UA81323C2 - Anthranylamide pyridones that inhibit vegfr-2 and vegfr-3 - Google Patents

Abstract

The invention relates to selected anthranylamide pyridones that inhibit VEGFR-2 and VEGFR-3 and to their use as medicaments for treating diseases that are triggered by persistent angiogenesis.

Description

Description of the invention

The present invention relates to new anthranilamidopyridones, which have an inhibitory effect on MESEK-2 and MESEK-3, and their 2 use as drugs for the treatment of diseases caused by persistent angiogenesis.

Persistent angiogenesis (development of blood vessels) can be the cause or prerequisite for the development of various diseases, such as tumor growth or metastases, psoriasis, arthritis, for example, rheumatoid arthritis, hemangioma, angiofibroma, eye diseases, for example, diabetic retinopathy, neovascular glaucoma, kidney disease, eg glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome 70, transplant rejection and glomerulopathy, fibrotic diseases such as liver cirrhosis, associated with mesangial cell proliferation disease and arteriosclerosis, or may lead to the progression and complication of these diseases.

Persistent angiogenesis is induced by the MESE factor (from the English "mazsiag epdoiNeiiai dhomly Tasog", vascular endothelial growth factor) through its receptor. The MESE factor must bind to its receptor and initiate tyrosine phosphorylation in order for it to exert such an effect.

Direct or indirect inhibition of the MECE-factor receptor can be used to treat similar diseases and other MECE-induced pathological angiogenesis, as well as neovascularization-related conditions, such as tumor vascularization. So, for example, it is known that tumor growth can be inhibited with the help of soluble receptors and antibodies to the MESE factor.

From (UMO application 00/27820 (see, in particular, example C38)) anthranilamidopyridonamides are known, which are used as drugs for the treatment of psoriasis, arthritis such as rheumatoid arthritis, hemangiomas, angiofibromas, eye diseases such as diabetic retinopathy and neovascular glaucoma , kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy, fibrotic diseases, such as liver cirrhosis, associated with mesangial cell proliferation diseases, arteriosclerosis, nerve tissue damage, and also for Ge) suppression of repeated occlusion of vessels after treatment with the use of a balloon catheter, during vascular prosthetics or when using, respectively, the introduction of mechanical devices, such as, for example, stents, to maintain vascular patency.

The compounds known from (application MUO 00/27820|) are generally effective for the above indications, but their effectiveness is rather weak.

In addition, from the application MUO 03/0401021, anthranilic acid amides are known, which, despite their rather high efficiency, also have a pronounced inhibitory effect on the ZA4 isoenzyme of cytochrome P 450. The ZA4 isoenzyme of cytochrome P 450 is one of the important metabolic enzymes under the influence of which decomposition of medicinal substances. Inhibition of this enzyme leads to undesirable drug-drug interactions, primarily in multimorbid patients (suffering from several diseases). Another disadvantage inherent to these known compounds is that when they are used in combined treatment with other medications, increased toxicity is observed, which is due to the inhibition of the decomposition of these compounds in the patient's body and the associated too high level of them in the serum. "

Taking this into account, there is a need for active substances that, on the one hand, would have good C efficiency, and on the other hand, would have superior tolerability, accordingly, would not have any unwanted side effects.

From" During the creation of the invention, it was established that the compounds of the general formula I (ee) - (95) with 50 syu"

F) name) 60 b5

: () and p

X Y

AND

"x and Tr (0),

MN

"h

M o s » in which (o)

A stands for aryl or heteroaryl,

X stands for hydrogen or fluorine,

B" and B" independently of each other mean hydrogen, halogen, C.4-Sioalkyl, C.41-Sioalkyloxy-C.4-C.alkylene, C.sub.2 halo-C.sub.Siroalkyl, C.sub.3-Socycloalkyl or halo-C.sub.3-Socycloalkyl, and

U means a bond or oxygen or a group -5-, -5(0)- or -505-, c as well as their isomers, enantiomers, diastereomers and salts make it possible to eliminate the above disadvantages. with

Alkyl in the context of this description in each case means a straight or branched chain alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, -- c5-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl. co

Alkoxy, in the context of this description, in each case means a straight or branched chain alkoxy residue such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy group, decyloxy group, " undecyloxy group or dodecyloxy group. By cycloalkyl in the context of this description is meant monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, but also bicyclic or tricyclic rings, such as, for example, adamantanyl .

