Anthranilic acid ortho-substituted amides and their using as medicinal agents

FIELD: organic chemistry, biochemistry, pharmacy.

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

wherein R1 represents the following groups:

wherein * means the addition point; R4 means fluorine, chlorine, bromine atom, -CF3, -N=C, -CH3, -OCF3 or -CH2OH; R5 means chlorine, bromine atom or -OCH3; R6 means -CH3 or chlorine atom; R7 means -CH3 or chlorine atom; R8 means -CH3, fluorine, chlorine atom or -CF3; R2 represents pyridyl or group:

or ; R3 represents hydrogen or fluorine atom, and their tautomers, E-isomers or Z-isomers, racemates, enantiomers and salts also that are inhibitors of activity of tyrosine kinase KDR and FLT. Also, invention describes medicinal agents comprising the claimed compounds and designated for treatment of diseases associated with inhibition of activity of kinase KDR and FLT.

EFFECT: valuable biochemical and medicinal properties of compounds.

6 cl, 1 tbl, 30 ex

 

The present invention relates to substituted in anthopology Amida Anthranilic acid and to their use as pharmaceuticals for the treatment of diseases caused by persistent angiogenesis.

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

For the treatment of such diseases, as well as other forms of pathological angiogenesis induced by vascular endothelially growth factor (VEGF), and to eliminate conditions that promote vascular permeability, such as vascularization of tumors, you can use the direct or indirect inhibition of VEGF-receptor. For example, it is known that the use of soluble receptors and antibodies to VEGF can inhibit the growth of tumors.

Persistent angiogenesis, induce is : VEGF-factor the mediator what is its receptor. A necessary condition for VEGF to show this action is its binding to the receptor and initiating phosphorylation by tyrosine.

Today known derivatives phenylanthranilic, which are used as antagonists of angiotensin II (see application EP 564356), as well as inhibitors of inflammation and as an anti-ulcer compounds (see patent US 3409668).

When creating the present invention, it was found that compounds of General formula I

in which R1represents a group

where R5denotes chlorine, bromine or co3or a group

where R7denotes CH3or chlorine, or a group

where R8denotes CH3, fluorine, chlorine or CF3, R4denotes fluorine, chlorine, bromine, -CF3, -N=C, CH3-, -OCF3or-CH2OH, a R6denotes-CH3or chlorine,

R2represents a pyridyl or a group

and R3represents hydrogen or fluorine,

as well as their isomers and salts inhibit tyrosine phosphorylation, respectively persistent angiogenesis and repetitious thereby the growth and spread of tumors.

There are various tyrosine kinase (Web-site: S. Hauk, A. M. Quinn, Meth. in Enzymol. 200, p.38-62 (1991), the link posted in the topic (domain)on the catalysts, the subgroup of RTC group XIV, Web-page: http://www.sdsc.edu/K.inases/pkr/pk_catalytic/pk_hanks_seq_align_long.html and Mc Tigue, and others, Structure 7, pages 319-330 (1999)), which can be suppressed similarly. So, for example, with compounds inhibiting VEGF (vascular endothelial growth factor), usually able to suppress including tyrosinekinase With the present, particularly in stem cells. With regard to the foregoing, understand the desire to get a connection with the election in respect of VEGF inhibiting action.

Proposed in the invention compounds are distinguished precisely by the fact that possess selective properties and are thus valuable compounds capable of inhibiting the growth and spread of tumors.

Compounds according to the invention of General formula I contain also the possible tautomeric forms and include the E - and Z-isomers or in the presence of a chiral center, the racemates and enantiomers.

The compounds of formula I, as well as their physiological acceptable salts, due to their inhibitory activity against the phosphorylation of VEGF receptor can be used as medicines. The mechanism of action allows you to apply offer the e compounds for the treatment of diseases, due to persistent angiogenesis.

Since the compounds of formula I, as defined, are inhibitors of tyrosine kinase KDR and FLT, they are primarily suitable for the treatment of such diseases, which are caused intervalym VEGF-receptor persistent angiogenesis or by increasing vascular permeability.

The object of the present invention in accordance with this is also the application of the proposed compounds as inhibitors of tyrosine kinase KDR and FLT.

Another object of the present invention are hereinafter medicines for the treatment of tumors, according to their application.

Compounds according to the invention can be applied individually or as part of a proper composition as medicines for the treatment of psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, tribomechanically, rejection of transplants and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with proliferation mesangial cells, arteriosclerosis and damage to the nervous tissue.

