RU2263666C1 - Heterocyclylsulfinic acids and their derivatives, focused library and pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1):

or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R¹ represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Y_n represents carbon atom of optionally substituted (C₃-C₇)-cycloalkyl or optionally substituted (C₄-C₇)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

Description

This invention relates to the synthesis of new chemicals, the search for new physiologically active substances, leader compounds and drug candidates, obtained by screening combinatorial or focused libraries of compounds, as well as to pharmaceutical compositions, methods for their preparation and use.

More specifically, the present invention relates to new heterocyclylsulfonyl-alkylcarboxylic acids and their esters and amides of interest as potential physiologically active substances (agonists, antagonists and modulators of receptors, enzyme inhibitors, oncolytics, antibacterial and antiparasitic agents, etc.), focused library and pharmaceutical composition.

There are a large number of synthetic sulfinic acids and their derivatives, primarily physiologically active sulfonylalkylcarboxylic acids, their esters and amides. For example, in the series of sulfinic acids, the most studied are alkyl sulfinic acids and arylsulfinic acids and their derivatives

(alkylsulfonyl) alkylcarboxylic and (arylsulfonyl) alkylcarboxylic acids, their esters and amides. Hundreds of publications are devoted to them in the scientific and patent literature. In particular, 3- (4-biphenylsulfonyl) propionic acid is known [Child, R.G .; Osterberg, A.C .; Sloboda, A.E .; Tomcufcik, A.S. Arzneim. Forch 1980, 30 (4a), 695-702], N-hydroxy-3- (4-methoxybenzenesulfonyl) -4-phenyl-butyramide [Groneberg, R.D .; Burns, C.J .; Morrissette, M.M .; Ullrich, J.W .; et al. J. Med. Chem. 1999, 42 (4), 541-544], 3-benzenesulfonyl-1- (2,6-dimethylphenyl) pyrrolidin-2,5-dione [Sumitomo Chemical Co. Pat. 1971, DE 2143601] and others.

Among the heterocyclylsulfonyl-alkylcarboxylic acids and their derivatives, the well-known are: (thiophen-2-sulfonyl) -acetic acid [JP 2001-294621A2, 2001], (pyrrole-3-sulfonyl) -acetic acid [Concepcio, M. et al. J. Chem. Soc., Perkin Tr. I, 1998, 19, 3285-3292. Chade, S. Et al. J. Heterocecl. Chem., 1998, 35 (4), 933-938], (pyrazole-4-sulfonyl) -acetic acid [Alabaster, R.J. tt fl. J. Chem. Soc. Sec. C, 1970, 78-81], (imizazole-4-sulfonyl) -acetic acid [Grant, B.J. J. Chem. Soc., Perkin Tr.I, 1990, 4, 955-963. Iradyan, M.A. Chem.-Farm. J., 1987, 27 (6), 667-672. Fisher, M.T. et al. Canad. J. Chem., 1961, 39, 785-788], (pyridin-3-sulfonyl) -acetic acid [JP 2001-294621A2, 2001], (benzo [1,2,3] thiadiazole-4-sulfonyl) -acetic acid and 1- (benzo [1,2,3] thiadiazole-4-sulfonyl) cyclopropanecarboxylic acid [Blumina, M.V .; Vatlina, L.P .; Korikov, P.V .; Kobylinsky, D. B. Izv. Universities. Chem. Chem. Technology, 2003, 46 (5), 24-25] and their esters, as well as 3- (2-thienylsulfonyl) propionic acid and 3- (5-bromo-2-thienylsulfonyl) propionic acid and their acid chlorides and amides [Tyuneva, I.V .; Filimonov, S.I .; Soloviev, M.Yu .; Balakin, K.B .; Skorenko, A.V .; Dorogov, M.V. Izv. Universities. Chem. Chem. Technology, 2003, 46 (7), 77-82].