Cycloalkyl residues may contain one or more heteroatoms, such as an oxygen, sulfur and/or nitrogen atom, instead of one or more carbon atoms, respectively. Similar heterocycloalkyl groups with

Go! 3-8 ring atoms.

Halogen in each case means fluorine, chlorine, bromine or iodine. - Haloalkyl refers to an alkyl residue mono- or polysubstituted by halogen atoms. 2) The aryl residue in each case has from 3 to 12 carbon atoms and in each case can be condensed with the benzene nucleus. Examples of aryl residues include cyclopropenyl, where cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl 4) and others.

The heteroaryl residue in each case has from 3 to 16 atoms in the ring and instead of one or more carbon atoms, it can contain in the ring, respectively, one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur, and can also be mono-, bi - or tricyclic and can additionally be condensed with a benzene nucleus in each case. As an example, thienyl, furanyl, pyrrolyl, (F) oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., as well as their benzo derivatives, such as, for example, benzofuranyl , benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. but also their benzo derivatives, such as, for example, quinolyl, isoquinolyl, etc., or azocinyl, indolizinyl, purinyl, etc. and their obenzo derivatives or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl and others.

If the compounds proposed in the invention have an acidic functional group, it is possible to form their 65 physiologically compatible salts with organic and inorganic bases, for example, well-soluble salts with alkali and alkaline earth metals, as well as salts with M-methylglucamine, dimethylglucamine,

ethylglucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, Sovak's base and 1-amino-2,3,4-butanetriol.

If the main functional group is present in the compounds proposed in the invention, it is possible to form their physiologically compatible salts with organic and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, and others.

Special properties are those compounds of the general formula I in which

A means phenyl or pyridyl,

X represents hydrogen or fluorine, 70 B" and B? independently of each other represent hydrogen, halogen, C.4-C.alkyl, C.4-Sioalkyl-C.4-C.sub.alkylene, halo-C.4-C.alkyl, C.3-C.sub.cycloalkyl or halo-C.sub.3 -S.ocycloalkyl, a

M means a bond or oxygen or the group -5-, -5(0)- or -5O 5-, including their isomers, enantiomers, diastereomers and salts.

Compounds of particular interest include those compounds of general formula I in which A is 75 phenyl, X is hydrogen or fluorine, B and B? independently of each other mean hydrogen, halogen, S.-S.halkyl,

C.-C.2-Alkoxy-C.4-C.alkylene, halo-C.4-Sialkyl, C.sub.3-Siocycloalkyl or halo-C.3-C.ocycloalkyl, and

M means a bond or oxygen or the group -5-, -5(0)- or -5O 5-, including their isomers, enantiomers, diastereomers and salts.

Preferable are those compounds of the general formula I in which

A means phenyl,

X stands for hydrogen,

B" and B" independently of each other mean hydrogen, halogen, C.4-C.alkyl, C.4-C-oalkoxy-C-C.oalkylene, halo-C.4-C.alkyl, C.sub.3-Cocycloalkyl or halo-C.3- Sopycloalkyl, a

M means a bond or oxygen or the group -5-, -5(0)- or -50 25-, including their isomers, enantiomers, CM diastereomers and salts. at

The compounds of general formula I proposed in the invention include all their possible tautomers and, in addition to them, E- or 7-isomers, as well as - if they have a chiral center - racemates and enantiomers.

Compounds of formula I, as well as their physiologically compatible salts, due to their inhibitory effect on the phosphorylation of the MESE-factor receptor can be used as medicinal products. The compounds proposed in the invention, taking into account the profile of their action, are suitable for the treatment of diseases caused by or stimulated by persistent angiogenesis.

Compounds of formula I, since they are inhibitors of the tyrosine kinases COC, RI T-1 and RI T-4, are primarily suitable for co-treatment of those diseases, the cause of which is or the development of which is facilitated by persistent angiogenesis, initiated through the "- receptor of the MECE factor, or increased degree of vascular neoplasm.

The object of this invention is also the use of the compounds proposed therein as inhibitors of tyrosine kinases d)

KOK, RIT-1 and R! tT-4.

