Compounds and pharmaceutical composition

 

(57) Abstract:

Use: in the pharmaceutical industry. Summary of the invention the new compounds of General formula:

< / BR>
where Y is naphthyl, tetrahydronaphthyl, hinely, indolyl, R is a group of the formula:

< / BR>
or their pharmaceutically acceptable salts, pharmaceutical composition exhibiting inhibitory activity against Terezin-kinase, comprising a pharmaceutically acceptable carrier or diluent and active component connection formula 1 in an effective amount. 3 S. and 2 C.p. f-crystals, 2 tab.

The invention relates to new derivatives of aryl - and heteroarylboronic, to the way they are received, to contain their pharmaceutical compositions and to their use as therapeutic agents.

This invention provides a compound represented the following General formula (I)

< / BR>
where Y is a bicyclic system selected from (A), (B), (E) and (G)

< / BR>
R is a group of formula (a), (c), (d), (e), (f), (g), (i) or (j)

< / BR>
in which R3is OH or NH2and Ph denotes phenyl, R1is hydrogen or C2-C6-alkanoyl, and n is 0, 1 or 2, or their pharmaceutically-acceptable salts, each of samassekou system (A), (E) and (G), while the bicyclic ring system (B) can be substituted only benzene residue, and with the additional condition that (i) when Y is a ring system (A), R is different from the group (a) or (d) as defined above, (ii), when Y is a ring system (B), and R is a group (d), as defined above, in which R3it is OH, n is non-zero, (iii), when Y is a ring system (G) and R is a group (e), as defined above, associated with the indole ring in position 2 or 3, n is non-zero, and (IV) when Y is a ring system (E), R is a group (d), as defined above, in which R3this OH that is associated with the quinoline ring (E) in position 2, and the group (OR1)nin which R1is hydrogen or C1-C6-alkyl and n is 1, is connected with the quinoline ring (E) in regulation 8, R2different from hydrogen.

The invention also covers all possible isomers, stereoisomers, in particular, Z and E isomers and their mixtures, and the metabolites and precursors of metabolites, or bioresistance (otherwise known as Pro-drugs) of the compounds of formula (I).

The substituent R is preferably attached in the system (G).

In the case when Y is a bicyclic ring system meets the definition of (A) or (E), group-OR1preferably bound to the same benzene residue, as the group R.

In ring systems (A) and (B) the Deputy OR1preferably attached in position 1, 2, 3, 4, 5 or 8, in particular, in position 1, 2 or 3 or 4. In the ring system (E) the Deputy OR1preferably attached in position 3, 4, 5, 6, 7 or 8, in particular, in position 5, 6, 7 or 8. In the ring system (G) the Deputy OR1preferably attached in position 3, 4, 5, 6 or 7, in particular, in position 4, 5, 6 or 7. Of course, in the ring systems (A) -(G) in the same position can join only one of the substituents R and-OR1.

In the case when n is 2 or 3, groups OR1may be the same or different.

Alkyl groups, and alkyl residues in alkanoyl groups can be branched or straight alkyl chain. Alkyl group, a C1-C6preferably represents an alkyl group,- C1-C4for example, methyl, ethyl, propyl, ISO-propyl, butyl, sec-butyl or tert-butyl, in particular, methyl or ethyl. Alcoolica geonim or butyryl.

Pharmaceutically acceptable salts of the compounds according to this invention includes salts of joining with acids, mineral, such as nitric, hydrochloric, Hydrobromic, sulphuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, maleic, malic, tartaric, citric, benzoic, cinnamic, almond and salicylic acids, and salts with inorganic bases, e.g. alkali metal, particularly sodium or potassium, or alkaline-earth metals, in particular, calcium or magnesium salts, or salts with organic bases, for example, alkylamines followed, in particular, triethylamine.

As already mentioned, the invention also includes the pharmaceutically acceptable bio-precursors (otherwise known as Pro-drugs) of the compounds of formula (I), i.e. compounds of the formula which differs from the above-mentioned formula (I), but which, nevertheless, when introduced into the human body in vivo become, directly or indirectly, in the compound of formula (I). Preferred compounds according to this invention are of the formula (I) in which Y represents a monocyclic or Wii with the above definition;

R1is hydrogen or alkanoyl C2-C4and

n, as defined above, and their pharmaceutically acceptable salts.

More preferred compounds according to this invention are the compounds of formula (1), in which

Y is a bicyclic ring system of formula (A), (B) or (E) in accordance with the above definition;

R is a group of formula (a), (d), (e), (i) or (j), as defined above;

R1this hydrogen;

n is zero or 1, and their pharmaceutically acceptable salts.

Specific examples of compounds according to this invention are the following compounds, which can be either individual Z-or B-diastereomers, or Z, E mixtures of these diastereomers:

2-cyano-3-(2-hydroxynaphthyl-1)acrylamide,

2-cyano-3-(3-hydroxynaphthyl-1)acrylamide,

2-cyano-3-(4-hydroximate-1-yl)acrylamide,

2-cyano-3-(1-hydroximate-2-yl)acrylamide,

2-cyano-3-(3-hydroximate-2-yl)acrylamide,

2-cyano-3-(4-hydroximate-2-yl)acrylamide,

2-cyano-3-(2-hydroximate-1-yl)acrylic acid,

2-cyano-3-(3-hydroximate-1-yl)acrylic acid,

2-cyano-3-(4-hydroximate-1-yl)acrylic acid,

2-cyano-3-(1-hydroximate-2-yl)acrylic acid,

2-cyano-3-(2-hydroximate-1-yl)diacrylate,

2-cyano-3-(3-hydroximate-1-yl)diacrylate,

2-cyano-3-(4-hydroximate-1-yl)diacrylate,

2-cyano-3-(1-hydroximate-2-yl)diacrylate,

2-cyano-3-(8-hydroximate-2-yl)diacrylate,

2-cyano-3-(4-hydroximate-2-yl)diacrylate,

2-(4-hydroxyphenyl)-3-(naphthas-1-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(naphthas-2-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(naphthas-1-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(naphthas-2-yl)acrylic acid;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylamide;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetraedron-2-yl)acrylamide;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid;