Sulfonylalkyl carboxylic acids and their derivatives are known, exhibiting various types of biological activity. So, for example, 2- (2-chlorobenzosulfonyl) -N-cyclopropylmethyl-propioamide is an antispasmodic [Taisho, 1990, JP 1992145062], 2- (6-nitro-2,3-dioxo-1-tetrahydro-benzo [t] quinoxaline -8-sulfonyl) -acetamide is an AMPA antagonist [Novo Nordisk, 1991, Pat. EP 0511152], 1- (1-guanidino-4-chloro-isoquinoline-7-sulfonyl) cyclopentanecarboxylic acid (2-dimethylamino-ethyl) -amide is an urokinase inhibitor [Pfiztr, 1999, Pat. EP 1077945, PCT WO 0005214], and N- (4-cyano-3-trifluoromethylphenyl) -3- (4-fluorobenzenesulfonyl) -2-hydroxy-2-methyl-propioamide (Bicalutamide, Casodex. Raffolutil) is an anti-cancer drug for treating the prostate [AstraZeneca, 1982, Pat. US 4,636,505, Pat. EP 0100172, Pat. JP 1990131462].

Given the high biological potential and a wide range of physiological activity of sulfonylalkylcarboxylic acids and their derivatives, the development of new compounds of this type, focused libraries and pharmaceutical compositions including these compounds, as well as methods for their preparation and use, is relevant.

As a result of studies aimed at searching for new physiologically active substances, leader compounds, the inventors obtained previously unknown heterocyclylsulfinic acids, and based on them new heterocyclylsulfonyl-alkyl carboxylic acids and their derivatives, which are characterized by physiological activity, a focused library and a pharmaceutical composition including these compounds, developed methods for their preparation and use.

It should be noted that information on heterocyclylsulfonyl-alkylcarboxylic acids and their derivatives, published in the patent and scientific literature, is limited only by the above examples.

The following are definitions of terms that are used in the description of the invention.

“Combinatorial library” means a collection of compounds obtained by parallel synthesis designed to search for a hit or leader compound, as well as to optimize the physiological activity of a hit or leader, each library compound corresponding to a common scaffold and the library is a collection of related homologues or analogues.

“Focused library” means a combinatorial library, or a collection of several combinatorial libraries, or a collection of libraries and substances, specially organized in order to increase the likelihood of finding hits and leaders or to increase the efficiency of their optimization. The design of focused libraries, as a rule, is associated with a directed search for effectors (inhibitors, activators, agonists, antagonists, etc.) of specific biological targets (enzymes, receptors, ion channels, etc.).

“Hit compound” (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process.

“Leader compound” (“leader”) means a compound with outstanding (maximum) physiological activity associated with a particular biotarget related to a specific (or several) pathology or disease.

“Parallel synthesis” means the method of conducting combinatorial chemical synthesis of a library.

“Scaffold” means the general structural formula, or molecular framework, or invariant region of compounds, characteristic of all compounds included in the combinatorial library.

"Nucleophilic" means an electron-rich reagent.

"Electrophilic" means an electron-deficient reagent.

“Substituent” means a chemical radical that binds to a scaffold or intermediate in the course of their synthesis, for example, “nucleophilic substituent”, “electrophilic substituent”, “NH-protective substituent” or “inert substituent”.

“Optionally substituted radical” means a radical without substituents or containing one or more substituents, including: “nucleophilic substituent”, “electrophilic substituent”, “NH-protective substituent” and / or “inert substituent”.

“Nucleophilic substituent” means a chemical radical that binds to scaffold as a result of reaction with nucleophilic reagents, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

“Electrophilic substituent” means a chemical radical that attaches to scaffold by reaction with an electrophilic reagent, for example, selected from the group of organic halides (optionally substituted C ₁ -C ₇ alkyl halides, optionally substituted aryl C ₁ -C ₇ alkyl halides, optionally substituted heterocyclyl C ₁ -C ₇ alkyl halides, optionally substituted aryl halides, optionally substituted heterocyclyl halides), organic acids or their derivatives (anhydrides, imidazolides, halides idrides), esters of organic sulfonic acids or organic sulfonyl chlorides, organic haloformates, organic isocyanates and organic isothiocyanataminomethyls.