Compounds according to the invention can the be used to suppress the re-occlusion of vessels after treatment with use of balloon catheter, when prosthetic vessels or after the use of mechanical devices designed to ensure patency of vessels, such as stents.

In the treatment of lesions of the nervous tissue using compounds according to the invention it is possible to prevent the rapid formation of scar tissue in damaged areas, i.e. possible to prevent scarring until the moment when axons again will restore the connection between them. Thus, obviously, there is possibility to restore the links between nerve cells.

In addition, using the proposed in the invention compounds can suppress the formation in patients ascites. Equally it is also possible suppression of edema caused by VEGF.

Medicines the above-mentioned type, their compositions and their use are also the object of the present invention.

The invention relates further to the use of compounds of General formula I to obtain the corresponding medicinal product intended for the treatment of tumors, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, tribomechanically, rejection of transplant is the ATA and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with proliferation mesangial cells, arteriosclerosis and damage to the nervous tissue, to prevent re-occlusion of vessels after treatment with use of balloon catheter, the prosthesis of the vessel or after the use of mechanical devices designed to ensure patency of vessels, such as stents.

For the application of compounds of the formula I in the quality of medicines of them make appropriate pharmaceutical preparation containing in its composition along with the active ingredient for enteral or parenteral administration are suitable for these purposes, pharmaceutical, organic or inorganic inert carriers, such as water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like, the Pharmaceutical preparations can be produced in solid form, for example in the form of tablets, pills, suppositories, capsules, or in liquid form, for example in the form of solutions, suspensions or emulsions. If necessary, they contain, in addition, excipients, such as preservatives, stabilizers, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers.

For parenteral PR is changing primarily suitable injectable solutions or suspensions, first of all aqueous solutions of the active compounds in polyhydroxyserratane castor oil.

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

For oral administration suitable especially tablets, coated tablets or capsules with talc and/or hydrocarbon carrier or binder, as, for example, lactose, corn or potato starch. You can also use liquid form, such as tincture, optionally with the addition of sweeteners.

The dosage of active substances can be varied depending on the method of administration, age and weight of the patient, type and severity of the relevant disease and the like factors. Daily dose of from 0.5 to 2000 mg, preferably from 50 to 1000 mg, and this dose may be administered in a single dose or based on two or more methods.

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

Compounds according to the invention can be obtained by known methods. For example, the compounds of formula I can be obtained due to the fact that

a) connection about the formula II

in which R4-R7have the above values, and T represents H or a protective group and a represents a halogen or or13where R13denotes a hydrogen atom, a C1-C4alkyl or C1-C4acyl or formed with a T ring, first to N-alkylate, and then pass the SOA in the amide and then if necessary otscheplaut protective group or initially transferred to the amide and then N-alkylate, or

b) the compound of formula III,

in which R4-R7have the above values, and T represents H or a protective group, metallinou in anthopology and then by capturing the electrophile transferred to the amide, and then the protective group otscheplaut and amino alkylate, or

C) the compound of formula IV,

in which R4-R7have the above values, and T represents H or a protective group and denotes halogen or O-triflate, O-tosylate or O-mesilate, transferred to the amide, and then the protective group otscheplaut and amino alkylate.

The sequence of carrying out the above operations may in all cases be varied.

The formation of amides are carried out by methods known from the literature. Thus, in particular, for the formation of amides can come from the corresponding complex EPE is and. This ester is subjected according Journ. Org. Chem. page 8414 (1995) interaction with trimethylaluminum and an appropriate amine in solvents such as toluene, at temperatures between 0°C to the boiling point of the used solvent. This method is applicable also in the case of unprotected esters of Anthranilic acid. If the molecule contains two ester groups, they both translate to the same amide.

When using instead of ester NITRILES get in similar conditions amidine.

For the formation of amides can also be used all methods known from the chemistry of peptides. For example, the corresponding acid can be subjected to in aprotic polar solvents, such as dimethylformamide, using the appropriate activated acid derivative, obtained, for example, using hydroxybenzotriazole and a carbodiimide, such as diisopropylcarbodiimide, or using the pre-generated reagents, such as GATA (Chem. Comm. p. 201 (1994)) or BTU, at temperatures in the range from 0°C to the boiling point of the solvent, preferably at 80°and interaction with the amine (using GATA preferably at room temperature). These methods are also applicable in the case of unprotected Anthranilic acid. For established what I amides can also be used a method where to use the mixed acid anhydride, imidazole or azide.