2-cyano-3-(4-guided;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)diacrylate;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)Tigrinya;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate;

2-cyano-3-(3-hydroxy-5,6,7,8,-tetrahedronal-2-yl)diacrylate;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahedronal-1-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahedronal-2-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahedronal-1-yl)acrylic acid;

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylamide;

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylamide;

2-cyano-3-(2-hydroxyquinolin-3-yl)acrylamide;

2-cyano-3-(4-hydroxyquinolin-3-yl)acrylamide;

2-cyano-3-(2-hydroxyquinolin-4-yl)acrylamide;

2-cyano-3-(3-hydroxyquinolin-4-yl)acrylamide;

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-3-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin-3-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-4-yl)acrylic acid;

2-cyano-3-(3-hydroxyquinolin-4-yl)acrylic acid;

2-cyano-3-(3-hydroxyquinolin-2-yl)diacrylate;

2-cyano-3-(4-hydroxyhydrocinnamate-3-yl)diacrylate;

2-cyano-3-(4-hydroxyquinolin-3-yl)diacrylate;

2-cyano-3-(2-hydroxyquinolin-4-yl)diacrylate;

2-cyano-3-(3-hydroxyquinolin-4-yl)diacrylate;

2-(4-hydroxyphenyl)-3-(quinoline-2-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinoline-4-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinoline-4-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinoline-2-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(quinoline-3-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(quinoline-4-yl)acrylic acid;

3-[(3-hydroxy-1-naphthyl)methylene]-2-oxindole;

3-[(4-hydroxy-1-naphthyl)methylene]-2-oxindole;

3-[(1-hydroxy-2-naphthyl)methylene]-2-oxindole;

3-[(4-hydroxy-2-naphthyl)methylene]-2-oxindole;

3-[(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)methylene]-2-oxindole;

3-[(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)methylene]-2-oxindole;

3-[(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)methylene]-2-oxindole;

3-[(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)methylene]-2-oxindole;

3-[(7-hydroxyquinolin-5-yl)methylene]-2-oxindole;

3-[(8-hydroxyquinolin-5-yl)methylene]-2-oxindole;

3-[(7-hydroxyquinolin-6-yl)methylene]-2-oxindole;

3-[(8-hydroxyquinolin-6-yl)methylene]-2-oxindole;

and also, if appropriate, their pharmaceutically acceptable salts.

Join SOE is densely aldehyde of formula (II)

< / BR>
where Y, R1and n are such as defined above, with a compound of formula (a'), (c'), (d), (e), (f') (g'), (i') or (j'), respectively.

< / BR>
where R3and Ph such as defined above, and, if required, converting the compounds of formula (I) into another compound of formula (I), and/or, if required, converting the compounds of formula(I) and its pharmaceutically acceptable salt and/or, if required, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of compounds of formula (I) into the individual isomers. The interaction of the compounds of formula (II) with the compound of the formula (a'), (c'), (d), (e), (f') (g') or (i') is a similar process that can be implemented in accordance with known methods, as will be described below, preferably in the presence of a basic catalyst such as pyridine, piperidine, dimethylamine, or a suitable hydroxide or alkoxide of an alkali metal.

For example, the reaction of the compound of formula (II) with the compound of the formula (a'), (c'), (e), (f) or (g') can be, respectively, in terms of reactions of knoevenagel, as they are described, for example, J. Jones b Organic Reactions 15, 204 (1967). Suitable catalysts are organic bases, such as Peru pyridine, ethanol, mataloni, benzene or dioxane, at temperatures approximately in the range from 0 to 100oC. In a preferred embodiment, the reaction is carried out in warm ethanol solution in the presence of piperidinium catalyst.

The reaction between the compound of formula (II) and compound of formula (d') can be performed can be performed by way of knoevenagel described above, but in specific conditions. In particular, apply higher temperatures due to the fact that in the process of condensation is also dekarboksilirovanie. For example, the condensation can be conducted in the environment of organic bases, such as pyridine (which is both a solvent and a catalyst) at a temperature of approximately from 50 to 140oC.

The reaction between the compound of formula (II) and the compound of the formula (i') can be performed in accordance with the description of R. T. Buchles et al, J. Am. Chem. Soc. 73, 4972 (1951). In this method interact equimolar amount of an aromatic aldehyde and vinylacetylene derived in 3-5 mol-equivalents of acetic anhydride in the presence of about 1 mol equivalent of triethylamine, in a temperature range from about 100 to 140oC.

The compound of formula (II) can one accepts onicescu chemistry methods to carry out the de-esterification of the compounds of formula (I), in which one or more of the substituents R1represent alkyl, C1-C6so you have a compound of formula (I) with one or more substituents represent hydrogen. In the case of methyl-phenol ether can be splitting using, for example, tribromide boron, as described by J. E. N. mcOncie, Tetrahedron 24, 2289 (1968). It is recommended to use about 1 mole of tribromide boron for each ester group, with one additional mole of reagent per group, which includes having the potential basicity of the nitrogen or oxygen. The reaction can be carried out in an inert organic solvent such as methylene chloride, pentane or benzene, in an inert atmosphere, for example nitrogen, in a temperature range from about -78oC to room.