According to this, another object of this invention is also drugs for the treatment of tumors, accordingly, the use of similar drugs for the specified purposes. "

The compounds proposed in the invention can be used either individually or in the composition of a suitable preparation as drugs for the treatment of tumor growth or metastases, psoriasis, Kaposi's sarcoma, restenosis, etc. such as restenosis induced by the use of a stent, endometriosis, Crohn's disease, h Hodgkin's, leukemia, arthritis such as rheumatoid arthritis, hemangiomas, angiofibromas, eye diseases such as diabetic retinopathy and neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver, associated with the proliferation of mesangial cells (ee) diseases, arteriosclerosis, damage to nervous tissue, to suppress repeated occlusion of vessels after - treatment with the use of a balloon catheter, during vascular prosthetics or after the use, respectively, of the introduction of mechanical devices, still x, for example, as stents, to maintain vascular patency, as well as immunosuppressants, as adjuncts that promote scarless wound healing, age spots and contact dermatitis.

In the treatment of nerve tissue damage using the compounds proposed in the invention, it is possible to prevent rapid scarring in damaged areas, that is, scarring can be prevented until the connection between axons is restored. Due to this, as is obvious, the restoration of nerve paths and connections is facilitated. 22 With the help of the compounds proposed in the invention, it is also possible to inhibit the formation of ascites in patients. Similarly, with the help of the compounds proposed in the invention, it is possible to suppress edema caused by

MESA-factor. where Lymphangiogenesis plays an important role in lymphogenic metastasis | see T. Kagrapep and others, Sapseg Kev. for March 1, 2001, 61(5), pp. 1786-1790, T. MeiKKoia and others, EMVO.). for March 15, 2001, 29(6), pp. 1223-12311. 60 The compounds proposed in the invention also exhibit exceptionally high activity as MESEK-kinase 3 inhibitors and therefore can also be effectively used as effective inhibitors of lymphangiogenesis. Treatment using the compounds proposed in the invention allows to reduce not only the growth of metastases, but also their number.

Similar medicinal products, compositions containing them, and their use are also objects of this invention. 65 Accordingly, this invention also relates to the use of compounds of the general formula | for obtaining a medicinal product used for therapeutic purposes in psoriasis, Kaloshi sarcoma, restenosis,

such as, for example, stent-induced restenosis, endometriosis, Crohn's disease, disease

Hodgkin's, leukemia, arthritis such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy and neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy, fibrotic diseases , such as cirrhosis of the liver, diseases associated with the proliferation of mesangial cells, arteriosclerosis, damage to nervous tissue, to inhibit re-occlusion of vessels after treatment with a balloon catheter, during vascular prosthetics or the use, respectively, of the introduction of mechanical devices, such as, for example, stents , to maintain vascular patency, and/or as immunosuppressants, as adjuncts that promote scarless wound healing, age spots and contact dermatitis.

In addition, with the help of the compounds proposed in the invention, it is possible, as mentioned above, to inhibit the formation of ascites in patients. Similarly, with the help of the compounds proposed in the invention, it is possible to suppress edema caused by the MESE factor.

The compounds of formula I proposed in the invention for their use as medicinal products are converted into the form of a pharmaceutical preparation, which, together with the active substance, also contains pharmaceutical organic or inorganic inert carriers suitable for enteral or parenteral use, such as, for example, water, gelatin, gum arabic, lactose , starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and others.

Such pharmaceutical preparations can be presented in solid form, for example, in the form of tablets, dragees, suppositories or capsules, or in liquid form, for example, in the form of solutions, suspensions or emulsions. If necessary, pharmaceutical preparations can also include various auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for regulating osmotic pressure or buffers.

For parenteral use, primarily solutions for injections or suspensions, preferably aqueous solutions of biologically active compounds in polyhydroxyethoxylated castor oil, are suitable.

Surface-active auxiliary substances can also be used as carriers, for example, salts of bile and) acids, or phospholipids of animal or vegetable origin, their mixtures, as well as liposomes or their components.

For oral use, tablets, dragees or capsules with talc and/or hydrocarbon carriers or binders, such as lactose, corn starch or soso potato starch, are primarily suitable. For oral administration, liquid dosage forms can also be used, for example, in the form of a mixture, to which a sweetener is optionally added, or, if necessary, with one or more flavoring substances. co

The dose of active substances prescribed to the patient may vary depending on the route of their introduction into the body, the age and weight of the patient, the type and severity of the disease to be treated, and other similar factors. Usually, the daily dose is from 0.5 to 100 Ωg, preferably from 50 to 20 Ωg, and can be calculated for a single dose up to a day or for taking twice or more times a day.