“NH-Protective Deputy” means a chemical radical that is attached to a scaffold or intermediate to synthesize the amino group in multifunctional compounds, including but not limited to: an amide Deputy such as formyl, optionally substituted acetyl (eg trichloroacetyl, trifluoroacetyl 3-phenylpropionyl, etc. ), optionally substituted benzoyl, etc .; a carbamate substituent such as optionally substituted C ₁ -C ₇ alkyloxycarbonyl, for example methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; optionally substituted C ₁ -C ₇ alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethixibenzyl, 9-phenylfluorenyl, etc .; a sulfonyl substituent, for example, benzenesulfonyl, p-toluenesulfonyl, etc. For more details, "NH-Protecting Substituents" are described in the book: Protective groups in jrganic synthesis, Third Edition Greene, TW and Wilts, PGM 1999, p. 494-653. John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Inert substituent" (or "non-interfering", "Non-interfering substituent") means a low or non-reactive radical including, but not limited to C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl substituted with inert substituents C ₁ -C ₇ alkyl substituted with inert substituents C ₂ -C ₇ alkenyl substituted with inert substituents aralkyl, C ₇ -C ₁₂ heterocyclylalkyl substituted with inert substituents of heterocyclylalkyl , C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ aoxy alkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m -N (C ₁ -C ₇ alkyl) _n aryl substituted with inert substituents; aryl substituted with inert substituents alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, substituted with inert substituents heterocyclyl and nitroalkyl; where m and n are from 1 to 7. Preferred “inert substituents” are C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₂ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl substituted with inert substituents C ₁ -C ₇ alkyl, phenyl substituted with inert substituents phenyl, (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m -N (C ₁ -C ₇ alkyl) _n , aryl substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

“Aryl” means one or more aromatic rings, each of which includes 5 or 6 carbon atoms. “Aryl” may be a fused polycycle, for example, like naphthalene, or non-condensed, such as biphenyl. “Substituted aryl” has one or more substituents.

“Halogen” means a fluorine, chlorine, bromine or iodine atom.

“Heterocycle” means one or more saturated, unsaturated or aromatic rings with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. A “heterocycle” may be a condensed polycycle, for example, as benzimidazole, benzoxazole, benzthiazole, quinoline, or non-condensed, for example, as bipyridyl.

“Azoheterocycle” means a heterocycle comprising at least one nitrogen atom, for example piperidine, morpholine, pyrrole, benzimidazole, benzoxazole, benzthiazole, quinoline.

“Substituted heterocycle” means a heterocycle having one or more substituents.

“Substituted azaheterocycle” means an azaheterocycle having one or more substituents.

The aim of the present invention are new heterocyclylsulfonyl-alkylcarboxylic acids and their derivatives.

This goal is achieved by heterocyclylsulfonyl-alkylcarboxylic acids and their derivatives of General formula 1

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

W represents an optionally substituted heterocyclic radical, including pyrrol-3-yl, thiophen-2-yl, isoxoxol-4-yl, pyrazol-4-yl, imidazol-4-yl, pyridin-3-yl, 1H-2, 4-dioxo-pyrimidin-5-yl, 2,3-dihydro-1H-indol-5-yl, 2,3-dihydro-1H-indol-7-yl, 1,3-dihydro-2-oxo-indole- 5-yl, 2,3-dioxo-1H-indol-5-yl, 2-oxo-3H-benzooxazol-6-yl, benzothiazol-6-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-5- silt, benzo [1,2,5] oxadiazol-4-yl, benzo [1,2,5] thiadiazol-4-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 3,4-dihydro 2-oxo-1H-quinolin-6-yl, quinolin-8-yl, 1,4-dihydro-2,3-dioxo-quinoxaline-6-yl, 3-oxo-4H-benzo [1,4] oxazin- 7-yl , 3-oxo-4H-benzo [1,4] thiazin-7-yl, 2,4-dioxo-1H-quinazolin-6-yl, 2,4-dioxo-1,5-dihydrobenzo [b] [1, 4] diazepin-7-yl or 2,5-dioxo-3,4-dihydrobenzo [b] [1,4] diazepin-7-yl;

Y represents an optionally substituted methylene group;

