Derivatives of phtalazine as inhibitors of phosphodiesterase 4

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

 

The present invention relates to derivatives phthalazine containing their pharmaceutical compositions, and use of these derivatives as inhibitors phosphodiesterase-4.

Phosphodiesterase are a family of isoenzymes, which form the Foundation of the basic mechanism of hydrolytic inaktivirovanie camp (cyclic adenosine-3′,5′-monophosphate). It was shown that cyclic amp is a second messenger mediating the biological response to many hormones, trasmitter and medicines [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When linking the corresponding agonist with the surface of the cell adenylate cyclase is activated and turns of Mg2+-ATP into camp. camp modulates the activity of most (if not all) of the cells that contribute to the pathophysiology of various respiratory diseases with allergic and non allergic nature. This implies that the increase in the concentration camp has beneficial effects, such as relaxation of smooth muscles of the respiratory tract, inhibition of release of mediators of mastocytes (granular cells basophils), suppression of degranulation of neutrophils and basophils, suppression of activation of monocytes and macrophages. Thus, compounds capable of activating adenylate is klasu or to inhibit phosphodiesterase, can suppress unwanted activity of smooth muscles of the respiratory tract, as well as a large number of inflammatory cells.

In the family of phosphodiesterase is a separate group of isoenzymes of phosphodiesterase-4 (hereinafter referred to as PDE 4)characteristic for hydrolysis of camp in smooth muscle of the respiratory tract and inflammatory cells (Torphy, "Phosphodiesterase Isoenzymes: Potential Targets for Novel Anti-asthmatic Agents in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd, 1989). Research conducted on this enzyme have shown that inhibition not only provides the relaxation of smooth muscles of the respiratory tract, along with the suppression of degranulation mastocytes, basophils and neutrophils, as well as the suppression of the activation of monocytes and neutrophils. Therefore, inhibitors of PDE-4 effective for therapy of asthma.

Selective inhibition of PDE-4 impair the functionality of the cells of the inflammatory focus, such as neutrophils, alveolar macrophages, and T cells, which are known to play a key role in chronic obstructive pulmonary disease (COPD); and such activity suggests how this class of compounds can provide an effective treatment of such pathologies (Duglas WP Hay, Curr. Opin.Chem. Biol., 2000, vol.4, pages 412-419).

Such compounds offer a unique application to the treatment of various respiratory diseases such as allergic, the AK and non-allergic origin, and they offer significant advantages over currently used therapy.

Excessive or substandard production of tumor necrosis factor (hereinafter referred to as TNFa), a cytokine with anti-inflammatory activity produced by cells of various kinds, affects the transfer of many pathologies, such as for example, respiratory distress syndrome of adults and chronic inflammatory lung disease, or aggravation. Therefore, compounds capable of regulating the negative effects of TNFai.e. inhibitors of the cytokine, should be considered suitable against many pathologies.

In the description of the patent EP 722936 (Eisai) incidentally claimed compounds of the formula

where n=0-4; R1represents an optionally substituted lower alkoxygroup, optionally substituted cycloalkyl, or9group, where R9represents an optionally substituted arylalkyl group; X represents-N= or-NR6-, where R6represents hydrogen, a lower alkyl group, or optionally substituted arylalkyl or heteroallyl group; Y represents-CO-or-SV=, where represents-NR7R8in which each of R7and R8can independently submit, the better a N, optionally substituted heteroallyl group, or represents hydrogen, or optionally substituted aryl, heteroaryl, arylalkyl or heteroallyl group; a represents a hydrogen atom or halogen, or optionally mono - or biznesmenow the amino group, substituted (optional) aryl, heteroaryl or heteroallyl group.

Among the groups, not necessarily substitute listed above residues, atoms of Halogens, and are also protected (optional) carboxyl group.

From the above example compounds with a very broad General formula, of particular interest are cases in which: values And are phthalazinone cycle, substituted (3-chloro-4-methoxy)-benzylamino or 3,4-methylendioxy-benzylamino group; the values of R1are halogen, nitro group, or cyano group when n=1; the values In the is-NR7R8where each of R7and R8independently represents hydrogen, optionally substituted group lower alkyl, optionally substituted heteroallyl group, or R7and R8together with the nitrogen atom to which they are connected by a chemical bond can form a cycle which can be substituted.

Thus, one aspect of the description, and none of the examples are not in the W ill result in compounds, in which R1represents methoxy or deformedarse when n=1 And a is phenyl or heterocycle, substituted carboxyl group, and (optional) to another functional group, and is a (3,5-dichloro-pyridine-4-yl-methyl group.