The acylation of compounds of formula (I), in which one or more of the substituents R1represent hydrogen, resulting in a corresponding compound of formula (I), in which one or more of the substituents R1is a group of alkanoyl C2-C6you can implement through its interaction with reactive deposition is intervale temperatures from about 0 to 50oC. In a preferred version, the acylation is carried out by reaction with an appropriate anhydride in the presence of an organic base, e.g. pyridine. Similarly you can spend, according to the known methods, the conversion of compounds of formula (I) in which R is a group of the formula or-CH=CH-COOH, into another compound of formula (I) in which R represents a group of formula-CH= C-CONH2or-CH=CH-CONH2. For example, the interaction of a reactive carboxylic acid derivative, for example, a suitable halide, preferably chloride, with an aqueous solution of ammonium hydroxide at a temperature of from about 5 to 40oC.

The possible formation of salts of the compounds of formula (I), as well as conversion of a salt into a free compound and the separation of a mixture of isomers into the individual isomers can be performed in the usual way.

For example, to separate a mixture of geometric isomers, in particular, CIS - and TRANS-isomers, can be fractional crystallization from a suitable solvent or by column chromatography or high pressure liquid.

The compounds of formula (II) can be obtained by known methods from compounds of formula (III)

Pharmacology

Compounds according to this invention have a special ability to inhibit the activity of tyrosine kinase. In this regard, they may be useful for treating cancer and other pathological proliferative conditions.

Recent studies of the molecular basis of transformation in neoplasma allowed us to identify a family of genes, called oncogenes, abnormal expression of which causes the formation of tumors.

For example, RNA tumor viruses have this sequence of oncogenes, expression of which defines the transformation of infected cells in neoplasma. Some of them encoded by oncogene proteins, which is to catalyze the transfer of phosphate from adenosine triphosphate (ATP) to tyrosinosis residues in protein substrate. In normal cells, the tyrosine kinase activity are some of the receptors of growth factors, for example, PDGF, EGF, a-TGF and insulin. Linking growth factor (SG) activates autophosphorylation tyrosine kinase receptor and phosphorylation of nearby molecules tyrosine.

I believe, therefore, that the phosphorylation of these receptors tyrosine kinase plays an important role in signal transduction and that the main function of tyrosine kinase activity in normal cells is the regulation of cell growth. Violation of this activity as a result of actions encoded by oncogene tyrosine kinase, which is either produced in excess, and/or has changed substratespecific, can lead to loss of growth control and/or neoplastic transformation. Accordingly, a specific inhibitor tyrosinekinase may be useful for studying the mechanism of carcinogenesis, proliferation and differentiation and may be an effective means of preventing and hemoterapia cancer and other pathological conditions of proliferation. Tyrosinaemia the protein kinase activity of these compounds is shown by, for example, their activity in vitro, described B. Ferguson et al in J. Biol. Chem. 1985, 260, 3652.

Ispolzovannom method B. Ferguson et al (ibidem). As the substrate used --casein or (Yal5)-angiotensin. Inhibitor pre thermostatic with the enzyme for 5 min at 25oC. the Reaction is carried out under the following conditions: 100 mm MOPS buffer, 10 mm MgCl2, 2M ( -32P) ATP (6 Ci/mmol), 1 mg/ml casein [alternative substrate is (Yal5)-angiotensin] and 7.5 mg/ml of enzyme in a total volume of 30 ml and at pH 7.0.

The reaction mixture thermostatic at 25oC for 10 minutes the precipitation of the protein under the action of trichloroacetic acid is accompanied by rapid filtration and quantification of phosphorylated substrate by using scintillation fluid. Alternatively, the reaction mixture was subjected to electrophoresis in an environment of sodium dodecyl sulphate/polyacrylamide and measure phosphorylated substrate using autoradiography or by counting the number of P32in the cut spot.

Due to the high activity and low toxicity of the compounds according to this invention it is safe to use in medicine.

Detected, for example, the approximate acute toxicity (LD50compounds of this invention defined in mice by a single injection of privacy in accordance with this invention can be introduced in the form of various dosage forms, for example, orally, in pill form, capsules, tablets, sugar or film coating, liquid solutions or suspensions; radically, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or injection; or topically.

The dosage depends on age, weight, condition of the patient and the method of administration; for example, by oral administration adult dosage can vary from about 10 to about 150-200 mg per dose, and 1-5 times a day.

Of course, the recommended dosage can be altered to obtain the optimal therapeutic effect.

This invention includes pharmaceutical compositions comprising a compound according to this invention in combination with a suitable excipient (which may serve as a carrier or diluent).

Pharmaceutical compositions comprising compounds according to this invention are usually obtained by traditional methods and is administered in a suitable pharmaceutical respect to the form.

For example, the solid form may contain together with the active compound diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or who do glycols; binder, such as starch, gum Arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrant, for example, starch, alginic acid, alginates or starch glycolate, sodium, effervescent mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, Polysorbate, laurylsulfate; and, finally, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be produced by known methods, for example by mixing, granulating, pelletizing with sugar coating or film coating.

Liquid dispersions for oral use may constitute, for example, syrups, emulsions and suspensions.

A syrup may contain as carrier, for example, sucrose or sucrose mixed with glycerine and/or mannitol and/or sorbitol. Part of suspensions and emulsions can log in as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may include, together with the active compound in pharmaceutically acceptable the solid fuel surface-active additives or lecithin.

Compositions for topical application, for example, creams, lotions or pastes can be prepared by mixing the active ingredient with conventional oily or emulsifying excipients.

Example 1.

2-cyano-3-(3-hydroxyquinolin-5-yl)acrylamide (FCE 26283, compound (I) [I, Y, E, R a, R1R2H, n 1, R3NH2]

A solution of 5-formyl-8-hydroxyquinoline solution (173 mg, 1 mmol), cyanoacetamide (92 mg, 1.1 mmol) and piperidine (60 mg, 0.7 mmol) in absolute ethanol (20 ml) was heated for 4 h at 50oC. the Reaction mixture was cooled to 0-5oC, the precipitate was filtered, the residue washed with a cooled ice with ethanol, and then dried under vacuum.

