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

32 cl, 1 tbl, 132 ex

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

SUBSTANCE: invention relates to novel derivatives of benzopyrane substituted with secondary amines comprising tetrazole, their stereoisomers or their pharmaceutical acceptable salts of the formula (I): wherein R1 represents hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom, -CF3, -NO2, -CN, -ORa, -NH2, or -OS(O)lRa under condition that Ra represents hydrogen atom (H) or unbranched or branched (C1-C4)-alkyl; l means a whole number 0-2; R2 represents -CH2ORa, under condition that Ra has values given above; Rb and Rc represent independently unbranched or branched (C1-C4)-alkyl; R3 represents -OH or under condition that Ra has values given above; R4 and R5 represent independently H, F, Cl, Br, unbranched or branched (C1-C3)-alkyl, -ORa, -CF3, -OCF3, -NO2, or -SO3Ra under condition that Ra has values given above; R6 represents H, unbranched or branched (C1-C3)-alkyl; n and m mean independently a whole number 0-2; * represents chiral carbon atom. Also, invention relates to a method of synthesis of these compounds and a pharmaceutical composition based on thereof. Invention provides preparing novel derivatives of benzopyrane possessing antioxidant activity.

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

15 cl, 14 tbl, 118 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

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

SUBSTANCE: invention relates to a method for preparing compound of the formula (I) wherein R1 and R2 represent independently of one another hydrogen atom or methyl; R3, R4, R5 and R6 represent independently of one another hydrogen atom (H), halogen atom, formyl group, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkylenyloxycarbonyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C4)-alkylcarbonylamido-group, (C3-C7)-cycloalkylcarbonylamido-group, phenylcarbonylamido-group, benzyl, phenyl or naphthyl wherein benzyl, phenyl and naphthyl are substituted optionally and independently of one another with substitutes in amount up to two and chosen independently from halogen atom, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three and (C1-C4)-alkoxy-(C1-C4)-alkyl. Proposed method involves the following successive stages: (a) interaction of compound of the formula (II) wherein R3, R4, R5 and R6 are determined independently as given above with lithium-organic compound in the presence of sulfur source in medium of the first reactively inert solvent to form the reactive intermediate compound of the formula (IIa) (b) interaction of indicated reactive intermediate compound of the formula (IIa) with compound of the formula (III) to form compound of the formula (IV) (c) interaction of indicated compound of the formula (IV) with alkaline (C1-C2)-alkoxide in (C1-C2)-alkanol medium to form derivative of simple ether of the formula (V) wherein Alk represents (C1-C2)-alkyl; (d) interaction of indicated compound of the formula (V) with mineral acid to form compound of the formula (VI) and (e) oxidation of compound of the formula (VI) in the second reactively inert solvent to form compound of the formula (I). Prepared pyridazinone compounds are effective inhibitors of aldose reductase activity and can be used in prophylaxis and/or treatment of diabetes mellitus complications, such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. Also, invention relates to new intermediate compounds of the formula (IV) used in synthesis of indicated inhibitors of aldose reductase, to a method for synthesis of compound of the formula (IV) and a method for synthesis of preferable pyridazinone compound of the formula (XI) .

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

10 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine. Method involves reaction of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine with alkaline metal methoxide in inert organic solvent, transfer of prepared 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine in aqueous acid medium and the following oxidation of this compound in the presence of catalyst if necessary, preferably, with an interphase catalyst, such as tricaprylmethylammonium chloride. Then method involves carrying out the purification stage wherein pH value of the aqueous acid reaction mixture is brought about to the value from 5 to 8 with aqueous base, such as alkaline metal hydroxide, for example, sodium hydroxide at temperature 10-90°C and stirring in the presence of absence of organic solvent, for example, aromatic hydrocarbon, such as benzene, toluene or isomeric xylenes, or alcohol, such as methanol or ethanol. Also, invention relates to using the prepared compound as an intermediate substance for synthesis of herbicide, in particular, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide by reaction of 7-mercapto-3-methylphthalide of compound in preparing herbicides, for example, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide.

EFFECT: improved preparing method.

24 cl, 2 sch, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of benzene or its salt of the formula (I): wherein X1 means -C(=O)-NR5-, -NR5-C(=O)-; X2 means -NR6-C(=O)-, -NR6-CH2-; R1 means halogen atom, lower alkyl or lower alkoxy-group; R2 and R3 mean hydrogen or halogen atom; R4 means hydrogen atom, -SO3H- or sugar residue; ring A represents benzene or pyridine ring; ring B represents piperidine ring, and a pharmaceutical composition based on thereof. Proposed compounds possess anti-coagulating effect based on inhibition of blood coagulation activated factor X that are useful as anti-coagulants or prophylactic agents against diseases caused by thrombosis and embolism.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 9 tbl, 38 ex

Ionic liquids ii // 2272043

FIELD: organic chemistry.

SUBSTANCE: invention relates to new ionic liquids designated for using in electrochemical cells and in organic synthesis. Invention describes ionic liquids of the general formula: K+A- (I) wherein K+ represents one of cations of the group consisting of the following formulae: wherein R1-R5 can be similar or different and can be bound to one another by a simple or double bond also, and each of them separately or in common can represent the following values: hydrogen atom (H), halogen atom, (C1-C8)-alkyl radical that can be partially or completely substituted with the following groups but preferably with fluorine atom (F), chlorine atom (Cl), N-[CnF(2n+1-x)Hx]2, O-[CnF(2n+1-x)Hx], SO2-[CnF(2n+1-x)Hx] or CnF(2n+1-x)Hx wherein 1 < n < 6 and 0 < x < 2n+1; A- means anion taken among the group consisting of [PFx(CyF(2y+1-z)Hz)6-x]- wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8 and 0 ≤ z ≤ 2y+1. Invention provides the development of ionic liquids showing broad range of liquid state, high thermal resistance and low corrosive activity.

EFFECT: improved and valuable properties of ionic liquids.

3 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to heterocyclic compounds of the formula I, values radicals cm

The invention relates to imidazole derivative of General formula I, where n=0 or 1, R1is hydrogen, alkyl, R2is hydrogen or R2and R3form a double bond, R3is hydrogen, alkyl, R4is hydrogen, alkyl, hydroxy-group, alkoxy, R5is hydrogen or alkyl, or R4and R5form a carboxyl group, R6, R7, R8is hydrogen, alkyl, hydroxy-group, alkoxy, hydroxyalkyl, halogen, X-CHR9-(CHR10)m-, m = 0 or 1, R9and R10is hydrogen or alkyl

The invention relates to products derived from histamine and, in particular, the condensation products of histamine or methylsiloxanes histamine and amino acids, the method of their preparation and use as active principle in areas such as therapy and cosmetology, as well as the factor (agent), improving the stability of compositions used in therapy, cosmetology, agriculture and food industry (region)

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

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

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

28 cl, 10 tbl, 16 ex

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