The compositions and dosage forms described above are also an object of this invention.

The compounds proposed in the invention are obtained by methods that are known in principle. So, for example, to obtain compounds of the general formula | compound of the general formula II « - c (1) : c» X o

WITH

' so about her (1), (95) mu 0 МН, syu" in which X has the specified for the general formula | value, and K X stands for hydrogen or S.--Svalkil, first

They are subjected to hydroamination, obtaining a compound of the general formula HER

F) name) 60 b5

XX in o tho (PI)

MN, eh ko

M o

H which is then converted into the corresponding amide of the general formula !, after which the obtained compounds of the general formula I are optionally oxidized to sulfur compounds. The stages described above can also be carried out in the reverse sequence, while KH in the original compound should preferably mean S.-Svalkil. If KH means o

S.-Sralkil, then the starting compound can optionally also be first subjected to saponification, and then converted into the corresponding amide.

Hydroamination is carried out using aldehydes or ketones, carrying out the reaction in the presence of a reducing agent, for example, sodium cyanoborohydride, in an acceptable inert solvent, for example, ethanol, at a temperature in the range from 09C to the boiling point of the solvent. In some cases, the addition of acids, for example, glacial acetic acid, may be useful. The specified sequence of reactions can be carried out in one reaction vessel. However, sometimes it may be preferable to first isolate the formed i) amine, and then at a separate stage subject it to reduction, for example, with sodium borohydride, in solvents, "- for example, acetonitrile.

The process of amide formation is carried out according to methods known from the literature. So, for example, for the formation of amide 90, a suitable ester can be used as a starting compound. This complex ether is based on the method described in Doygp. Ogud Spet., 1995, p.8414), react with trimethylaluminum and the corresponding amine in solvents, for example, toluene, at a temperature in the range from 0C to the boiling point of the solvent used. If there are two ester groups in the molecule, both of these groups are converted into the same amide.

Sodium hexamethyldisilazide can also be used instead of trimethylaluminum. At the same time, all methods known from the chemistry of peptides can be used for the formation of amide. Thus, in particular, the corresponding acid can first be converted into its activated derivative, obtained, for example, by reaction with hydroxybenzotriazole and a carbodiimide, such as diisopropylcarbodiimide, and then subjected to reaction with an amine in aprotic polar solvents, such as dimethylformamide, at a temperature in the range from 0 9C to the boiling point of the solvent used, preferably at 809. However, the reaction between carboxylic acid and amine can also be carried out with the help of activating reagents, such as GATU (M-oxide - hexafluorophosphate M-dimethylamino-1H-1,2,3-triazol -|(4,5-v|Ipyridin-1-ylmethylene|-M-methylmethanammonium), while polar aprotic solvents such as dimethylformamide are suitable for this reaction.In this case, a base such as M-methylmorpholine must be added. The reaction takes place at a temperature of 250°C in the range from 0 to 1002. For the formation of the amide, methods that involve the use of acid halides, mixed anhydrides are also suitable acid, imidazolide or azide. The preliminary protection of an additional amino group, represented, for example, in the form of an amide, is not required in all cases, but it can affect the reaction.

The process of sulfur oxidation is carried out according to methods known from the literature. Thus, in particular, a sulfur compound can be reacted with an oxidizing agent, such as m-chloroperbenzoic acid, in solvents, for example, in

HF) dichloromethane, resulting in a mixture of sulfoxide and sulfone. Hydrogen peroxide in solvents, for example, glacial acetic acid, can also be used as an oxidant. It is also possible to oxidize with sodium periodate in the presence of ruthenium trichloride in solvents, for example, in acetonitrile in a mixture with carbon tetrachloride, or with sodium periodate in a mixture of methanol and water. , while the first method mainly produces a sulfone, and the second - a sulfoxide.

Preparation of the proposed compounds of the invention

Below, the preparation of the compounds proposed in the invention is explained in more detail using examples, which, however, do not limit the scope of the invention. in Example 1: 2-((6-oxo-1,6-dihydropyridin-3-ylmethyl)amino|-M-(4-trifluoromethoxyphenyl)benzamide o.