Thus obtained is indicated in the name of pure connection with the release of 70% (167 g). The connection of higher purity is obtained by crystallization from ethanol, melting point 275oC.

C13H9N3O2< / BR>
Calculated: C 65,27, H 3,79, N 17,58.

Found: C 65,15, H 3,65, N 17,49.

MC v/z 239

IR cm-1(KBr): 3100-3600 (NH, OH), 2200 (CN), 1690 (CONH2), 1610, 1590, 1560, 1510 (C=C).

With the aforementioned method can be obtained the following compounds:

2-cyano-3-(2-hydroximate-1-yl)acrylamide, (FCE 26434, compound 2)

2-cyano-Grilamid, (FCE 26844, connection 3)

2-cyano-3-(3-hydroximate-2-yl)acrylamide,

2-cyano-3-(4-hydroximate-2-yl)acrylamide,

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylamide,

2-cyano-2-(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylamide,

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylamide,

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide,

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide,

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide,

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylamide,

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylamide,

2-cyano-3-(2-hydroxyquinolin-3-yl)acrylamide,

2-cyano-3-(4-hydroxyquinolin-3-yl)acrylamide,

2-cyano-3-(2-hydroxyquinolin-4-yl)acrylamide,

2-cyano-3-(3-hydroxyquinolin-4-yl)acrylamide,

3-[(1-naphthyl)methylene]-2-oxindole,

3-[(2-hydroxy-1-naphthyl)methylene]-2-oxindole,

3-[(3-hydroxy-1-naphthyl)methylene]-2-oxindole,

3-[(4-hydroxy-1-naphthyl)methylene]-2-oxindole (FCE 26807, compound 4),

3-[(2-naphthyl)methylene]-2-oxindole (FCE 26808, compound 5),

3-[(1-hydroxy-2-naphthyl)methylene]-2-oxindole (FCE 26843, compound 6),

3-[3-hydroxy-2-naphthyl)methylene]-2-oxindole,

3-[4-hydroxy-2-naphthyl)methylene]-2-oxindole,

3-[(5,6,7,8-tetrahedronal-1-yl)stands the XI-5,6,7,8-tetrahedronal-1-yl)methylene]-2-oxindole,

3-[(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)methylene] -2-oxindole, (FCE 27713, compound 8)

3-[(5,6,7,8-tetrahedronal-2-yl)methylene]-2-oxindole,

3-[(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)methylene] -2-oxindole, (FCE 27714, compound 9),

3-[(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)methylene] -2-oxindole, E isomer: FCE 27746, compound 10,

Z isomer: FCE 27748, compound II

3-[(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)methylene-]-2-oxindole,

3[(quinoline-5-yl)methylene]-2-oxindole,

3-[(6-hydroxyquinolin-5-yl)methylene]-2-oxindole,

3-[(7-hydroxyquinolin-5-yl)methylene]-2-oxindole,

3-[(8-hydroxyquinolin-5-yl)methylene] -2-oxindole, (FCE 26285, compound 26)

3-[(quinoline-6-yl)methylene]-2-oxindole,

3[(5-hydroxyquinolin-6-yl)methylene]-2-oxindole,

3-[(7-hydroxyquinolin-6-yl)methylene]-2-oxindole,

3-[(8-hydroxyquinolin-6-yl)methylene]-2-oxindole,

3-[(1,4-dihydroxy-5,6,7,8-tetrahedronal-2-yl)methylene] -2-oxindole (E isomer: FCE 26806, 12, Z isomer: FCE 27846, compound 13)

C19H17NO3< / BR>
Calculated: C Sampled At 74.25, H 5,58, N 4,56.

Found: C 74,01, H 5,74, N 4,48.

MS m/z: 307

IR cm-1(KBr): 3500-3100 (OH, NH), 1670 (CO), 1605 (C=C)

3-[(quinoline-2-yl)methylene]-2-oxindole (FCE 27124, compound 14)

C18H12N2O

Calculated: C 79,39, H Of 4.44, N 10,29.<"ptx2">

3-[(4-hydroxyquinolin-2-yl)methylene] -2-oxindole (FCE 26967, compound 15)

C18H12N2O2< / BR>
Calculated: C 74,98, H 4,20, N 9,72.

Found: C 74,66, H 4,25, N 9,38.

MS m/z: 288

IR cm-1(KBr): 3430 (OH, NH), 1675 (CO), 1630 (C=C), 1595-1580-1530-1515 (arene.).

3-[(quinoline-4-yl)methylene]-2-oxindole (FCE 27048, compound 16)

3-[(3-indolyl)methylene]-2-oxindole (FCE 26841, compound 17)

so pl. 230oC

C17H12N2O

Calculated: C 78,44, H 4,65, N 10,76.

Found: C 78,35, H Br4.61, N 10,55.

MS (m/z): 260

IR cm-1(KBr): 3500-3200 (NH), 1675 (CO), 1610 (C=C)

NMR d M. D. 6,83 (d, 1H), 6,9-to 7.3 (m, 4H), 7.5 (m, 1H), 7,87 (d, J=6,8 Hz, 1H), 8,14 (c, 1H), 8,17 (m, 1H), 9,44 (c, 1H), 10,52 (broad s, 1H), 12,0 (wide CH, 1H).

C18H12N2O

Calculated: C 79,39, H Of 4.44, N 10,29.

3-[(quinoline-3-yl)methylene[-2-oxindole (FCE 26913, compound 18)

C18H12N2O

Calculated: C 79,39, H Of 4.44 N, 10,29.

Found: C 79,20, H 4,71, N 10,14.

