Heterocyclylsulfinic acids and their derivatives, focused library and pharmaceutical composition


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 Yn 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

 

This invention relates to the synthesis of new chemicals, the search for new physiologically active substances, compounds leaders and drug candidates that can be derived from the combinatorial or screening of focused libraries of compounds, and to pharmaceutical compositions, methods for their preparation and use.

More specifically, the present invention relates to new heterocyclisation-alkalicarbonate acids, their esters and Amida of interest as a potential physiologically active substances (agonists, antagonists and modulators of receptors, enzyme inhibitors, oncolytic, antibacterial and antiparasitic agents, etc), to the focused library and pharmaceutical compositions.

There are a large number of synthetic Sultanovich acids and their derivatives, primarily physiologically active sulphonilecarbomide acids, their esters and amides. For example, in a series Sultanovich acids most studied are alkylsulfonate acid and arylsulfonic acids and their derivatives

(alkylsulfonyl)alkalicarbonate and (arylsulfonyl)alkalicarbonate acids, their esters and amides. In the scientific and patent literature devoted to them hundreds of publications. In particular, the known 3-(4-biphenylmethanol)-propionic who Isleta [Child, R.G.; Osterberg, A.S.; Sloboda, A.E.; Tomcufcik, A.S. Arzneim. Forsch. 1980, 30(4A), 695-702], N-hydroxy-3-(4-methoxybenzenesulfonyl)-4-phenyl-butyramide [Bend, R.D.; Burns, C.J.; Morrissette, M.M.; Ullrich, J.W.; et al. J. Med. Chem. 1999, 42 (4), 541-544], 3-benzazolyl-1-(2,6-dimetilfenil)pyrrolidin-2,5-dione [Sumitomo Chemical Co. Pat. 1971, DE 2143601] and others

Among heterocyclisation-alkylcarboxylic acids and their derivatives the famous: (thiophene-2-sulfonyl)-acetic acid [JP 2001-A, 2001], (pyrrol-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], (imidazol-4-sulfonyl)-acetic acid [Grant, B.J. J. Chem. Soc., Perkin Tr.I, 1990, 4, 955-963. Iradian, M.A. Chem.-Pharm. J., 1987, 27(6), 667-672. Fisher, M.T. et al. Canad. J. Chem., 1961, 39, 785-788], (pyridine-Z-sulfonyl)-acetic acid [JP 2001-A, 2001], (benzo[1,2,3]thiadiazole-4-sulfonyl)-acetic acid and 1-(benzo[1,2,3]thiadiazole-4-sulfonyl)-cyclopropanecarbonyl acid [Blumina, M.V.; Vallina, L.P.; korikov, P.V.; kobylinsky, B. math. Higher education institutions. Chem. Chem. Technology, 2003, 46(5), 24-25] and their esters, and 3-(2-thienylmethyl)propionic acid and 3-(5-bromo-2-thienylmethyl)propionic acid and their anhydrides and amides [Tuneva, I.V.; Filimonov, S.; Soloviev, M.; Balakin, K.B.; Skorenko, A.V.; roads, M.V. Izv. Higher education institutions. Chem. Chem. Technology, 2003, 46(7), 77-82].

Known sulfonylated carboxylic acids and their derivatives, expressed the managing various kinds of biological activity. So, for example, 2-(2-chlorobenzenesulfonyl)-N-cyclopropylmethyl-propionamide is spazmolitiki [Taisho, 1990, JP 1992145062], 2-(6-nitro-2,3-dioxo-1-tetrahydro-benzo[t]cinoxacin-8-sulfonyl)-ndimethylacetamide is AMPA antagonist [Novo Nordisk, 1991, Pat. EP 0511152], 1-(1-guanidino-4-chloro-isoquinoline-7-sulfonyl)-cyclopentanecarboxylic acid (2-dimethylamino-ethyl)-amide is urokinase inhibitor [Pfiztr, 1999, Pat. EP 1077945, PCT WO 0005214], and N-(4-cyano-3-triptoreline)-3-(4-permentantly)-2-hydroxy-2-methyl-propionamide (Bicalutamide, Casodex. Raffolutil) is an anticancer drug for the treatment of prostate [AstraZeneca, 1982, Pat. US 4636505, Pat. EP 0100172, Pat. JP 1990131462].