CE, 70 МН от jun 5 sh about 441 mg (1, vmmol) of 2-((6-oxo-1,6-dihydropyridin-3-ylmethyl)amino|benzoic acid under conditions that exclude the access of moisture, and in an atmosphere of argon, add to 12 ml of methylene chloride, after which it is successively mixed with 456 mg (4.5 mmol) of M-methylmorpholine, 33 mg of 4-trifluoromethoxyaniline and 822 mg (2.1 b6 mmol) of GATU (M-oxide of hexafluorophosphate M-dimethylamino-1H-1,2,3-triazolo- 14,5-b|Ipyridin-1-ylmethylene|-M-methylmethanammonium) and stirred for 2.5 hours at room temperature. At the same time, the acid goes into solution. After that, the mixture is kept for 1.5 hours at a bath temperature equal to 100 "C. At the same time, the product first precipitates, which then goes into solution again. After that, the mixture is concentrated in a vacuum and the residue is distributed between a dilute solution of sodium hydrogen carbonate and ethyl acetate. The organic phase is washed, dried, filtered and concentrated. The residue is chromatographed on LOg silica gel (Izoishche, (9 express chromatography, 5i) by gradient elution with the use of CH 2oSi as an eluent, and then the SNSIL/Meon mixture with a gradual change in the ratio between them to 9:11, thus obtaining 414 mg of the product, which is isolated by mixing with a mixture of methylene chloride/isopropyl ether in a ratio of 5:11, obtaining after vacuum -filtration of Zbamg (50.1960 from theory) about 2-MK6-oxo-1,6-dihydropyridin-3-ylmethyl)amino|-M-(4-trifluoromethoxyphenyl)benzamide with a melting point of 189.26.

The following compounds are obtained in a similar way: o "- d) - c . and? (ee) - (95) from 50 syu"

F) ime) 60 b5 o t ; Su chuchya

Come on!

Example l- Molecular | Melting temperature (c) or --A mass molecular peak of the mass spectrum (p/e) x ' "-k a С 349.39 150.6

OiRgor ptn uy 12 r 377.44 resin 13 ro 363.42 172.2 . s 7 la un 405.50 159 o, . t 1.5 b shis 1417.39 o

Y s 1.6 uv 335.36 o - h- 1.7 rf 403.36 so . ose, --- ( YЖ - - - - - - 1.8 rf 419.43 « 40 . se - s 1.9 С 419.43 ;» . - mon 18 1.10 re nai 393.44 111.2 (Fe) - - Li SS 417.39 191 o t -4 se, 1 What c) 70 142 SS 385.37 178.8

Fo - Ve - 5( A. t - Zh

F) ko bo b5

Example y- Molecular |Melting temperature (7) or --d mass molecular peak of the mass spectrum (p/e)

H

-in

I.I3 C 379.41. oMe is 1.14 385.37

Sun, current 1.15 ro 385.37 110.6 1.16 re 349.39

OmMe m Ll7 yo 377.44

OIRhor 1.18 o7 is I1431,42

BB 5 (8)

AH | axis, 467.40 120 -. 148539 ШЧИ о и -

A, sch

Zh o st,

ХУ a -Е g "- 1.21 zm 513.44 y " s 7 y se 1.22 s tu 383.84 y uv ? s shocha p ;" 1.23 at 391.30

T pcs (ee) .

Preparation of starting compounds - 2-M6-oxo-1,6-dihydropyridin-3-ylmethyl)amino|benzoic acid o a) 2-I(6b-oxo-1,6-dihydropyridin-3-ylmethyl)amino|benzoic acid acid, 4.53 g (ZOmmol) of methyl ether of anthranilic acid are mixed in 209 ml of methanol with 2.09 ml of glacial im)acetic acid and 5.76 g (42 mmol) of 2-pyridone-5-carbaldehyde and stirred for 24 hours. at room temperature in an argon atmosphere and in conditions that exclude the access of moisture. Next, it is mixed with 2.64 g (42 mmol) of sodium cyanoborohydride in portions and the mixture is stirred for 3 days at room temperature. After that, the mixture is evaporated to dryness under vacuum and dissolved in 150 ml of diluted sodium bicarbonate solution, after which the above product is isolated by stirring and separated by vacuum filtration. In this way, 4.75 g (6195 from theory) of methyl ether of 2-((6b-oxo-1,6-dihydropyridin-3-ylmethyl)amino|benzoic (F. acid) is obtained as a residue.