MS m/z: 272

IR cm-1(KBr): 3500-3100 (NH), 1695 (CO), 1620-1580-1500 (C=C, C=N)

4-[(indol-3-yl)methylene]-1-phenylpyrazole-3,5-dione,

C18H13B3O2< / BR>
Calculated: C 71,27, H 4,32, N 13,85.

Found: C 71,05, H 4,33, N 13,64.

MS m/z: 303

IR cm-1(KBr): 3600-3100 (NH), 1705 which read: C 63,43, H 3,99, N BE 18.49.

Found: C 63,20, H 3,71, N 18,31.

MS m/z: 227

IR cm-1(KBr): 3600-3100 (NH), 1740-1700-1650 (CONH), 1620-1580-1530 (C= C)

Example 2.

2-cyano-3-(2-hydroximate-1-yl)diacrylate (FCE 26627, compound 19) [I, Y=A, R=c, R1=R2=H, n=1]

A mixture of 2-hydroxy-1-naphthaldehyde (172 mg, 1 mmol), 2-cyanothioacetamide (110 mg, 0.2 mmol), N,N-Diethylaminoethanol (23 mg, 0.2 mmol) and 15 ml of ethanol was stirred for 30 min in nitrogen atmosphere while heating under reflux. The mixture is then cooled, the precipitate was filtered, washed ice-cold ethanol, dried in a vacuum oven. Thus obtained almost pure the specified connection with the release of 85% (1080 mg). After recrystallization from ethanol received a very pure samples.

C14H10N2OS

Calculated: C 66,12, H 3.96 Points, N Br11.01, S 12,61.

Found: C 66,05, H Of 3.85, N 10,95, S 1255.

MS m/z: 254

IR cm-1(KBr): 3300-2500 (H, OH), 2020 (CN), 1640 (C-N, N-H), 1600-1560-1510 (C=C).

According to the above technique, it is possible to obtain the following compounds;

2-cyano-3-(3-hydroximate-1-yl)diacrylate,

2-cyano-3-(4-hydroximate-1-yl)diacrylate,

2-cyano-3-(1-hydroximate-2-yl)diacrylate,

2-cyano-3-(3-hydroximate-2-yl)diacrylate,

2-cyano-3-(4-hydroximate-2--tetrahedronal-2-yl)diacrylate,

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)diacrylate,

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate,

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate,

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate,

2-cyano-3-(3-hydroxyquinolin-2-yl)diacrylate,

2-cyano-3-(4-hydroxyquinolin-2-yl)diacrylate,

2-cyano-3-(2-hydroxyquinolin-3-yl)diacrylate,

2-cyano-3-(4-hydroxyquinolin-3-yl)diacrylate,

2-cyano-3-(2-hydroxyquinolin-4-yl)diacrylate,

2-cyano-3-(3-hydroxyquinolin-4-yl)diacrylate and

2-cyano-3-(8-hydroxyquinolin-5-yl)diacrylate (FCE 26968, compound 20)

C13H9N3OS

Rasschitano: C 61,16, H 3,55, N 16,46.

Found: C 60,99, H 3,59, N 16,26.

MS m/z: 255

IR cm-1(KBr): 3440 (OH), 3330-3180 (H), 2220 (C), 1650 (H), 1610-1570-1510 (C=N).

Example 3.

2-cyano-3-(1-hydroximate-2-yl)acrylic acid

[I, Y=A, R a, R1=R2=H, R3=OH, n=1]

To a mixture of 1-hydroxy-2-naphthaldehyde (172 mg, 1 mmol) and tsianuksusnogo acid (85 mg, 1 mmol) in dry dioxane (2 ml) is added dropwise piperidine (42 mg, 0.5 mmol) at a temperature of 0-5oC. the Mixture was kept overnight at room temperature. Filtered education is called in the title, which corresponds to 90% of the output.

C14H8NO2< / BR>
Calculated: C 75,33 H 4,06 N 6,28

Found: C 75,20 H 3,95 N 6,15

MS m/z: 223

IR cm-1(KBr): 3300-2500 (COOH), (OH), 2200 (CN), 1690 (COOH), 1600-1560-1510 (C=C).

Following the above methodology and selecting as the source corresponding aldehyde derivative, we can obtain the following connections:

2-cyano-3-(2-hydroximate-1-yl)acrylic acid,

2-cyclo-3-(3-hydroximate-1-yl)acrylic acid,

2-cyano-3-(4-hydroximate-1-yl)acrylic acid,

2-cyano-3-(3-hydroximate-2-yl)acrylic acid,

2-cyano-3-(4-hydroximate-2-yl)acrylic acid,

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid,

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid.

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid,

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid,

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid,

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid,

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylic acid,

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylic acid,

2-cyano-2-(2-hydroxyquinolin-3-yl)acrylic acid,
/BR>2-cyano-3-(3-hydroxyquinolin-4-yl)acrylic acid,

Example 4.

3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid (I, Y=B, R= i, R1= R2=H, R3=OH, n=1)

A mixture of 1-hydroxy-5,6,7,8-tetrahydro-2-naphthaldehyde (176 mg, 1 mmol), malonic acid (208 mg, 2 mmol), piperidine (85 mg, 1 mmol) and pyridine (1 ml) was heated at 100oC for 3 h and irrigation within 1/2 hours the mixture is Then cooled and poured on ice, mixed with hydrochloric acid. Usageprice material was separated by filtration, and then recrystallize from ethanol, gave the titled compound in pure form with the release of 80% (174 mg).

C13H14O3< / BR>
Calculated: C 71,54 H 6,46

Found: C 71,35 H 6,30

MS m/z: 218

IR cm-1(KBr): 3320-2500 (COOH, OH), 1690 (COOH), 1640 (C=C)

Example 5.