R ^{1 is} a chlorine atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted azaheterocyclyl;

n is 1, 2 or 3; or

Y _n represents a carbon atom of an optionally substituted C ₃ -C ₇ cycloalkyl or an optionally substituted C ₄ -C ₇ heterocyclyl;

excluding (thiophen-2-sulfonyl) -acetic acid, (pyrrole-3-sulfonyl) -acetic acid, (pyrazole-4-sulfonyl) -acetic acid, (imizazole-4-sulfonyl) -acetic acid, (pyridin-3- sulfonyl) -acetic acid, (benzo [1,2,3] thiadiazole-4-sulfonyl) -acetic acid, 1- (benzo [1,2,3] thiadiazole-4-sulfonyl) -cyclopropanecarboxylic acid and their esters, 3 - (2-thienylsulfonyl) propionic acid, 3- (5-bromo-2-thienylsulfonyl) propionic acid, their chlorides and amides.

According to the invention, the most preferred compounds of the general formula 1 are 3- (heterocyclylsulfonyl) -propionic acids and their derivatives of the general formula 1.1

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

W and R ¹ have the above meaning; R ² and R ³ independently represent a hydrogen atom or an inert substituent, or R ² and R ³ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; excluding 3- (2-thienylsulfonyl) propionic acid, 3- (5-bromo-2-thienylsulfonyl) propionic acid, their acid chlorides and amides.

According to the invention, the most preferred compounds of the general formula 1 are (heterocyclylsulfonyl) -acetic acids and their derivatives of the general formula 1.2

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which:

W and R ¹ have the above meaning; R ⁴ and R ⁵ independently represent a hydrogen atom, an inert substituent, or R ⁴ and R ⁵ together with the carbon atom to which they are attached form an optionally substituted C ₃ -C ₇ cycloalkyl or C ₄ -C ₇ heterocyclyl; excluding (thiophen-2-sulfonyl) -acetic acid, (pyrrole-3-sulfonyl) -acetic acid, (pyrazole-4-sulfonyl) -acetic acid, (imizazole-4-sulfonyl) -acetic acid, (pyridin-3- sulfonyl) acetic acid, (benzo [1,2,3] thiadiazole-4-sulfonyl) acetic acid, 1- (benzo [1,2,3] thiadiazole-4-sulfonyl) cyclopropanecarboxylic acid and their esters.

An object of the present invention is to provide a focused library for searching for biologically active leader compounds.

This goal is achieved by a focused library comprising at least one (heterocyclylsulfonyl) -alkylcarboxylic acid and its derivative of the general formula 1 or a pharmaceutically acceptable salt, N-oxide or hydrate thereof.

The aim of the present invention is a new pharmaceutical composition in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package.

The goal is achieved by a pharmaceutical composition comprising at least one (heterocyclylsulfonyl) -alkylcarboxylic acid and its derivative of the general formula 1 or a pharmaceutically acceptable salt, N-oxide or hydrate thereof.

Pharmaceutically acceptable salts of the compounds can be prepared in a conventional manner, for example, by treating the compounds with an appropriate acid or base. N-oxides can be obtained by oxidation of the corresponding nitrogen-containing compounds. Hydrates of the compounds can be obtained, for example, by recrystallization from aqueous solutions or are formed spontaneously in the synthesis process.

The method for producing new heterocyclylsulfonyl-alkylcarboxylic acids and their derivatives is based on known reactions and consists in sulfochlorination of heterocyclic compounds of the general formula 2, conversion of the resulting sulfochlorides 3 by the action of sodium sulfite in an aqueous alkaline medium into sodium salts of sulfinic acids 4, and then by the action of acetic acid on the latter. to sulfinic acids 5 according to the scheme below:

where W has the above meaning.

By the interaction of salts of sulfinic acids of general formula 4 with alkylators of general formula 6, heterocyclylsulfonyl-alkylcarboxylic acids and their derivatives are prepared according to the scheme below:

in which W, R ¹ , Y and n have the above meaning.