GI b) 2-((6b-oxo-1,6-dihydropyridin-3-ylmethyl)amino|benzoic acid

(12.7 mmol) of 2-((6b-oxo-1,6-dihydropyridin-3-ylmethyl)amino)benzoic acid methyl ester is mixed in 15 ml of dimethylformamide with 30 ml of caustic sodium solution and stirred for 1.5 hours . at room temperature. After that, while cooling with ice, the precipitate that has formed is mixed with approximately 5 ml of 4N hydrochloric acid, separated by vacuum filtration and washed with water. In this way, 3.1 g of the product is obtained, which is dissolved in 29.3 ml of a 1N caustic solution of sodium and 142 ml of ethanol and kept for 1.5 hours at a bath temperature equal to 1202 C. After that, the ethanol is distilled off in a vacuum, acidified with 2 N hydrochloric acid, the precipitated product is separated by vacuum filtration and finally dried thoroughly.

In this way, 2.9 g (93.595 from theory) of 2-(6b-oxo-1,6-dihydropyridin-3-ylmethyl)amino|benzoic acid are obtained.

Below, in the application examples, which do not limit the scope of the invention, the biological effect of the compounds proposed in the invention and their use are considered in more detail.

Solutions necessary for experiments

Initial solutions: initial solution A: 3mMM ATP in water, pH7.0 (-702С), initial solution B: y-ZR-ATP 1mKi/100μl, initial solution B: poly(Sish4Tug), 1Omg/ml in water. 70 Dilution solution substrate solvent: 10 mM DTT (dithiothreitol), 10 mM manganese chloride, 100 mM magnesium chloride, enzyme solution: 120 mM Tris-HCl, pH7.5, 10 μM sodium-vanadium oxide.

Application example 1

Inhibition of the activity of KOK, RI T-1 and RI T-4 kinases in the presence of the compounds proposed in the invention

In the titration microplate, which is narrowed in an M-shape (without protein binding), add 1 µl of the substrate mixture (1 µl of the initial solution A, which contains ATP, 425 mKkCi in 3-ATP (approximately 2.5 µl of the initial solution B) and 1-30 µl of the initial solution B, containing poly(siISH4Tug), -1.21 ml of the substrate solvent), 1 μm of the inhibitor solution (the tested compounds according to the dilutions, the 39% DMSO solution in the substrate solvent serves as a control) and 1 μm of the enzyme solution (11.25 μg of the original enzyme solution (kinase KOK, RI T-1 or g tT-4), diluted at 42C in 1.25 ml of enzyme solution). The specified ingredients are thoroughly mixed and incubated for 1 hour. at room temperature. Then add 1 μm of stop solution (250 mM EDTC, pH 7.0), mix, and transfer 1 μm of the solution to a phosphocellulose filter of type P 81. Then wash several times in 0.1 M phosphoric acid. The filter paper is dried, coated with meltylex (MeiCiech) and radioactivity is measured using a beta-particle micro-counter. with

After that, the values of IS are calculated, which correspond to the concentration of the inhibitor that is necessary to inhibit the incorporation of phosphate by 5095 from the level of its incorporation in the absence of the inhibitor, except for the value obtained for the control (reaction stopped with EDTC).

Application example 2

Inhibition of cytochrome P 450 o

The experiment with the inhibition of cytochrome P 450 was carried out in accordance with (the publication of the authors of Sgezri et al. (Apai. Viospet. 248, 1997, p. 188-190)) using human cytochrome P 450 isoenzyme (ZA4) expressed by baculovirus/insect cells. at

The results of inhibition of kinases (value of IC 50 in NM) and inhibition of cytochrome P 450 isozyme ZA4 (value of "-

ISo U NM) are presented in the table below. d) "n-s. "» The results obtained in the experiments described above clearly indicate that the compounds proposed in the invention are superior to known compounds in terms of their action. The formula of the invention is 1. Compounds of the general formula I -B2 (), ko) m o i syu" u ra M, n schu cho