Given the high biological potential and a wide range of physiological activity sulphonilecarbomide acids and their derivatives, it is important to develop new compounds of this type, focused libraries and pharmaceutical compositions comprising these compounds and methods of their preparation and use.

As a result of research aimed at finding new physiologically active substances, compounds leaders, inventors received previously unknown heterocyclisation acid, and on their basis new heterocyclisation-alkalicarbonate acids and their derivatives, which possess physiological activity, focuser the private library and pharmaceutical composition including these compounds, have developed methods for their preparation and use.

It should be noted that information about heterocyclisation-alkylcarboxylic acids and their derivatives, published in the patent and scientific literature, limited to the above examples.

Below are definitions of terms used in the description.

"Combinatorial library" means a collection of compounds obtained by parallel synthesis, designed to search for connections-hit or leader, as well as to optimize the physiological activity of hit or leader, each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

"Focused library" means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, typically associated with directional search effectors (inhibitors, activators, agonists, antagonists, etc.) certain biological targets (enzymes, receptors, ion channels, and so on).

"Connection-hit" ("hit") means a compound, a CR is revealed during the initial screening of the desired physiological activity.

"Connection-leader" ("leader") means the connection is outstanding (maximum) physiological activity associated with a specific biomechani relating to a particular (or several) of pathology or disease.

"Parallel synthesis" means a method of doing combinatorial chemical synthesis library.

"Scaffold" means the General structural formula, or molecular skeleton, or invariant connections area common to all compounds included in the combinatorial library.

"Nucleophilic" means elektronoizbytochnye reagent.

"Electrophilic" means electron reagent.

"Deputy" means a chemical moiety that is attached to scaffold or semi-synthesis in the process of their synthesis, for example, nucleophilic Deputy", "electrophilic Deputy", "NH-protective Deputy" or "inert Deputy".

"Optionally substituted radical" means a radical without substituents or with one or more substituents, including: "nucleophilic Deputy", "electrophilic Deputy", "NH-protective Deputy" and/or "inert Deputy".

"Nucleophilic Deputy" means a chemical moiety that is attached to scaffold in the reaction with nucleophilic reagents, for example, selected from the group of Erwinia or secondary amines, alcohols, phenols, mercaptans and thiophenols.

"Electrophilic Deputy" means a chemical moiety that is attached to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic halides (optionally substituted C1-C7alkyl halides, optionally substituted aryls1-C7alkyl halides, optionally substituted heterocyclyl1-C7alkyl halides, optionally substituted aryl halides, optionally substituted heterocyclyl halides), organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothiocyanatobenzene.

"NH-Protective Deputy" means a chemical moiety that is attached to scaffold or semi-synthesis for the temporary protection of amino groups in multifunctional compounds including, but not limited to: amide Deputy such as formyl, optionally substituted acetyl (such as trichloroacetyl, TRIFLUOROACETYL 3-phenylpropionyl and others), optionally substituted benzoyl and others; urethane Deputy such as optionally substituted C1-C7allyloxycarbonyl, for example, ethoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and others; optionally substituted C1-C7alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorene and others; sulfanilic the Deputy, for example, benzazolyl, p-toluensulfonyl and other More "NH-Protective substituents" described in the book: Protective groups in jrganic synthesis, Third Edition, Greene, T.W. and Wilts, P.G.M. 1999, p. 494-653. Publisher John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Inert Deputy" (or "not interfering", "Non-interfering substituent"means low or directionspanel radical including, but not limited to C1-C7alkyl, C2-C7alkenyl, C2-C7quinil, C1-C7alkoxy, C7-C12aralkyl substituted with inert substituents C1-C7alkyl, substituted with inert substituents C2-C7alkenyl substituted with inert substituents, aralkyl,7-C12geterotsiklicheskikh substituted with inert substituents, geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl, C2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2) m-N(C1-C7alkyl)n, aryl, substituted with inert substituents aryl, substituted with inert substituents, alkoxy, foralkyl, aryloxyalkyl, heterocyclyl substituted with inert substituents heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred inert substituents are C1-C7alkyl, C2-C7alkenyl, C2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl substituted with inert substituents C1-C7alkyl, phenyl, substituted by inert substituents phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