In addition, these compounds are known for their activity as inhibitors of cGMP-fosfodiesterazu, i.e. PDE 5, where fosfodiesterasa effect on cGMP-dependent mechanism and application of these compounds is basically the cardiovascular system (Schudt .et al., Phosphodiesterase Inhibitors, Academic Press).

International patent application WO 00/05218 (Zambon Group S.p.A) among other claims compounds of the formula

in which a chemical bond between the carbon atom is linked substituent R1and the neighboring nitrogen atom is single or double; R is a (C1-C6)alkyl or polyflor(C1-C6)alkyl group; R1no if a chemical bond between the carbon atom is linked substituent R2and the neighboring nitrogen atom is double, or if this relationship is simple, then R1represents a hydrogen atom, optionally substituted (C1-C6)alkyl group or (C1-C4)alkylsulfonyl g is upoi; if a chemical bond between the carbon atom is linked substituent R2and the neighboring nitrogen atom is double, R2represents a hydrogen atom, cyano group, amido group, (C1-C8)alkyl, (C2-C8)alkenylphenol or (C2-C8)alkylamino group, alkoxy group, or optionally substituted aryl or heterocycle; R3represents hydrogen or (C1-C8)alkyl, (C2-C8)alkenylphenol group, or (C2-C8)alkylamino optionally substituted group; Z represents NH, methylene or (C2-C6)alkylenes chain, optionally branched and/or unsaturated and/or interrupted (C3-C7)cycloalkyl residue; a represents a phenyl or a heterocycle, optionally substituted by one or more substituents.

These compounds are very active in the role of PDE inhibitors, and inhibitors of the release of TNFain addition, they have no activity against the enzyme PDE 3 and 5.

It is obvious that such specificity and selectivity of action makes these compounds suitable as therapeutic agents for the treatment of pathologies involving PDE 4 and TNFa.

However, compounds of the above patent descriptions have some of the physico-chemical characteristics (for example, such as solubility in water), suitable for a limited number of compounds.

Indeed, the limited solubility of the active element is the basis of the difficulties encountered in the preparation of compositions which can ensure sufficiently high bioavailability.

Moreover, usually to eliminate weak solubility in preclinical models in vitro and in vivo use special formulations allow you to apply nefiziologichnoe media, and therefore, creates difficulties in determining the activity of compounds and their biological availability.

It would be preferable to use these compounds for their purposes, we have a wide range of formulations, for most classical cases, the use of which requires that the active ingredients were largely soluble in water.

Oral method, for example, represents the most convenient and widely used way of administering drugs, and it is therefore particularly important is the ability to improve the solubility of potentially active ingredients and the opportunity to develop oral formulations, without resorting to special skills to create recipes.

Currently, we have unexpectedly discovered that by introducing carboxyl pool phenyl or heterocyclic Deputy, included in the values of R4(see international application WO 00/05218), the resulting compounds have powerful inhibitory activity on the release of PDE 4 and TNFa, inertness with respect to PDE 1, 2, 3, and 5, and therefore, they are selective, and endowed with optimal properties in terms of solubility in water.

Such compounds comprise a subclass within the boundaries of the General formula from the above description of the patent application from Zambon Group, which is not cited as an example, and therefore, these compounds are new.

Additional polarity entered into molecules with carboxyl group, gives the possibility of obtaining compounds endowed with the physical and chemical properties that are easier feasible from the point of view of formulation and evaluation of bioavailability of the compounds of formula I in carriers suitable for pharmaceutical compounds; it is proved that the biological availability of comparable or much higher bioavailability identified for compounds of the above-mentioned patent applications, which was determined by dissolving these compounds in nefiziologichnoe media.

Introduction at position 1 of the phenyl or heterocycle carboxylic groups with specific characteristics of polarity allows the compounds of the formula I to acquire the necessary water-lip is a multidisciplinary molecular balance, which is required to be dissolved in the fluid, and permeability through biological membranes in processes of absorption and distribution, with high activity suppression in respect of the enzyme PDE 4 is stored.

Thus, there were obtained compounds that, by introducing a carboxyl substituent, acquire properties that are optimal from the viewpoint of solubility, they are easy to include in the prepared recipes, connection get high inhibitory activity, selectivity and bioavailability, which is comparable with similar characteristics of other compounds.

Thus, the subject of the present invention are the compounds of formula

in which R represents a methyl or deformational group; R1represents phenyl or 5 - or 6-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and associated chemical bond with phthalazinone cycle through carbon-carbon connection, with the specified phenyl and heterocycle substituted with carboxyl group, and (optional) second functional group selected from methoxy-, nitro-, N-acetylamino-, N-methanesulfonyl;

N-oxide derivatives of the compounds of formula I and their pharmaceutically acceptable salts.