2-(4-hydroxyphenyl)-3-(naphthas-2-yl)acrylic acid (FCE 26437, compound 21)

(I, Y=A, R2=H, R3=OH, n=null)

A mixture consisting of 2-naphthaldehyde (156 mg, 1 mmol), 4-hydroxyphenylarsonic acid (152 mg, 1 mmol), triethylamine (101 mg, 1 mmol) and acetic anhydride (510 mg, 5 mmol), was heated for 5 h at 100oC.

After cooling, the mixture was treated with diluted hydrochloric acid, and then extra the Oia. Separated aqueous phase and besieged the crude product by the action of hydrochloric acid. A pure compound is obtained by crystallization from isopropanol to yield 60% (174 mg).

C19H14O3< / BR>
Calculated: C 78,60 H 4,86

Found: C 78,69 H 4,89

MS m/z: 290.

IR cm-1(KBr): 6000-2500 (OH, COOH), 1680 (COOH), 1600, 1585, 1510 (C= C).

The same method can be obtained the following compounds:

2-(4-Hydroxyphenyl)-3-(quinoline-3-yl)acrylic acid

(FCE 26458, compound 22)

C18H13NO3< / BR>
Calculated: C 74,21 H 4,50 N 4,81

Found: C 73,85 H 4,37 N 1,53

MS m/z: 291.

IR cm-1(KBr): 3380 (OH), 3,100 to 1,800 (COOH) 1670 (COOH), 1605, 1580, 1510 (C=C)

2-(4-hydroxyphenyl)-3-(naphthas-1-yl)acrylic acid,

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahedronal-1-yl)acrylic acid,

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahedronal-2-yl)acrylic acid,

2-(4-hydroxyphenyl)-3-(quinoline-2-yl)acrylic acid and

2-(4-hydroxyphenyl)-3-(quinoline-4-yl)acrylic acid.

Example 6.

2-(4-Hydroxyphenyl)-3-(naphthas-2-yl)-acrylamide (FCE 26438, compound 23)

(I, Y, A, R i, R2=H1, R3NH2n nil)

Was heated for 5 h at 100oC a mixture of 2-naphthaldehyde (156 mg, 1 mmol), 4-hydroxypyridine the mixture was treated with diluted coloradosaturday acid, followed by extraction with ethyl acetate. The organic layer was extracted with sodium hydroxide solution. After separation the aqueous phase was besieged crude carboxylic acid by the action of hydrochloric acid.

The crude carboxylic acid was converted into the acid chloride by treatment with thionyl chloride (1190 mg, 10 mmol) in boiling benzene (5 ml) for 2 hours After evaporation to dryness under vacuum, the crude acid chloride was converted into the amide by reaction with dilute ammonium hydroxide at room temperature for 1 h by filtering, washing and drying under vacuum was obtained as crude product. Crystallization from isopropanol gave the titled compound in pure form with the release of 50% (145 mg).

C19H15NO2< / BR>
Calculated: C 78,87 H 5,23 N 4,84

Found C 78,71 H 5,09 N 4,65

MS m/Z: 289

IR cm-1(KBr): 3600-3100 (OH, NH), 1650 (CONH), 1610, 1560, 1510 (C=C)

The above method can be obtained the following compounds:

2-(4-hydroxyphenyl)-3-(quinoline-3-yl)acrylamide

C18H14N2O2< / BR>
Calculated: C 74,47 H a 4.86 N 9,65

Found: C 74,32 H 4,71 N 9,51

MS m/Z: 290

IR cm-1(KBr): 3450, 3320 (NH), 3500-2300 (OH), 1665 (CONH), 1615, 1565, 1510, 1490 (C=C, C=N),

2-(4-hydroxyphenyl)-3-(naphthas-1-yl)acrylamide,

2-(4-hydroxyphenyl)-3-(quinoline-2-yl)acrylamide and

2-(4-hydroxyphenyl)-3-(quinoline-4-yl)acrylamide.

Example 7.

2-(4-Hydroxyphenyl)-3-(naphthas-2-yl)Acrylonitrile (FCE 26436, compound 25).

(I, Y, A, R j, R2H, n, nil)

To a solution of 2-naphthaldehyde (156 mg, 1 mmol) and 4-hydroxybenzylated (133 mg, 1 mmol) in dry ethanol (2 ml) was added to individual portions while cooling ethoxide sodium (204 mg, 2 mmol) and kept the resulting solution for 96 h at room temperature. Then the solution is poured into a mixture of ice and dilute hydrochloric acid. The formed precipitate was filtered, washed, chilled ice water with ethanol and dried in a vacuum oven. Thus has been named compound in pure form with the release of 80% (217 mg).

C19H13NO

Calculated: C 84,11 H a 4.83 N 5,16

Found: C 83,91 H 4,87 N 4,86

MS m/Z: 271

IR cm-1(KBr): 3340 (OH), 2220 (CN), 1605, 1510 (C=C).

Example 8.

2-Cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide

(I, Y B, R a, R1=R2=H, R3=NH2, n 1)

The starting material in this example, the de-esterification is a 2-acino-3-(1-methoxy-5,6,7,8-tetrahedronal-2-yl)acrylamide, which can be obtained as described in the 256 mg, 1 mmol) in anhydrous dichloromethane (10 ml) was added at -78oC in nitrogen atmosphere for 10 min 1.0 M solution tribromide boron in dichloromethane (3 ml, 3 mmol). The resulting mixture was stirred for another 1 h at -78oC, and then left to warm to room temperature. After stirring for 1.5 h at 20-25oC the mixture was cooled to -10oC and then tempered by adding dropwise water (10 ml) for 10 minutes After adding ethyl acetate (10 ml), separated the organic layer, washed with water, dried over Na2SO4to dryness under vacuum. The residue was led from ethanol, gave 169 mg of the above compound in pure form (yield 70%).