"Aryl" means one or more aromatic cycles, each of which includes 5 or 6 carbon atoms. "Aryl" may be condensed political, such as naphthalene or unfused, such as biphenyl. "Substituted aryl" has one or more substituents.

"Halogen" means fluorine atom, chlorine, bromine or iodine.

"Heterocycle" means one or more saturated, unsaturated or aromatic cycles 5, 6 Il is 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. "Heterocycle" may be condensed political, such as benzimidazole, benzoxazole, benzthiazole, quinoline or unfused, for example, as bipyridyl.

"Azaheterocycle" means a heterocycle comprising at least one nitrogen atom, such as piperidine, morpholine, pyrrole, benzimidazole, benzoxazole, benzthiazole, quinoline.

"Substituted heterocycle" means a heterocycle having one or more substituents.

"Substituted azaheterocycle" means azaheterocycle with one or more substituents.

The aim of the present invention are new heterocyclisation-alkalicarbonate acids and their derivatives.

This goal is achieved heterocyclisation-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, thiophene-2-yl, isooctanol-4-yl, pyrazole-4-yl, imidazol-4-yl, pyridine-3-yl, 1H - 2,4-dioxo-pyrimidine-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-benzox the evil-6-yl, benzothiazol-6-yl, 1H-benzimidazole-5-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazol-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxo-cinoxacin-6-yl, 3-oxo-4H-benzo[1,4]oxazin-7-yl, 3-oxo-4H-benzo[1,4]thiazin-7-yl, 2,4-dioxo-1H-hinzelin-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;

R1the chlorine atom, optionally substituted hydroxyl group, optionally substituted amino group, optionally substituted azaheterocyclic;

n is 1, 2 or 3; or

Ynis a carbon atom optionally substituted C3-C7cycloalkyl or optionally substituted C4-C7heterocyclyl;

excluding (thiophene-2-sulfonyl)-acetic acid, (pyrrol-3-sulfonyl)-acetic acid, (pyrazole-4-sulfonyl)-acetic acid, (imidazol-4-sulfonyl)-acetic acid (pyridine-3-sulfonyl)-acetic acid (benzo[1,2,3]thiadiazole-4-sulfonyl)-acetic acid, 1-(benzo[1,2,3]thiadiazole-4-sulfonyl)-cyclopropanecarbonyl acid and their esters, 3-(2-thienylmethyl)propionic acid, 3-(5-bromo-2-thienylmethyl)propionic acid, their anhydrides and amides.

According to the invention the most preferred with the connections of General formula 1 are 3-(heterocyclisation)-propionic acids and their derivatives of General formula 1.1

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

W and R1have the above meaning; R2and R3independently from each other represent a hydrogen atom or an inert Deputy, or R2and R3together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl; excluding 3-(2-thienylmethyl)propionic acid, 3-(5-bromo-2-thienylmethyl)propionic acid, their anhydrides and amides.

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

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

W and R1have the above meaning; R4and R5independently from each other represent a hydrogen atom, an inert Deputy or R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-C7cycloalkyl or4-C7heterocyclyl; excluding (thiophene-2-sulfonyl)-acetic acid, (pyrrol-3-sulfonyl)-acetic acid, (pyrazole-4-sulfonyl)-acetic acid, (imidazol-4-sulfonyl)-acetic acid (pyridine-3-sulfonyl)-acetic acid (benzo[1,2,3]thiadiazole-4-sulfonyl)-acetic acid, 1-(benzo[1,2,3]thiadiazole-4-sulfonyl)-cyclopropanecarbonyl acid and their esters.