With the organisations of the formula I are active as inhibitors of PDE 4 and TNF aand therefore they are used in the role of therapeutic agents for treating allergic and inflammatory pathologies, such as respiratory distress syndrome in adults, chronic obstructive pulmonary disease, asthma, and allergic rhinitis.

Under the 5 - or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, understand such aromatic heterocycles as pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazol, isoxazol, oxazole, pyridine, pyrazin, pyrimidine, pyridazine, piperazine, triazole and thiadiazole.

N-oxide form (if present) may include nitrogen atoms in phthalazinium cycle, and the nitrogen atoms located on pyridinium cycle.

Pharmaceutically acceptable salts of compound I are salts of alkaline or alkaline earth metals, zinc salts, and salts with organic bases, acceptable from a pharmaceutical point of view, such as trometamol(2-amino-2-hydroxymethylpropane-1,3-diol), N-methylglucamine.

Preferred compounds of formula I are those compounds in which R1represents phenyl, substituted carboxyl group, and specifically, such compounds, carboxyl group which is in the meta position relative to ftal the new cycle.

Typical examples of the compounds which are the subject of the present invention are:

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

4-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-nitrobenzoic acid;

5-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-2-methoxybenzoic acid;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-4-methoxybenzoic acid;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-methanesulfonylaminoethyl acid;

3-acetylamino-5-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxy-phthalazine-1-yl]-benzoic acid;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-methoxybenzoic acid;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-deformationsanalyse-1-yl]-benzoic acid;

2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-oxazol-4-carboxylic acid;

2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-thiophene-3-carboxylic acid;

(2-amino-2-hydroxymethylpropane-1,3-diol) salt of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

N-methylglucamine salt of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-the l]-benzoic acid.

The compounds of formula I, which is the subject of the present invention, is obtained by reaction of aromatic nucleophilic substitution or by the reaction of binding in the presence of a catalyst (such as palladium) between the compound of formula II

in which R has the meanings mentioned for the compounds of formula I,

and reagent type derived tin or Bronevoy acid, which is suitable for substitution of the halogen atom, chemically linked directly from phthalazinone cycle phenyl or heterocycle, substituted carboxyl group, and substituted (optional) in the second functional group whose values have been defined for R1formula I.

Derivatives phthalazine formula II receive under the scheme of synthesis described in the application for international patent WO 00/05218 (Zambon Group S.p.A), example 45, 35 and example 99, p.57.

For derivatives tin use the binding reaction, it would be better if these derivatives contain precursors of the free carboxyl group, such as cyano group or ester group. Preferably, the binding reaction by Suzuki between compounds of formula II and the right of Baranovich acid proceeded in the presence of palladium triphenylphosphine, and an aqueous solution of potassium carbonate.

Used sour the AMI boron, for example, are optionally substituted carboxy-(phenyl or heterocycle)boranova acid, or optionally substituted formyl-(phenyl or heterocycle)boranova acids, which are then subjected to oxidation to obtain the corresponding compounds of formula I.

Alternatively, for derivatives, in which R1represents a substituted heterocycle, heteroaromatic cycle receive a multi-stage reaction according to standard patterns of synthesis, using as a substrate suitable for this cycle phthalazine.

Obtaining N-oxide compounds of the formula I is carried out by treatment with percolate, such as m-chloroperbenzoic acid.

If the oxidation reaction is directed to the nitrogen atom present in the pyridine cycle, to ensure the selectivity of the process performed on the cycle isobenzofuranone, which is the predecessor phthalazinone cycle, the method is carried out according to the scheme described in the application for international patent WO 00/05218.

Obtaining salts of the compounds of formula I is carried out by known methods.

The compounds of formula I are inhibitors of PDE 4, as it was revealed by tests on inhibition of enzymatic activity (example 18), they are also able to suppress the release of TNFa(example 19).

In addition, the compounds according to the present invention will monsterous no inhibitory activity against the enzyme PDE 1, 2, 3 and 5, as shown by tests conducted by the suppression of the enzymatic activity.

It is obvious that such selectivity and specific features in combination with a lack of activity in relation to cardiovascular system, make these compounds of formula I are especially suitable for the treatment of various pathologies involving PDE 4 and TNFasuch as asthma, chronic obstructive pulmonary disease, respiratory distress syndrome in adults, allergic rhinoconjunctivitis, psoriasis, atopic dermatitis, rheumatoid arthritis, septic shock, ulcerative colitis, although in this context, the interest is focused on virtually respiratory pathologies. In particular, the compounds of the present invention is particularly suitable for the treatment of allergic and inflammatory conditions, and especially for the treatment of chronic obstructive pulmonary diseases, asthma and allergic rhinitis.