Pre-protection of amino groups, such as amide, is not mandatory in all cases, however, it is better to provide such protection, because it has a positive effect on the reaction. Special source material are the anhydrides isatool acid, which simultaneously presents and a protected amino group and an activated acid functional group.

If Amin pre-translate SIDEWAYS-secure connection, the metallation in anthopology can be accomplished by interaction with ORGANOMETALLIC compounds, such as n-utility, and then capture reaction with isocyanates or isothioscyanates to turn in anthranilamide, respectively anthranilamide. Use this orthopaedie this Vice, as bromine or iodine, by sharing the halogen-metal to more effectively carry out autometallography. As solvents for these reactions can be used ethers such as diethyl ether or tetrahydrofuran, or hydrocarbons, such as hexane, and mixtures thereof. It is advisable to add at this complexing agents, such as tetramethylethylenediamine (TMEDA). Temperature varies in the interval for the Les from -78° With up to room temperature. Cleavage of the SIDE-amides carried out by the action of acids, such as triperoxonane acid, without the use of solvents or in solvents such as methylene chloride, at temperatures in the range from 0°C to the boiling point of the solvent or by using aqueous hydrochloric acid, preferably 1 N. hydrochloric acid, in solvents such as ethanol or dioxane, at temperatures in the range from room temperature up to the boiling point of the solvent.

The amide group can be entered by carbonylation. To this end extend from the corresponding compounds of formula IV (iodine-, bromine - or-triglycerine), which is subjected to interaction with carbon monoxide at normal or increased pressure and with an amine in the presence of catalysts based on transition metals, such as palladium(II) chloride or palladium(II) acetate or palladianatravertin, in solvents, such as dimethylformamide. It may be appropriate to add a ligand, such as triphenylphosphine, and adding a base, such as tributylamine (see, for example, Journ. Org. Chem., page 3327 (1974); Journ. Org. Chem., page 7482 (1996); Synth. Comm., page 367 (1997); Tetr. Lett, p. 2835 (1998)).

If provides for the introduction into the molecule of the various amide groups, it is necessary, for example, the second ester groups is to introduce into the molecule after the formation of the first amide group and then lidirovat or in the case of molecules, in which one group is presented in the form of ester, and the other in the form of acids, both groups lidiruyut sequentially using different methods.

Thioamides can be obtained from anthranilamide interaction with dephosphatation according to Bull. Soc. Chim. Belg. 87, page 229 (1978) or by interaction with pentasulfide phosphorus in solvents such as pyridine, or without solvents at temperatures in the range from 0 to 200°C.

Products in the form of electron-rich aromatic compounds can also be electrophilic aromatic substitution. Substitution in these cases is carried out in ortho - or paraprotein relative to the amino groups or one amino group. Thus, in particular, it is possible to carry out the acylation according to Friedel-Crafts with acid anhydrides in the presence of catalysts of the Friedel-such as trichloride aluminum, in solvents such as nitromethane, carbon disulfide, methylene chloride or nitrobenzene, at temperatures in the range from 0°C to the boiling point of the used solvent, preferably at room temperature. By known literature methods, for example using nitrious acid, nitric acid in various concentrations without the use of solvents or using a nitrate of the metals, such as nitrate m is di(II) or iron nitrate(III), in polar solvents, such as ethanol or glacial acetic acid, or acetanhydride you can enter one or more nitro groups.

Halogen is injected by known literature methods, for example the exchange reaction with bromine, N-bromo - or N-iodosuccinimide or hydrotribromide urotropine in polar solvents, such as tetrahydrofuran, acetonitrile, methylene chloride, glacial acetic acid or dimethylformamide.

The restoration of the nitro group is carried out in polar solvents at room temperature or at elevated temperature. As catalysts for the recovery of suitable metals, such as Raney Nickel, or catalysts based on noble metals such as palladium or platinum, and palladium hydroxide, optionally deposited on the media. Instead of hydrogen in a known manner can also be used, for example, ammonium formate, cyclohexene or hydrazine. Equally you can use and reductants such as tin chloride(II) or chloride titanium(III), as well as such as complex metal hydrides, optionally in the presence of salts of heavy metals. As a reducing agent acceptable to the iron. In these cases, the reaction is carried out in the presence of an appropriate acid, such as acetic acid, or ammonium chloride, with optional add is the group of solvent, such as water, methanol, iron/ammonia, etc. With a longer duration of response in this embodiment may begin the acylation of the amino group.