3- (Heterocyclylsulfonyl) propionic acids and their derivatives of the general formula 1.1 are prepared by reacting sulfinic acids of the general formula 5 with acrylic acids and their derivatives of the general formula 7.

in which W, R ¹ , R ² and R ³ have the above meaning.

The invention is described below using examples of the preparation of specific compounds and a focused library. The structures of the obtained compounds were confirmed by chromatographic and spectral analysis.

The following examples illustrate but do not limit the invention.

Example 1. The general method for producing heterocyclylsulfonyl chlorides of the general formula 3. Heterocyclic compound 2 (0.1 mol) was added over 30 minutes with stirring to chlorosulfonic acid [20 ml (0.3 mol)]. The reaction mixture was stirred at 40 ° C for 15 minutes and PCl ₅ [25.0 g (0.12 mol)] was added with stirring at 50-70 ° C. The reaction mixture was heated to 80 ° C and stirred for 1 hour, after which it was cooled to 5 ° C and poured into ice (500 g). The precipitate was filtered off, washed on the filter with water and extracted with chloroform (100 ml). The extract was washed with water, dried, chloroform was distilled off in vacuo, the residue was recrystallized, if necessary, from a suitable solvent. Received heterocyclylsulfonyl chloride 3, yield, and so pl. which are given in table 1.

Example 2. The general method for the preparation of sodium salts of heterocyclylsulfinic acids of the general formula 4. To a solution of Na ₂ SO ₃ [63 g (0.5 mol)] and NaHCO ₃ [4.2 g (0.05 mol] in water (330 ml) were added over 1 hours at 85-90 ° C and stirring heterocyclylsulfonyl chloride 3 (0.5 mol), maintaining a pH of 9-10 by adding 30% aqueous NaOH.The reaction mixture was stirred for 30 min, cooled at 5 ° C overnight, the precipitate was filtered off and dried at room temperature Received the sodium salt of heterocyclylsulfinic acid of General formula 4 with a yield of 75-97%, which was used in distant yshih syntheses without further purification.

Example 3. The General method of obtaining 3- (heterocyclylsulfonyl) -propionic acids of General formula 1 (n = 2, R ¹ = OH). A method suitable for parallel synthesis of a combinatorial library of compounds of general formula 1 (n = 2, R ¹ = OH). Acetic acid (0.5 mol) was added to a solution of the sodium salt of heterocyclylsulfinic acid of the general formula 4 (0.5 mol) in a mixture of water (500 ml). To the resulting solution of heterocyclylsulfinic acid of the general formula 5, acrylic acid of the general formula 7 (R ¹ = OH) (0.5 mol) was added over 20-30 minutes with stirring. The precipitate was filtered off, and 3- (heterocyclylsulfonyl) -propionic acid of the general formula 1 (R ¹ = OH) was obtained in a yield of 80-92% (Table 2).

Example 4. A General Method for the Preparation of (heterocyclylsulfonyl) alkylcarboxylic acid chlorides of the general formula 1 (R ¹ = Cl). Heterocyclylsulfonyl-alkylcarboxylic acid of general formula 1 (R ¹ = OH) (0.1 mol) was added over 40 minutes at room temperature to a solution of PCl ₅ (0.15 mol) in toluene (300 ml). Then the reaction mass was boiled with stirring until acid 1 was completely dissolved (R ¹ = OH), after which the reaction mass was cooled, the precipitate was filtered off and recrystallized, if necessary, from a suitable solvent. Received acid chlorides (heterocyclylsulfonyl) -alkylcarboxylic acids of General formula 1 (R ¹ = Cl) with a yield of 50-75% (Table 3).

Example 5. General method for the preparation of amides of (heterocyclylsulfonyl) alkylcarboxylic acids of the general formula 1 (R ¹ = NR ⁷ R ⁸ ). A method suitable for parallel synthesis of a combinatorial library of compounds of general formula 1 (R ¹ = NR ⁷ R ⁸ ).