Therapeutic doses usually range from 0.1 to 1,000 mg per day, and after a single dose of oral way from 1 to 200 mg.

therapeutically effective amount will depend on the age and General physiological condition of the patient, the route of administration and specifically used in the pharmaceutical composition.

Another object of the present invention are pharmaceutical is ostavi, containing therapeutically effective amounts of compounds of formula I or their pharmaceutically acceptable salts in mixture with a suitable carrier.

Pharmaceutical compositions that are the subject of the present invention may be a liquid suitable for oral and/or parenteral administration (e.g., such as drops, syrups, ready-to-eat or get breeding liofilizovannyh drugs injectable solutions), solid or pseudoepherdine (such as tablets, capsules, granules, powders, vaginal suppositories, suppositories, creams, ointments, gels, ointment), or nishiuchi solutions, suspensions, emulsions, and other forms suitable for transdermal or inhalation.

Depending on the type of composition for pharmaceutical use, he shall, in addition to therapeutically effective amount of one compound of formula I (or more, to include a certain amount of solid or liquid fillers or diluents, and (optional) other fillers commonly used in obtaining pharmaceutical compositions; these substances include thickeners, binders, lubricants, flavoring agents and dyes.

Preparation of pharmaceutical compositions that are the subject of the present invention may be implemented is found by known methods.

For a better understanding of the present invention examples.

EXAMPLE 1

Synthesis of 4-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid (compound 1)

To a mixture of 4-chloro-1-(3,5-dichloropyridine-4-yl-methyl)-6-methoxy-phthalazine (intermediate compound 1) (300 mg; 0.85 mmol; 1 EQ), prepared according to the application for international patent WO 00/05218 (example 45, p.35) 4-carboxybenzeneboronic acid (155 mg; 0,93 mmol; 1.1 EQ), palladium tetrakis(triphenylphosphine) (50 mg; 5 mol.%), added 2N aqueous solution of potassium carbonate 91,26 ml), DME (10 ml) and ethanol (0.5 ml), pre-washed in a strong stream of nitrogen. The process was carried out at room temperature in an inert atmosphere of argon. The reaction mixture was stirred at 90°C for 4-16 h Reaction "extinguished" 5% aqueous solution of citric acid until then, until the pH value was 6. The product obtained in the binding assays was extracted with ethyl acetate (2×15 ml), dried (Na2SO4), and was evaporated under reduced pressure. The resulting compound I in the form of a light yellow solid (216 mg; 0.49 mmol; yield 58%).

MS: 440 [M+H]+

NMR _d6: 8.70 (s, 2H, PY); 8.58 (d, 1H, JHH=9.1 Hz, *CH=CH-C-OMe); 8.14 (d-broadened, 2H, JHH=8.3 Hz, C-(*CH=CH)2-C), 7.87 (d-broadened, 2H, JHH=8.3 Hz, C-(CH=*CH)2-C); 7.79 (dd, 1H, CH=*CH-C-OMe); 7.29 (d, 1H, JHH=2.5 Hz, C=*CH-C); 5.04 (s, 2H, *CH2-PY); 3.89 (s, 3H, OMe).

p> EXAMPLE 2

Synthesis of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid (compound 2)

Compound 2 was synthesized acting in the same way as described for compound 1; the substrate used intermediate compound 1 (5 g; 14 mmol) and 3-carboxybenzeneboronic acid (2.5 mg, 15 mmol). The product obtained in the binding assays was extracted with ethyl acetate (2×15 ml), dried (NB2SO4), and then was filtered through celite, washing with ethyl acetate (2×30 ml). The resultant filtrate was acidified with concentrated hydrochloric acid to pH=4, and then was stirred for 1 h the Precipitate was collected by filtration and dried it at 50°With; the resulting compound 2 as a pale yellow solid (3.4 g; 8 mmol; yield 57%).

MS: 440 [M+H]+

NMR _d6: 13.20 (s-broadened, 1H, HE); 8.71 (s, 2H, PY); 8.58 (d, 1H, JHH=8.7 Hz, *CH=CH-C-OMe); 8.25 (s-broadened, 1H, C=*CH-C-CO2H); 8.14 (d-broadened, 1H, JHH=8.1 Hz, *CH), 8.02 (d-broadened, 1H, JHH=8.1 Hz, *CH); 7.80 (dd, 1H, CH=*SN-C-OMe); 7.77-7.69 (m, 1H, CH=*CH-CH); 7.29 (d, 1H, JHH=2.3 Hz, O=*CH-C); 5.04 (s, 2H, *CH2-PY); 3.88 (s, 3H, OMe).