C14H14N2O2< / BR>
Calculated: C 69,40 H of 5.82 N TO 11.56

Found: C 69,20 H 5,85 N 11,41

MS m/z: 242

IR cm-1(KBr): 3500-3100 (NH, OH), 2210 (CN), 1685 (CONH2), 1610, 1590, 1560

According to the above method from the corresponding phenolic methyl ethers can be obtained the compounds mentioned in examples 1, 2 and 3.

Example 9.

2-cyano-3-(1-acetoxy-5,6,7,8-tetrahedronal-2-yl)acrylamide

[I, Y, B, R a, R1COCH3, R3=NH2, n 1]

The starting material for this example, the acylation is 2-cyano-3-(1-hydroxy-5,6,7,8-tetr the resultant solution of 2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide (242 mg, 1 mmol) in dry pyridine (0.5 ml) was added acetic anhydride (240 mg, 2 mmol) and kept the mixture overnight at 0-5oC. After which the mixture was concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer was washed with water, and then boiled away under reduced pressure. The crude product is recrystallized from a mixture of chloroform/methanol and obtained in pure form called a connection with the release of 90% (256 mg).

C16H16N2O3< / BR>
Calculated: C 67,59 H 5,67 N 9,85

Found: C 67,41 of 5.45 H N 9,71

MS m/z: 284

IR cm-1(KBr): 3300-3200 (NH), 2200 (CN), 1750 (CH3COO), 1690 (CONH2), 1610, 1590, 1560.

According to the above method, you can turn phenols obtained in examples 1-9, corresponding alcoholnye derivatives of C2-C6.

Example 10.

Tablets, each weighing 0,150 g, containing 25 mg of active substance can be prepared as follows:

composition (for 10,000 tablets):

2-cyano-3-(1-hydroximate-2-yl)acrylamide 250 g

Lactose 800 g

Corn starch 415 g

The talcum powder 30 grams

Magnesium stearate 5 g

Mix 2-cyano-3-(1-hydroximate-2-yl)acrylamide, lactose and half the corn starch; the mixture is then passed through to the APCS for granulated powder. The granules are dried, crushed into a sieve with cells of 1.4 mm, then add the remaining quantity of starch, talc and magnesium stearate, mix thoroughly and make into pills.

Example 11.

It is possible to make capsules, each weighing 0,200 g and contains 20 mg of active substance.

The composition of 500 capsules:

2-cyano-3-(3-hydroximate-2-yl)acrylamide 10 grams

Lactose 80 g

Corn starch 5 grams

Magnesium stearate 5 g

This train was Packed up in hard gelatin capsules consisting of two parts, with each capsule contained 0,200 g of the composition.

Example 12.

Capsules, each 0.5 g, containing 50 mg of active substance, can be prepared:

Composition for 200 capsules, g:

3-[(1,4-dihydroxy-5,6,7,8-tetrahedronal-2-yl)methylene]-2-oxindol 10

Lactose 80

Corn starch 5

Magnesium stearate 5

This new form is encapsulated in hard gelatin capsules of the two parts when the content in each capsule of 0.5 g

Example 13.

Using conventional pharmaceutical techniques can be obtained suppositories of the following composition, g:

3-[(1,4-dihydroxy-5,6,7,8-tetrahedronal-2-yl)methylene]-2-oxindol 0,10

the active substance, can be obtained in the following way:

Composition for 1000 tablets, g:

3-[(quinoline-2-yl)methylene]-2-oxindol 500

Lactose 710

Corn starch 237,5

The talcum powder is 37.5

Magnesium stearate 15

3-[(Quinoline-2-yl)methylene] -2-oxindole, lactose and half the corn starch are mixed, the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 mg) is suspended in warm water (180 ml). The resulting paste is used for granulation of powder. The granules are dried, crushed on the sieve hole size 1.4 mm, add the remaining quantity of starch, talc and magnesium stearate, thoroughly mixed and a lot tabletirujut when using media with a diameter of 8 mm

Physico-chemical data are presented in table.1.

Example 12.

Data biological activity

A representative group of compounds (1) were tested in vitro for activity inhibition of tyrosine kinases by the method Ferguson described in J. Biol. Chem. 1985, 260, 3652 (see page 16 for details).

The following results were obtained, are presented in table.2.

1. The compound of General formula I

< / BR>
where Y is a bicyclic system, selected from A, B, E and G

< / BR>
< / BR>
< / BR>
< / BR>
R group of formula R3-OH, or NH2;

Ph is phenyl;

R1hydrogen;

n is 0, 1 or 2,

or their pharmaceutically acceptable salts, each of the substituents R and OR1can independently be either aryl or heteroaryl residue bicyclic system A, E and G, whereas in the bicyclic ring system B can be substituted only benzene residue and with the additional condition that i when Y is A ring, R is different from group a or d above, ii simultaneously when Y is a ring system of B and R is a group d, as defined above, in which R3OH, then n is non-zero; and iii simultaneously when Y is a ring system of G and R is a group e as defined above, associated with the indole ring in position 2 or 3, n is non-zero.

2. The compound of formula I on p. 1, wherein Y is a bicyclic ring system selected from A, B, E and G, as defined in paragraph 1, the R group of formula a, c, d, e or i, as defined in paragraph 1, R1is hydrogen, and its pharmaceutically acceptable salt.