The aim of the present invention are focused library to search for biologically active compounds leaders.

This goal is achieved by the focused library that includes at least one (heterocyclisation)-alkalicarbonate acid and its derivative of the General formula 1 or pharmaceutically acceptable salt, N-oxide or hydrate.

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

This goal is achieved by a pharmaceutical composition comprising at least one (heterocyclisation)-alkalicarbonate acid and its derivative of the General formula 1 or pharmaceutically acceptable salt, N-oxide or hydrate.

Pharmaceutically acceptable salts of the compounds can be obtained in a traditional way, for example, the effect on the connection of the appropriate acid or base. N-oxides can be obtained by oxidation of the corresponding nitrogen-containing compounds. Hydrates of compounds can be obtained, for example, by recrystallization from water solutions or formed spontaneously in the synthesis process.

Way to generate new heterocyclisation-alkalicarbonate Ki the lot and their derivatives based on known reactions and is sulfochlorinated heterocyclic compounds of General formula 2, transformation of the resulting sulfochloride 3 by the action of sodium sulfite in aqueous-alkaline medium in sodium salt Sultanovich acids 4, and then the action on the last acetic acid in sulfinamide acid 5 on the diagram below:

where W has the above value.

The interaction of salts Sultanovich acids of General formula 4 with alciatore General formula 6 get heterocyclisation-alkalicarbonate acids and their derivatives the scheme below:

in which W, R1, Y and n have the above meaning.

3-(Heterocyclisation)-propionate acids and their derivatives of the General formula 1.1 is produced by interaction Sultanovich acids of General formula 5 with acrylic acids and their derivatives of General formula 7.

in which W, R1, R2and R3have the above value.

Below the invention is described using the examples of the preparation of specific compounds and focused libraries. The structure of the obtained compounds was confirmed by chromatographic and spectral data analysis.

The following examples illustrate but do not limit the invention.

Example 1. A common way to obtain heterocyclisation chlorides of General formula 3. Added is within 30 minutes under stirring and 30-40° With a heterocyclic compound 2 (0.1 mole) chlorosulfonic acid [20 ml (0.3 mol)]. The reaction mixture was stirred at 40°15 min and was added with stirring and 50-70°PCl5[25.0 g (0.12 mol)]. The reaction mixture was heated to 80°and was stirred 1 h, then was cooled to 5°and poured into ice (500 g). The precipitate was filtered, washed on the filter with water and extracted with chloroform (100 ml). The extract was washed with water, dried, kept in vacuum chloroform, the balance, if necessary, recrystallized from a suitable solvent. Received heterocyclisation chlorides 3, exit and TPL which are listed in table 1.

Example 2. A common method of obtaining sodium salts geterotsiklicheskikh acids of General formula 4. To a solution of Na2SO3[63 grams (0.5 mol)] and NaHCO3[of 4.2 g (0.05 mol] in water (330 ml) was added for 1 hour at 85-90°and With stirring heterocyclisation chloride 3 (0.5 mol), maintaining the pH 9-10 by addition of 30% aqueous NaOH. The reaction mixture was stirred 30 min, cooled at 5°during the night, the precipitate was filtered and dried at room temperature. Received sodium salt geterotsiklicheskikh KIS is the notes of General formula 4 with the release of 75-97%, which was used for further syntheses without further purification.

Example 3. General method for the preparation of 3-(heterocyclisation)-propionic acid of General formula 1 (n=2, R1=HE). The method is suitable for parallel synthesis of combinatorial libraries of compounds of General formula 1 (n=2, R1=HE). To a solution of sodium salt geterotsiklicheskikh acid of General formula 4 (0.5 mol) in a mixture of water (500 ml) was added acetic acid (0.5 mol). To the resulting solution geterotsiklicheskikh acid of General formula 5 was added for 20-30 minutes under stirring, and 20°acrylic acid of General formula 7 (R1= HE) (0.5 mol). The precipitate was filtered, was obtained 3-(heterocyclisation)-propionic acid of General formula 1 (R1=HE) with the release of 80-92% (table 2).