If there alkylation of an amino group, this group can be alkilirovanii by conventional methods, for example by alkylhalogenide, or under option Mitsunobu (Mitsonubo) interaction with the corresponding alcohol in the presence of, for example, triphenylphosphine and ester of azodicarboxylic acid. There is another approach, namely to expose Amin reductive alkylation with aldehydes or ketones, carrying out this reaction in the presence of a reducing agent, such as cyanoborohydride sodium, in an appropriate inert solvent, for example ethanol, at temperatures between 0°C to the boiling point of the solvent. If we proceed from primary amino groups, the reaction may be carried out if necessary with sequential use of two different carbonyl compounds, while receiving mixed derivatives [see, for example, Verardo, etc., Synthesis, p.121 (1993); Synthesis, str (1991); Kawaguchi, Synthesis, str (1985); Micovic and other Synthesis, str (1991)]. It may be appropriate to and a variant in which the first interaction of the aldehyde with the amine in solvents such as ethanol or methanol, optionally with the addition of auxiliary substances such to the to the glacial acetic acid, form chiffolo basis and only after that add a reducing agent, such as cyanoborohydride sodium.

Hydrogenation alkenovich or alkenovich groups in the molecule carried out in the usual manner, for example by means of catalytically activated hydrogen. As catalysts may apply heavy metals, such as palladium or platinum, optionally deposited on a suitable carrier, or Raney Nickel. As solvents suitable alcohols, such as ethanol. While working at temperatures in the range from 0°C to the boiling point of the used solvent and at a pressure up to 20 bar, preferably, however, operate at room temperature and normal pressure. Thanks to the use of catalysts, such as Lindlar catalyst, a triple bond is able to partially gidrirovanii to double bonds with the preferred formation of a Z-shape.

The acylation of the amino group carried out in the usual way, for example the corresponding acid halide or acid anhydride, optionally in the presence of a base, such as dimethylaminopyridine, in solvents such as methylene chloride, tetrahydrofuran or pyridine, according to the variant of Schotten's-Bauman in aqueous solution at alkaline pH-value, or interaction with ACC is stoysin anhydride in glacial acetic acid.

The introduction of Halogens - chlorine, bromine, iodine or azide group with the amino group can also be carried out, for example, by the reaction of Sandmeyer interaction salts, page formed by using nitrite as an intermediate product, with chloride of copper(I) or copper bromide(I) in the presence of an appropriate acid, such as hydrochloric acid or Hydrobromic acid, or by interaction with potassium iodide.

In the case of using the organic ether nitrous acid, the halogen can be entered, for example, by adding methylaniline or tetrabromomethane in a solvent, such as dimethylformamide. Removal of the amino group, there are two possibilities: either the interaction with the organic ether nitrous acid in tetrahydrofuran or diazotization and restorative cooking diazonium salts, for example, using phosphorous acid, optionally with the addition of copper oxide(I).

Fluorine can be entered, for example, by the reaction of Balsa-Shiman using tetrafluoroborate the page or under Journ. Fluor. Chem. 76 (1996), pages 59-62, by diazotization in the presence of HF x pyridine and subsequent cooking, optionally in the presence of a fluoride ion source, such as tetrabutylammonium fluoride.

Introduction sidegroup can be done after the diazotization interaction with the azide is m sodium at room temperature.

The simple removal of the ether is carried out by known literature methods. Thus in the case of the presence in the molecule of several groups can be achieved by selective cleavage. For these purposes, the ether is treated with, for example, tribromide boron in solvents such as dichloromethane, at temperatures in the range from -100°C to the boiling point of the used solvent, preferably at -78°C. however, there is another approach, namely to split the ester under the action of timedelta sodium in solvents, such as dimethylformamide. The temperature may be in the range from room temperature up to the boiling point of the solvent, it is preferable to operate at 150°C.