F) and in 60 Ma

N in which

A stands for aryl or heteroaryl,

X means hydrogen or fluorine, 65 B" and B? independently of each other mean hydrogen, halogen, C.4-Sigoalkyl, C.4-Sioalkyl-C.4-C.oalkylene, halo-C.4-C.alkyl, C.sub.3-Socycloalkyl or halo-C3-Cocycloalkyl and

Claims (11)

M means a bond or oxygen or a group -5-, -5(0)- or -50 5-, as well as their isomers, enantiomers, diastereomers and salts. 2. Compounds of the general formula | according to claim 1, in which A means phenyl or pyridyl, X means hydrogen or fluorine, B" and B" independently of each other mean hydrogen, halogen, C.4-Ci»alkyl, C.41-Sioalkyl-C.4-Sralkylene, halo- C.4-Cralkyl, C3-Cocycloalkyl or halo-C3-Cocycloalkyl and Y means a bond or oxygen or a group -5-, -5(0)- or -505-, 70 as well as their isomers, enantiomers, diastereomers and salt 3. Compounds of the general formula I according to claim 1 or 2, in which A means phenyl, X means hydrogen or fluorine, B" and B" independently of each other mean hydrogen, halogen, C.4-Cioalkyl, C.4-Cioalkyl C4-C.oalkylene, 75 halo-C.4-Sialkyl, C3-C-ocycloalkyl or halo-C3-Siocycloalkyl and U means a bond or oxygen or a group -5-, -5(0)- or -505- , as well as their isomers, enantiomers, diastereomers and salts. 4. Compounds of the general formula I! according to any one of claims 1-3, in which A means phenyl, X means hydrogen, B" and B" independently of each other mean hydrogen, halogen, C.4-Sioalkyl, C.4-Sioalkyl-C.4-C. oalkylene, halo-C.4-C.alkyl, C.sub.3-Cocycloalkyl or halo-C.sub.3-Cocycloalkyl and Y means a bond or oxygen or a group -5-, -5(0)- or -505-, as well as their isomers, enantiomers , diastereomers and salts. p 5. Medicinal product containing at least one compound of general formula I according to any of claims 1-4. at 6. Medicinal product according to claim 5 for use in tumor growth or metastases, psoriasis, Kaposi's sarcoma, restenosis such as stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis such as rheumatoid arthritis, hemangiomas, angiofibromas, eye diseases such as diabetic retinopathy and neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, acute transplant rejection and glomerulopathy, fibrotic diseases such as liver cirrhosis, diseases associated with the proliferation of mesangial cells, arteriosclerosis, damage to nervous tissue, for the suppression of repeated occlusion of vessels after treatment with the use of a balloon catheter, during prosthetics of vessels or when using, accordingly, the introduction of mechanical devices, such as, for example, stents, to maintain the patency of vessels , as well as immunosuppressants, such as auxiliaries that contribute to scarless d) healing of wounds, age spots and contact dermatitis. 7. Compounds according to any of claims 1-4 for the preparation of medicinal products with commonly used excipients and carriers. " 8. Use of compounds of the general formula I according to any of claims 1-4 as inhibitors of tyrosine kinases KOK, RI T-1 and T.A. at) with 9. Use of compounds of the general formula I according to any of claims 1-4 in the form of a pharmaceutical preparation for enteral, parenteral and oral administration. » 10. Use of the compounds according to any one of claims 1-4 in tumor growth or metastases, psoriasis, Kaposi's sarcoma, restenosis, such as, for example, stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia, arthritis, such as rheumatoid arthritis, hemangiomas, angiofibromas, eye diseases such as diabetic retinopathy and neovascular glaucoma, kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy, fibrous diseases such as liver cirrhosis, diseases associated with the proliferation of mesangial cells, arteriosclerosis, damage to nervous tissue, to inhibit re-occlusion of vessels after treatment with a balloon catheter, in vascular prosthetics or when applied by the introduction of mechanical devices, such as stents, to support vascular patency, as well as immunosuppressants, as auxiliaries that promote scarless healing of wounds, age spots and contact dermatitis. 11. Use of compounds according to any one of claims 1-4 as MESEK-kinase 3 inhibitors that inhibit lymphangiogenesis. Gee! Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 21, 25.12.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 60 b5