Example 4. A common way of gaining dichlorides (heterocyclisation)-alkylcarboxylic acids of General formula 1 (R1= Cl). Was added for 40 min at room temperature heterocyclisation-alkalicarbonate acid of General formula 1 (R1=HE) (0.1 mol) to a solution of PCl5(0.15 mol) in toluene (300 ml). Then the reaction mass was heated under stirring until complete dissolution of the acid 1 (R1=HE), after which the reaction mass was ohlidal OS, the iPod was filtered and recrystallized, if necessary, of a suitable solvent. Received anhydrides (heterocyclisation)-alkylcarboxylic acids of General formula 1 (R1=Cl) with the release of 50-75% (table 3).

Example 5. A common way of gaining amides (heterocyclisation)-alkylcarboxylic acids of General formula 1 (R1=NR7R8). The method is suitable for parallel synthesis of combinatorial libraries of compounds of General formula 1 (R1=NR7R8).

Method A. To a solution of the appropriate amine or azaheterocycles General formula HNR7R89 (1.5 mmol), triethylamine [of 0.26 ml (1,8-2 mmol)in DMF cooled to 10°under stirring was added the appropriate acid chlorides of General formula 1 (R1=Cl) (1.5 mmol). The reaction mass was stirred for 1 hour at 55°and was diluted with water, precipitation was filtered and precrystallization from methanol. Was obtained with the yield 30-95% combinatorial library of substituted amides (heterocyclisation)-alkylcarboxylic acid 1 (R1=NR7R8), are presented in Tables 4 and 5.

Method b was Heated mixture heterocyclisation-alkylcarboxylic acids of General formula 1 (R1=HE) (0,0011 mol) and carbodiimide [0.16 g (0.001 mol)] in dry dioxane (5 ml) at 40-60°C for 2 hours. To the reaction mass was added with the appropriate amine or azaheterocycle General formula 9 (0,0011 mol). The reaction mass was heated for 1-2 hours, cooled and diluted with water. The precipitate was filtered and recrystallized from Meon or MeOH/DMF. Got a combinatorial library of amides 1 (R1=NR7R8with 30-75%, are presented in Tables 4 and 5.

Examples 6. Was focused library, including 196 compounds of General formula 1.1 (table 4) and 46 of the compounds of General formula 1.2 (table 5) and tested its ability to inhibit the activity of protein kinase, which was determined as follows. The solution of the polypeptide (Calbiochem, USA), consisting of a random sequence of glutamic acid and tyrosine in the proportion 4:1, respectively, was maintained in the wells of 96-hole plates with optically transparent bottom during the night. During this time, the polypeptide firmly sorbirovtsa on the surface of the hole. Adsorbed polypeptide served as substrate for the kinase, which was fosfaurilirovania irosin in this polypeptide.

Added 100 microliters 1U kinase (Calbiochem, USA, 1U is defined as the concentration of this enzyme is able to attach to the substrate 1 picomole phosphate for 1 minute) in the wells with the adsorbed polypeptide without the test compounds (control activity) or in the presence of different concentrations of these compounds. After 30 minutes of incubation, the solutions were removed by shaking from the wells and the wells were washed twice with saline. The wells were filled with 100 microlitres solution antiphosphotyrosine monoclonal IGg antibodies conjugated with horseradish peroxidase from horseradish (Sigma, USA). The amount of bound peroxidase antibodies was determined by the activity of peroxidase, which, in turn, was determined by conversion speed peroxidase substrate (OPD, o-phenolenediamme dihydrochloride, Sigma) into a colored product. The concentration of the product formed in 30 minutes the reaction was determined by optical density at 490 nm, measured using a parallel 96-well reader VICTOR2V (PerkinElmer, USA).

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

1) the reaction solution containing all components except kinase;

2) the reaction solution together with the kinase.