N - or O-alkylation of amides, such as pyridine-2-it 2-hydroxypyridine, carried out by methods known from the literature. Thus, in particular, when using bases, such as sodium hydride or potassium carbonate, in solvents such as dimethylformamide, and alkylation with alkylhalogenide, such as methyliodide provide N-alkylation. When using such basis as silver carbonate, in solvents such as tetrahydrofuran or toluene, or preferably mixtures thereof with alkylhalogenide, such as methyliodide provide O-alkylation. O-alkylation can be ensured that the same interaction with tetrafluoroborate trialkylamine in inert solvents, such as methylene chloride. Interaction with diazomethane or trimethylsilyldiazomethane in solvents, such as methanol or toluene, preferably in their mixtures, at temperatures up to the boiling point of the solvent, preferably, however, at room temperature, to obtain a mixture of N - and O-alkyl derivatives. These methods allow for the selective alkylation of the pyridone unlike benzoic acid amide.

Mixture of isomers using conventional methods, for example by crystallization, chromatography or salt formation can be divided into enantiomers, respectively, E/Z-isomers.

The process of obtaining salts carried out in the usual manner, namely:

a solution of the compounds of formula I is mixed with an equivalent amount or an excess of the appropriate base or acid, it is not necessarily presented in dissolved form, and the formed precipitate was separated or solution is subjected to normal processing.

In the following examples in more detail, explains the formation of compounds according to the invention is characterised by the selective action.

Example 1

Amide N-[2-oxo-2H-1-benzopyran-3-yl]-2-[(4-pyridyl)methyl]aminobenzoic acid

1. 484 mg of 3-amino-2-oxo-2H-1-benzopyran previously placed in 20 ml of methylene chloride, then with ice cooling is added dropwise at 0.42 ml triethylamine and 0.40 ml of 2-nitrobenzotrifluoride. Then for 4 h and stirred at room temperature, the solvent is distilled off, the residue is dissolved in sodium hydrogen carbonate solution and the resulting product is separated by vacuum filtration. The result is 0.88 g of amide N-[2-oxo-2H-1-benzopyran-3-yl]-2-nitrobenzoic acid. The above 3-amino-2-oxo-2H-1-benzopyran was obtained according to the method Bonsignore and Loy described in Journ. Heterocyclic Chem. 35, str (1998), from 2-oxo-2H-1-benzopyran-3-carboxylic acid (Journ. Org. Chem. 64, str-1035 (1999)).

2. 880 mg of amide N-[2-oxo-2H-1-benzopyran-3-yl]-2-nitrobenzoic acid pre-placed in a nitrogen atmosphere in 30 ml of ethanol, and then mixed with 11 ml of cyclohexene and 176 mg of palladium hydroxide on charcoal, and in the course of 2 hours and stirred at 110°C. Then the catalyst is filtered off and the filtrate is concentrated almost to dryness. The resulting product is separated by vacuum filtration, to deliver 593 mg of amide N-[2-oxo-2H-1-benzopyran-3-yl]-2-aminobenzoic acid.

3. 645 mg of amide N-[2-oxo-2H-1-benzopyran-3-yl]-2-aminobenzoic acid in 50 ml of methanol and 170 ml of glacial acetic acid pre-placed in the reactor at room temperature, and then mix from 0.38 ml of 4-pyridinecarboxamide. The mixture is stirred for 15 h and then mixed with 206 mg of cyanoborohydride sodium. Then continue stirring for 24 h, and education is ovaries crystals is separated by vacuum filtration. These crystals are mixed with 70 ml of methanol, 40 ml of glacial acetic acid and 95 μl of 4-pyridinecarboxamide and stirred for 48 hours After that add 57 mg cyanoborohydride sodium and stirring is continued for 15 hours the Resulting product is separated by vacuum filtration, washed with methanol and dried. The result 521 mg of amide N-[2-oxo-2H-1-benzopyran-3-yl]-2-[(4-pyridyl)methyl]aminobenzoic acid with a melting point 195-197°C.

Example 2

Amide N-[6-chlorinator-5-yl]-2-[(4-pyridyl)methyl]aminobenzoic acid

194 mg of 0.85 mmole) of 2-(4-pyridylmethyl)aminobenzoic acid are mixed in 8 ml of dimethylformamide with 283 mg (1,69 mmole) of 5-amino-6-chlorendate. To this solution in an argon atmosphere and without access of moisture added 215 mg (2.13 mmole) N-methylmorpholine and 386 mg (1,02 mmole) of hexafluorophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium. This mixture is stirred for 4 h at room temperature, then diluted with about 40 ml of water and extracted three times with ethyl acetate portions to 30 ml Combined organic phase is washed with water, dried, filtered and concentrated. The remainder chromatographic on silica gel using as eluent a mixture of methylene chloride/ethanol in a ratio of 10:1. The result is 97 mg (30,2% of theory) of amide N-[6-chlorinator-5-yl]-2-[(4-pyridyl)methyl]aminobenzoic key is lots with a melting point 222,8° C.