3. The compound of formula I under item 1, characterized in that under the conditions p. 1 Y bicyclic ring system of formula A, B or E, as defined in paragraph 1, the R group to. A compound selected from the group of the following compounds, which, when necessary, can be either Z - or E-diastereomers, or Z, E-mixtures of these diastereomers: 2-cyano-2-(2-hydroximate-1-yl)diacrylate, 2-cyano-3-(3 - hydroximate-1-yl)diacrylate, 2-cyano-3-(4-hydroximate-1-yl)diacrylate, 2-cyano-3-(1-hydroximate-2-yl)diacrylate, 2-cyano-3-(3 - hydroximate-2-yl)diacrylate, 2-cyano-3-(4-hydroximate-2 - yl)diacrylate, 2-(4-hydroxyphenyl)-3-(naphthas-1-yl)acrylamide, 2-(4-hydroxyphenyl)-3-(naphthas-2-yl)acrylamide, 2-(4-hydroxyphenyl)-3- (naphthas-1-yl)acrylic acid, 2-(4-hydroxyphenyl)-3- (naphthas-2-yl)acrylic acid, 2-cyano-3-(2-hydroxy-5,6,7,8 - tetrahedronal-1-yl)acrylamide, 2-cyano-3-(3-hydroxy-5,6,7,8 - tetrahedronal-1-yl)acrylamide, 2-cyano-3-(4-hydroxy-5,6,7,8 - tetrahedronal-1-yl)acrylamide, 2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide, 2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide, 2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylamide, 2-cyano-3-(2-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid, 2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid, 2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)acrylic acid, 2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)acrylic acid, 2-cyano-3-the slot, 2-cyano-3-(2-hydroxy-5,6,7,8-tetrahedronal-1-yl)diacrylate, 2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)diacrylate, 2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)diacrylate, 2-cyano-3-(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate, 2-cyano-3-(3-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate, 2-cyano-3-(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)diacrylate, 2-[4-hydroxyphenyl(-3-)-5,6,7,8-tetrahedronal-1-yl]acrylamide, 2-[4-hydroxyphenyl(-3-)-5,6,7,8-tetrahedronal-2-yl] acrylamide, 2-[4-hydroxyphenyl(-3-)-5,6,7,8-tetrahedronal-1-yl] acrylic acid, 2-[4-hydroxyphenyl(-3-)-5,6,7,8-tetrahedronal-2-yl] acrylic acid, 2-cyano-3-(3-hydroxyquinolin-2-yl)acrylamide, 2-cyano-3-(4-hydroxyquinolin-2-yl)acrylamide, 2-cyano-3-(2 - hydroxyquinolin-3-yl)acrylamide, 2-cyano-3-(4-hydroxyquinolin-3-yl)acrylamide, 2-cyano-3-(2-hydroxyquinolin-4-yl)acrylamide, 2-cyano-3-(3-hydroxyquinolin-4-yl)acrylamide, 2-cyano-3-(3 - hydroxyquinolin-2-yl)-acrylic acid, 2-cyano-3-(4 - hydroxyquinolin-2-yl)acrylic acid, 2-cyano-3-(2 - hydroxyquinolin-3-yl)acrylic acid, 2-cyano-3-(4 - hydroxyquinolin-3-yl)acrylic acid, 2-cyano-3-(2 - hydroxyquinolin-4-yl)acrylic acid, 2-cyano-3-(3 - hydroxyquinolin-4-yl)acrylic acid, 2-cyano-3-(3 - hydroxyquinolin-2-yl)diacrylate, 2-cyano-3-(4-hydroxycinnamic, 2-cyano-3-(2-hydroxyquinolin-4-yl)diacrylate, 2-cyano-3-(3-hydroxyquinolin-4-yl)diacrylate, 2-[4-hydroxyphenyl(-3-)quinoline-2-yl] acrylamide, 2-[4-hydroxyphenyl(-3-)quinoline-3-yl] acrylamide, 2-[4-hydroxyphenyl(-3-)quinoline-4-yl]acrylamide, 2-[4-hydroxyphenyl(-3-)quinoline-2-yl] acrylic acid, 2-[4-hydroxyphenyl(-3-)quinoline-3-yl] acrylic acid, 2-[4-hydroxyphenyl(-3-)quinoline-4-yl]acrylic acid, 2-[(3-hydroxy-1-naphthyl)methylene]-2-oxindole, 3-[(4-hydroxy-1-naphthyl)methylene]-2-oxindole, 3-[(1-hydroxy-2-naphthyl)methylene]-2-oxindole, 3-[(4-hydroxy-2-naphthyl)methylene] -2-oxindole, 3-[(3-hydroxy-5,6,7,8-tetrahedronal-1-yl)methylene] -2-oxindole, 3-[(4-hydroxy-5,6,7,8-tetrahedronal-1-yl)methylene] -2-oxindole, 3-[(1-hydroxy-5,6,7,8-tetrahedronal-2-yl)the methylene] -2-oxindole, 3-[(4-hydroxy-5,6,7,8-tetrahedronal-2-yl)methylene] -2-oxindole, 3-[(7-hydroxyquinolin-5-yl)methylene]-2-oxindole, 3-[(8-hydroxyquinolin-5-yl)methylene] -2-oxindole, 3-[(7-hydroxyquinolin-6 yl)methylene]-2-oxindole, 3-[(8-hydroxyquinolin-6-yl)methylene] -2-oxindole, 3-[(1,4-dihydroxy-5,6,7,8-tetrahedronal-2-yl)methylene] -2-oxindole, as well as their pharmaceutically acceptable salts.

5. The pharmaceutical composition exhibiting inhibitory activity against Terezin-kinase, comprising a pharmaceutically acceptable carrier or the amount of compounds of General formula I

< / BR>
where Y is a bicyclic system, selected from A, B, E and G

< / BR>
< / BR>
< / BR>
< / BR>
R group of formula a, c, d, e, g, f or i

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R3OH or NH2;

Ph is phenyl;

R1hydrogen;

n is 0, 1 or 2,

or its pharmaceutically acceptable salt, each of the substituents R and OR1can independently be either aryl or heteroaryl residue bicyclic system A, E and G, whereas in the bicyclic ring system B can be substituted only benzene residue when the additional condition specified in paragraph 1 of the formula.

 

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