The optical density measured in control wells (1), which was imals for zero activity (OD 0), and the optical density measured in control wells (2), 100% (OD100). The optical density measured in the presence of test compounds (ODi), was expressed as a percentage of the maximum activity, and the percentage of inhibition of kinase activity was calculated by the following formula:

The magnitude of inhibition of ABL-kinase (tyrosinemia kinase responsible for the development of leukemia Abelson, chronic myelogenous leukemia) were obtained when testing focused library of compounds 1 at a concentration of 30 μm, varies in the range from 2 to 20%, which confirms the biological activity of the compounds of General formula 1.

1. Geterotsiklicheskikh acids and their derivatives of General formula 1

(1)

or their pharmaceutically acceptable salts, N-oxides or hydrates,

in which W represents optionally substituted heterocyclic radical, including pyrrol-3-yl, thiophene-2-yl, isooctanol-4-yl, pyrazole-4-yl, imidazol-4-yl, pyridine-3-yl, 1H-2,4-dioxo-pyrimidine-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-benzimidazole-5-yl, benzo[1,2,5]oxadiazol-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 3,dihydro-2-oxo-1H-quinoline-6-yl, the quinoline-8-yl, 1,4-dihydro-2,3-dioxopiperidin-6-yl, 3-oxo-4H-benzo[1,4]oxazin-7-yl, 3-oxo-4H-benzo[1,4]thiazin-7-yl, 2,4-dioxo-1H-hinzelin-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;

R1represents a chlorine atom, optionally substituted hydroxyl group, optionally substituted by an amino group, optionally substituted azaheterocyclic;

n has the value 1, 2 or 3;

or Ynis a carbon atom optionally substituted C3-C7cycloalkyl or optionally substituted C4-C7heterocyclyl, excluding (thiophene-2-sulfonyl)-acetic acid, (pyrrol-3-sulfonyl)-acetic acid, (pyrazole-4-sulfonyl)-acetic acid, (imidazol-4-sulfonyl)-acetic acid (pyridine-3-sulfonyl)-acetic acid (benzo[1,2,3]thiadiazole-4-sulfonyl)-acetic acid, 1-(benzo[1,2,3]thiadiazole-4-sulfonyl)-cyclopropanecarbonyl acid and their esters, 3-(2-thienylmethyl)propionic acid, 3-(5-bromo-2-thienylmethyl)propionic acid, their anhydrides and amides.

2. Compounds according to claim 1, which represents a 3-(heterocyclisation)-propionic acids and their derivatives of General formula 1.1

1.1

or their formats whitesky acceptable salt, N-oxides or hydrates,

in which W and R1have the above meaning;

R2and R3independently from each other represent a hydrogen atom or an inert Deputy or R2and R3together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl; excluding 3-(2-thienylmethyl)propionic acid, 3-(5-bromo-2-thienylmethyl)propionic acid, their anhydrides and amides.

3. Compounds according to claim 1, which represents the (heterocyclisation)-acetic acids and their derivatives of General formula 1.2

1.2

or their pharmaceutically acceptable salts, N-oxides or hydrates,

in which W and R1have the above meaning;

R4and R5independently from each other represent a hydrogen atom, an inert Deputy or R4and R5together with the carbon atom to which they are attached form an optionally substituted C3-C7cycloalkyl or optionally substituted C4-C7heterocyclyl; excluding (thiophene-2-sulfonyl)-acetic acid, (pyrrol-3-sulfonyl)-acetic acid, (pyrazole-3-sulfonyl)-acetic acid, (imidazol-4-sulfonyl)-acetic acid (pyridine-3-sulfonyl)-acetic acid (benzo[1,2,3]thiadiazole-4-sulfonyl)-acetic acid, 1-(benzo[1,2,3]TIA is eazol-4-sulfonyl)-cyclopropanecarbonyl acid and their esters.

4. Focused library to search for biologically active compounds leaders, including at least one (heterocyclisation)-alkalicarbonate acid or its derivative of General formula 1 according to claim 1 or their pharmaceutically acceptable salt, N-oxide or hydrate.

5. Pharmaceutical composition having the action of a kinase inhibitor, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing comprising at least one (heterocyclisation)-alkalicarbonate acid and its derivative of the General formula 1 or pharmaceutically acceptable salt, N-oxide or hydrate.