A similar technique also receive the following compounds of formula

In the following examples in more detail, explains the biological action proposed in the invention compounds with selective properties and their application.

Used in the experiments solutions

The original solutions:

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

the original solution B: g-R-ATP (1 MCI/100ð¼ðºð",

source solution: poly(Glu4r) 10 mg/ml in water.

The solution for dilutions:

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

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

Example application 1

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

In tapering at the ends titration microplate (without binding protein) add 10 ál of nutrient mixture (initial solution volume of 10 μl ATP + 25 µci g-R-ATP (approximately 2.5 ál of solution B) + source solution: 30 ál poly(Glu4r) + 1,21 ml solvent substrates), 10 μl of inhibitor solution (compounds in accordance with the dilutions, as control is 3%solution of DMSO in the solvent substrates) and 10 μl of p is the target enzyme of 11.25 µg initial solution of the enzyme (kinase KDR or FLT-1), divorced with 4°With 1.25 ml of an enzyme solution). These ingredients are thoroughly mixed and incubated for 10 min at room temperature. Then add 10 ál of stop solution (250 mm add, pH 7.0), mix and 10 μl of the solution is transferred to phosphocellulose filter type P 81, and then washed several times in 0.1-molar phosphoric acid. Filter paper is dried, cover with a layer of Meltilex and with the help of microscience beta particles measured radioactivity.

IC50values represent the values defined by the concentration of inhibitor required to inhibit the incorporation of phosphate by 50% from its embedding in the absence of inhibitor, minus the control values obtained in the result of blind experience (reaction stopped using etc).

Results inhibition of kinase IC50in microns presented in the table below.

Example application 2

The experiment for the determination of inhibition of kinase activity of selected receptor C-Kit

The original solutions:

solvents for 10 portions: 400 mm HCl, pH 7.5; 10 mm DTT, 10 mm manganese chloride, 100 mm magnesium chloride,polyethylene glycol 20000;

inhibitors: 2 mm in dimethyl sulfoxide;

the original substrate solution: 3 mg/ml poly(Glu4r)nSigma P275 in water, frozen components;

the original Rast is the PR ATP: 37.5 mm ATP in water with pH, installed 7.5 and frozen components;

A 100-fold solution of Vanadate 1 mm sodium Vanadate in water;

stop solution: 250 mm ethylenediaminetetraacetic acid (edtc), pH 7.0;

wash solution for the filter of 0.5%phosphoric acid.

Solutions for analysis:

solutions of substrates for 125 tests:

10 μl of ATP (to 37.5 μm), 25 µci γR-ATP (˜+2,5 ál solution Amersham redivue solution) and 10 μl of poly(glu, tyr) is mixed with 1.23 ml of solvent (once);

the inhibitor solution:

compounds are dissolved in the solvent (once), leading to the desired concentration;

the enzyme solution:

the appropriate preparation of the enzyme is dissolved with a solvent (once) to the desired concentration, bringing the amount to 1.24 ml, then added to 12.5 μl of a solution of sodium Vanadate.

Analysis

Components carry on tetrazinni the microplate with round or petechial holes in the following sequence: 10 μl of inhibitor in triple final concentration and 10 μl of a mixture of substrates, and after mixing them initiate the reaction by adding 10 μl of the enzyme preparation.

The mixture is incubated for 10 min and then incubated stopped by adding 10 μl of stop solution. Next, 10 μl processed in this way the mixture is transferred to phosphocellulose filter, washed in phosphoric acid, then dried, after CEG is melted in the scintillator mentilex and conduct measurements.

ExampleKDR

IC50(µmol/l)
C-Kit IC50(µmol/l)
10,0036
20,2>10
30,038
40,03>10
50,01>10
60,210
70,2>10
90,0410
100,01>10
111>10
130,055
140,0015
150,0022
17JOI>10
260,0012
280,050,5
290,2>10
300,0210
Note: OI means "lack of inhibition".