Method A. To the solutions of the corresponding amines or azoheterocycles of the general formula HNR ⁷ R ⁸ 9 (1.5 mmol), triethylamine [0.26 ml (1.8-2 mmol)] in DMF, the corresponding acid chlorides were added with stirring cooled to 10 ° C with stirring general formula 1 (R ¹ = Cl) (1.5 mmol). The reaction masses were stirred for 1 hour at 55 ° C and diluted with water, the precipitates were filtered off and recrystallized from methanol. Received with a yield of 30-95% combinatorial library of substituted amides (heterocyclylsulfonyl) -alkylcarboxylic acids 1 (R ¹ = NR ⁷ R ⁸ ), are presented in Tables 4 and 5.

Method B. A mixture of heterocyclylsulfonyl-alkylcarboxylic acids of the general formula 1 (R ¹ = OH) (0.0011 mol) and carbodiimidazole [0.16 g (0.001 mol)] in dry dioxane (5 ml) was heated at 40-60 ° C for 2 hours. The corresponding amine or azoheterocycle of the general formula 9 (0.0011 mol) was added to the reaction mass. The reaction mass was boiled for 1-2 hours, cooled and diluted with water. The precipitate was filtered off and recrystallized from MeOH or MeOH / DMF. Received a combinatorial library of amides 1 (R ¹ = NR ⁷ R ⁸ ) with a yield of 30-75%, are presented in Tables 4 and 5.

Examples 6. Compiled a focused library comprising 196 compounds of general formula 1.1 (table 4) and 46 compounds of general formula 1.2 (table 5) and tested its ability to inhibit the activity of protein kinase, which was determined as follows. A solution of the polypeptide (Calbiochem, USA), consisting of a random sequence of glutamic acid and tyrosine in a quantitative ratio of 4: 1, respectively, was kept in the wells of 96-well plates with an optically transparent bottom overnight. During this time, the polypeptide was firmly absorbed on the surface of the wells. The sorbed polypeptide served as a substrate for the kinase that phosphorylated tyrosine in the polypeptide.

100 microliters of 1U kinase (Calbiochem, USA, 1U was determined as the concentration of this enzyme capable of attaching 1 picomole phosphate to the substrate in 1 minute) to wells with an adsorbed polypeptide without test compounds (control activity) or in the presence of different concentrations of these compounds was added. After a 30-minute incubation, these solutions were removed by shaking from the wells and the wells were washed twice with physiological saline. 100 microliters of a solution of antiphosphothyrosine monoclonal IGg antibodies with conjugated horseradish peroxidase were poured into the wells (Sigma, USA). The amount of bound antibodies was determined by the corresponding peroxidase activity, which, in turn, was determined by the rate of conversion of the peroxidase substrate (OPD, o-phenolenediamme dihydrochloride, Sigma) to the colored product. The concentration of this product, formed after 30 minutes of the reaction, was determined by the optical density at 490 nm, measured using a parallel 96-well reader VICTOR ² V (PerkinElmer, USA).

To calculate the percent inhibition of kinase activity, each 96-well plate contained the following control wells:

1) a reaction solution containing all components except kinase;

2) the reaction solution together with the kinase.

The optical density measured in the control wells (1) was taken as zero activity (OD ₀ ), and the optical density measured in the control wells (2) was taken as 100% (OD ₁₀₀ ). The optical densities measured in the presence of the test compounds (OD _i ) were expressed as a percentage of the maximum activity, and the percentage inhibition of kinase activity was calculated by the following formula:

The inhibition values of ABL kinase (tyrosine kinase responsible for the development of Abelson’s leukemia, chronic myelogenous leukemia) obtained by testing a focused library of compounds 1 at a concentration of 30 μM, range from 2 to 20%, which confirms the biological activity of compounds of the general formula 1 .