 

Same patents:

The invention relates to N-substituted aminotetralin formula 1

< / BR>
where R1independently selected from the group consisting of hydrogen; hydroxy; halogen; C1-8-alkoxy; substituted C1-8-alkoxy, where the Deputy is a halogen; n is 0-2; Y is methylene; m is 0-3;1means hydrogen;2means hydrogen; R2selected from the group consisting of hydrogen; hydroxy; C1-6-alkyl, C1-6-alkenyl; phenyl; substituted phenyl where the Deputy is chosen from halogen, C1-6-alkyl, C1-6-alkoxy, trifter-C1-6-alkyl, nitro; naphthyl and pyridyl; L is chosen from the group consisting of C1-8-alkylene; C1-4-alkylen-C3-7-cycloalkyl-C1-4-alkylene; C1-4-alkylen-aryl-C1-4-alkylene; R3selected from phenyl; substituted phenyl where the Deputy is chosen from halogen, nitro, C1-8-alkoxy, trifloromethyl and amino-C1-8-alkyl; naphthyl; and tanila and their enantiomers, diastereoisomers and pharmaceutically acceptable salts

The invention relates to new derivatives of nitromethylene General formula 1 in which R represents the radical (I), (II) or (III)

The invention relates to a new group of antibiotics, the carbapenems and their non-toxic pharmaceutically acceptable salts, having antimicrobial activity, which can be used both separately and in combination with other antibiotics to treat bacterial infections in humans and animals

The invention relates to new heterocycles compounds, more particularly to a new heterocycles compounds which are inhibitors of the enzyme 5-lipoxygenase (5-LO)

The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds

The invention relates to new heterocyclic substituted phenoxyacetamide, methods for their preparation and use as a means protivodiareynogo

FIELD: organic chemistry, chemical technology, explosive substances.

SUBSTANCE: invention relates to a method for preparing 4,4'-bis-[4-aminofurazan-3-yl-N(O)N-azoxy]-3,3'-azofurazane of the general formula (1):

that is a new thermostable explosive substance with improved exploitation indices. Method for preparing compound of the formula (1) involves treatment of 4,4'-diaminoazoxyfurazane with potassium bromate solution (KBrO3) in hydrochloric acid medium or its mixture with organic acid. Proposed compound can be used as a component of explosive compositions, solid rocket fuels and power-consuming compositions of different designations exploited at elevated temperatures (for example, in blast-hole drilling in depth mines).

EFFECT: improved preparing method, valuable properties of substance.

1 tbl, 2 ex

The invention relates to new inclusion complexes of derivatives of 1,2,5-oxadiazol-2-oxide of General formula I, where1=R2=CN or together with the adjacent carbon atoms form annelirovannymi 3,6-bis(lower alkyl)pyridazin-1,2-dioxideis cycle, polycyclic derivatives of glucopyranose General formula II, where if n= 1, R3fragment 11-oxo-18, 20-Olean-12-EN-29-OIC acid of the formula III, R4=H, R5--D-glucuronidase, R6=R7=H and R8= C(O)OH, or, if n= 7, R3=N, R4and R7- simple connection, R5and R6= H or (CH2CH(CH3)O)mH, where m=1 to 14, and R8=CH2OH or CH2O(CH2CH(CH3)O)mH, where m=1-14, generating nitric oxide and activating the soluble form of guanylate cyclase (RGC), antispasmodic, vasodilator and hypotensive means quick action and platelet aggregation inhibitors, method for their production and pharmaceutical compositions based on