1. Compounds of General formula I

in which

R1/sup> represents a group

where * denotes the attachment point,

R4denotes fluorine, chlorine, bromine, -CF3, -N=C, CH3-, -OCF3or-CH2OH,

R5denotes chlorine, bromine or co3,

R6denotes-CH3or chlorine,

R7denotes CH3or chlorine,

R8denotes CH3, fluorine, chlorine or CF3,

R2represents a pyridyl or a group

and R3represents hydrogen or fluorine,

as well as their tautomers, E-isomer or Z-isomers, racemates, enantiomers and salts.

2. Drug, possess inhibitory activity against kinases KDR and FLT, containing in its structure at least one connection on p. 1 and a pharmaceutically acceptable carrier.

3. Drug under item 2, having inhibitory activity against kinases KDR and FLT and intended for the treatment of tumors, psoriasis, arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetics the traveler nephropathy, malignant nephrosclerosis, tribomechanically, rejection of transplants and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, diseases associated with proliferation mesangial cells, arteriosclerosis and damage to the nervous tissue, to prevent re-occlusion of vessels after treatment with use of balloon catheter, the prosthesis of the vessel or after the use of mechanical devices designed to ensure patency of vessels, such as stents.

4. Connection on p. 1 intended to receive medicines at PP. 2 and 3.

5. The compounds of formula I on p. 1, characterized in that they are inhibitors of tyrosine kinase KDR and FLT.

6. Compounds of General formula I under item 1 as an active substance that inhibits tyrosine kinase KDR and FLT, as part of a pharmaceutical preparation for enteral, parenteral and oral administration.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: claim describes substituted anthranylamides of the general formula (I): wherein A means group =NR7; W means oxygen atom; D, E, F, G, X, Z, R1, R2, R7 and R9 have values given in the description and their isomers and salts also. Also, claim describes intermediate compounds used in preparing indicated anthranylamides. Also, invention relates to medicinal agents, their compositions and their using. Proposed compounds can be used in treatment of diseases associated with persistent angiogenesis that can be cause of different diseases, such as psoriasis, arthritis, for example, rheumatic arthritis, hemangioma, angiofibroma, ophthalmic diseases, for example, diabetic retinopathy, neovascular glaucoma, kidney diseases, for example, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombosis microangiopathy, rejection of transplants and glomerulopathy, fibrosis diseases, for example, hepatic cirrhosis, diseases associated with proliferation of mesangial cells and arteriosclerosis that can result to progression of these diseases. Invention provides the development of the corresponding medicinal agent designated for treatment of abovementioned diseases. The development of the preparation allows expanding assortment of agents used in treatment of such diseases.

EFFECT: valuable medicinal properties of compounds.

FIELD: organic chemistry, medicine, pharmacy.

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

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

33 cl, 7 tbl, 42 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: pharmaceutical chemistry, medicine.

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

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

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

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 6-alkyl-5-(2-isonicotinoylsulfohydrazoyl)uracil hydrochlorides of the general formula (I) wherein R means alkyl comprising 1-4 carbon atom. Compounds possess an anti-mycobacterial and an immunotropic activity and can be used as an immunomodulating agent and an anti-mycobacterial agents. Also, invention relates to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds.

4 cl, 10 tbl, 2 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to compounds represented by the formula (Ia) and compositions used in treatment of gastroenteric diseases based on thereof and their complexes being optionally in combination with compounds of the formula (Ib) . Also, invention describes pharmaceutical preparations and methods for their preparing these compounds. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

28 cl, 115 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: claim describes substituted anthranylamides of the general formula (I): wherein A means group =NR7; W means oxygen atom; D, E, F, G, X, Z, R1, R2, R7 and R9 have values given in the description and their isomers and salts also. Also, claim describes intermediate compounds used in preparing indicated anthranylamides. Also, invention relates to medicinal agents, their compositions and their using. Proposed compounds can be used in treatment of diseases associated with persistent angiogenesis that can be cause of different diseases, such as psoriasis, arthritis, for example, rheumatic arthritis, hemangioma, angiofibroma, ophthalmic diseases, for example, diabetic retinopathy, neovascular glaucoma, kidney diseases, for example, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombosis microangiopathy, rejection of transplants and glomerulopathy, fibrosis diseases, for example, hepatic cirrhosis, diseases associated with proliferation of mesangial cells and arteriosclerosis that can result to progression of these diseases. Invention provides the development of the corresponding medicinal agent designated for treatment of abovementioned diseases. The development of the preparation allows expanding assortment of agents used in treatment of such diseases.

EFFECT: valuable medicinal properties of compounds.

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

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