Claims (7)

1. Heterocyclylsulfonylalkylcarboxylic acids and their derivatives of General formula 1

(1) or their pharmaceutically acceptable salts, N-oxides or hydrates, in which W represents an optionally substituted heterocyclic radical, including pyrrol-3-yl, thiophen-2-yl, isoxoxol-4-yl, pyrazol-4-yl, imidazol-4-yl, pyridin-3-yl, 1H- 2,4-dioxo-pyrimidin-5-yl, 2,3-dihydro-1H-indol-5-yl, 2,3-dihydro-1H-indol-7-yl, 1,3-dihydro-2-oxo indol-5-yl, 2,3-dioxo-1H-indol-5-yl, 2-oxo-3H-benzoxazol-6-yl, benzothiazol-6-yl, 1H-benzimidazol-5-yl, benzo [1, 2,5] oxadiazol-4-yl, benzo [1,2,5] thiadiazol-4-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 3,4-dihydro-2-oxo-1H- quinolin-6-yl, quinolin-8-yl, 1,4-dihydro-2,3-dioxoquinoxalin-6-yl, 3-oxo-4H-benzo [1,4] oxazin-7-yl, 3-oxo- 4H-bin o [1,4] thiazin-7-yl, 2,4-dioxo-1H-quinazolin-6-yl, 2,4-dioxo-1,5-dihydrobenzo [b] [1,4] diazepin-7-yl or 2,5-dioxo-3,4-dihydrobenzo [b] [1,4] diazepin-7-yl; Y represents an optionally substituted methylene group; R ¹ represents a chlorine atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted azaheterocyclyl; n is 1,2 or 3; or Y _n represents a carbon atom of an optionally substituted C ₃ -C ₇ cycloalkyl or optionally substituted C ₄ -C ₇ heterocyclyl, excluding (thiophen-2-sulfonyl) -acetic acid, (pyrrole-3-sulfonyl) -acetic acid, (pyrazole -4-sulfonyl) -acetic acid, (imidazole-4-sulfonyl) -acetic acid, (pyridin-3-sulfonyl) -acetic acid, (benzo [1,2,3] thiadiazole-4-sulfonyl) -acetic acid, 1- (benzo [1,2,3] thiadiazole-4-sulfonyl) cyclopropanecarboxylic acid and esters thereof, 3- (2-thienylsulfonyl) propionic acid, 3- (5-bromo-2-thienylsulfonyl) propionic islotu, chlorides and amides. 2. The compounds according to claim 1, which are 3- (heterocyclylsulfonyl) -propionic acids and their derivatives of General formula 1.1

1.1 or their pharmaceutically acceptable salts, N-oxides or hydrates, in which W and R ¹ have the above meaning; R ² and R ³ independently represent a hydrogen atom or an inert substituent, or R ² and R ³ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; excluding 3- (2-thienylsulfonyl) propionic acid, 3- (5-bromo-2-thienylsulfonyl) propionic acid, their acid chlorides and amides. 3. The compounds according to claim 1, which are (heterocyclylsulfonyl) -acetic acids and their derivatives of the general formula 1.2

1.2 or their pharmaceutically acceptable salts, N-oxides or hydrates, in which W and R ¹ have the above meaning; R ⁴ and R ⁵ independently represent a hydrogen atom, an inert substituent, or R ⁴ and R ⁵ together with the carbon atom to which they are attached form an optionally substituted C ₃ -C ₇ cycloalkyl or optionally substituted C ₄ -C ₇ heterocyclyl; excluding (thiophen-2-sulfonyl) -acetic acid, (pyrrole-3-sulfonyl) -acetic acid, (pyrazol-3-sulfonyl) -acetic acid, (imidazole-4-sulfonyl) -acetic acid, (pyridin-3- sulfonyl) acetic acid, (benzo [1,2,3] thiadiazole-4-sulfonyl) acetic acid, 1- (benzo [1,2,3] thiadiazole-4-sulfonyl) cyclopropanecarboxylic acid and their esters. 4. A focused library for searching for biologically active leader compounds, comprising at least one (heterocyclylsulfonyl) alkylcarboxylic acid or a derivative thereof of the general formula 1 according to claim 1, or a pharmaceutically acceptable salt, N-oxide or hydrate thereof. 5. A pharmaceutical composition having the action of a kinase inhibitor in the form of tablets, capsules or injections in a pharmaceutically acceptable package, comprising at least one (heterocyclylsulfonyl) alkylcarboxylic acid and its derivative of the general formula 1 or a pharmaceutically acceptable salt thereof, N-oxide or hydrate.