The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a method for preparing derivatives of benzoxazine and describes a method for preparing compound represented by the formula . Method involves of compound represented by the formula (I): with compound represented by the formula (II-1-a): in the presence of a base to form compound represented by the formula (III-1-a): followed by reduction of this compound to compound represented by the formula (IV-a): , interaction of this compound with compound represented by the following formula: to form compound represented by the formula (V-a): and the following treatment of this compound in the presence of a base to obtain compound represented by the formula (VI-a): , treatment of this compound with compound of boron trifluorine and its conversion by this manner to the boron chelate compound represented by the following formula: followed by reaction of this compound with 4-methylpiperazine to obtain compound represented by the following formula: followed by cleavage and elimination of boron chelate of this compound. In each of above given formulas X1, X2 and X3 represents independently halogen atom; R1 represents a leaving group; R3 represents hydrogen atom or carboxyl-protecting group; R4 represents hydroxyl-protecting group; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms; R7 represents carboxyl-protecting group; Y represents alkoxy-group comprising 1-6 carbon atoms, halogen atom or dialkylamino-group (wherein alkyl groups can be similar or different and each represents alkyl group comprising 1-6 carbon atoms). Also, invention describes variants above described method, methods for preparing intermediate compounds and intermediate compound. Invention provides industrially favorable methods for preparing intermediate compounds that are useful for preparing compounds with antibacterial properties.

EFFECT: improved preparing methods, valuable properties of compounds.

96 cl, 102 ex

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

SUBSTANCE: invention relates to derivatives of aryl carboxylic acids and describes a compound of the formula (I):

, wherein groups R1, R2, R3, R4 and groups R5 and R6 when they are joined to carbon atom can be similar or different and mean hydrogen, halogen atom, hydroxy-group or optionally substituted group taken among alkyl, alkoxy-group, phenyl, carboxylic acid or sulfonic acid; one or both substitutes R5 and R6 can mean oxo-group also if they are joined to carbon atom; if R5 and R are joined to nitrogen atom then they mean hydrogen atom, hydroxy-group or optionally substituted alkyl or benzyl; X means heteroatom taken among oxygen and sulfur atom or NH; Ar means optionally substituted bivalent a single or condensed aromatic or heterocyclic group wherein aromatic ring represents phenyl, naphthyl and heterocyclic group represents furan; R7 means hydrogen, halogen atom, alkoxy-group, alkyl, or it forms a bond with the adjacent group R8; R8 means hydrogen atom, hydroxy-, alkoxy-group, alkyl or optionally substituted benzyl; or R8 forms a bond in common with R7; R9 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; R10 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; Y means oxygen atom or NR12 wherein R12 means hydrogen atom, alkyl or benzyl; R10 and R12 can form in common five- or six-membered cyclic structure comprising carbon atoms that involves optionally one or some heteroatoms taken among oxygen, sulfur or nitrogen atoms; a binding group represented by the formula: -(CH2)n-(O)m- can be joined through nitrogen atom or through carbon atom and wherein n means a whole number from 1 to 4; m means a whole number from 0 to 1 under condition that when a binding group is joined through carbon atom then R5 either R6 represents oxo-group; Y means oxygen atom; R9 doesn't mean hydrogen atom; or its derivatives, analogs, its tautomeric forms, its stereoisomers, its polymorphic forms, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates. Also, invention describes methods for preparing compounds of the general formula (I), intermediate compounds and methods for their preparing, a pharmaceutical composition eliciting activity with respect to hPPRα, hPPRγ and inhibitory activity with respect to HMG-CoA-reductase and involving compound of the formula (I). Also, invention relates to methods for prophylaxis and treatment of different diseases caused by above said activity, a method for reducing the total cholesterol level and a method for reducing the glucose level. Invention provides preparing new compounds eliciting valuable biological properties.

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

27 cl, 64 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

The invention relates to new benzoxazine and piridokshinom compounds of formula I, where part of the Q - condensed phenyl, or condensed pyridyl; Z1is hydrogen, halogen, C1-C6alkyl, phenyl, nitro, sulfonylamino or trifluoromethyl; Z2is hydrogen or halogen; X is hydrogen or oxygen; And - C1-C6-alkyl, C1-C6-alkylaryl or C1-C6-Alkylglucoside, where aryl and heterocyclyl described in the claims, n = 0 to 3; Y is the portion described in the claims, and their pharmaceutically acceptable salts, esters and proletarienne forms
Up!