EXAMPLE 3

Synthesis of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-nitrobenzoic acid (compound 3)

Compound 3 was synthesized by acting in the same way as described for compound 1; the substrate used PR is an interstitial compound 1 (300 mg; 0.85 mmol) and 3-carboxy-5-nitrophenylarsonic acid (196 g; 0,93 mmol). The product obtained in the binding assays was extracted with ethyl acetate (2×15 ml), dried (Na2SO4). Then it was evaporated under reduced pressure and filtered through celite, washing with ethyl acetate (10 ml). The resulting filtrate was evaporated under reduced pressure; the resulting compound 3 as a pale yellow solid (235 mg; 0.48 mmol; yield 57%).

MS: 485 [M+H]+

NMR _d6: 8.78-8.73 (m, 2H, *CH,*CH); 8.71 (s, 2H, PY); 8.64-8.60 (m, 2H, *CH=CH-C-OMe, *CH); 8.84 (dd, 1H, JHH=9.2 Hz, 2.5 Hz, CH=*CH-C-OMe); 7.32 (d, 1H, JHH=2.5 Hz, MeO-C=*CH-C); 5:07 (s, 2H,, *CH2-PY); 3.89 (s, 3H, OMe).

EXAMPLE 4

Synthesis of 5-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-2-methoxybenzaldehyde (intermediate compound 2)

Intermediate compound 2 was synthesized acting in the same way as described for compound 1; the substrate used intermediate compound 1 (450 mg; of 1.26 mmol) and 2-formyl-4-methoxyphenylalanine acid (248 g; 1.38 mmol). The reaction mixture was poured into a Varian ChemElut CE100S and washed with dichloromethane (3×10 ml). The filtrate was evaporated under reduced pressure and the product was purified on a Varian Mega Bond ChemElut (SiO2), rinsing with a mixture of CH2Cl2/methanol (in a ratio of from 100:0 to 97:3 volume/volume). The resulting product was recrystallize from m is canola; the resulting intermediate compound 2 as a pale yellow solid (260 mg; 0, 6 mmol; yield 48%).

MS: 455 [M+H]+

NMR _d6: 10.40 (s, 1H, CHO); 8.70 (s, 2H, PY); 8.57 (d, 1H, JHH=9.1 Hz, *CH=CH-C-OMe); 8.10 (dd, 1H, JHH=2.3 Hz, 8.5 Hz, C-*CH=CH-C (OMe)-C-CHO); 8.04 (d, 1H, JHH=2.3 Hz, *CH-C-CHO); 7.79 (dd, 1H, JHH=2.5 Hz, 9.1 Hz, CH*CH=C-OMe); 7.46 (d, 1H, JHH=8.7 Hz, *CH=C(OMe)-C-CHO); 7.32 (d, 1H, JHH=2.6 Hz, C=*CH-C); 5.02 (s, 2H, *CH2-PY); 4.04 (s, 3H, OMe); 3.89 (s, 3H, OMe).

EXAMPLE 5

Synthesis of 5-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-2-methoxybenzoic acid (compound 4)

To the rapidly stirred solution of intermediate compound 2 (70 mg; 0.15 mmol; 1 EQ) in tert-butyl alcohol (3 ml) and 2 N solution of 2-methyl-2-butene in tetrahydrofuran (0,77 ml; 1.5 mmol; 10 EQ) in inert atmosphere of nitrogen was added dropwise a solution of sodium chloride (16 mg; 0.18 mmol; 1, 2 equiv) in 1 N aqueous acidic phosphate buffer (pH=3,5; 1 ml; 1.12 mmol; 7.5 EQ). The process was carried out at room temperature in an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 5 h and evaporated under reduced pressure. The resulting product was diluted with water (5 ml), was extracted with dichloromethane (2×7 ml) and evaporated under reduced pressure. Then the product was purified on a Varian Mega Bond ChemElut (SiO2), rinsing with a mixture of CH2Cl2/methanol (in a ratio of from 100:0 to 97:3 volume/volume). After purification was carried out by washing with 100% methanol; in R. the result was obtained intermediate compound 4 as a yellow solid (47 mg; 0, 1 mmol; yield 67%).

MS: 471 [M+H]+

NMR _d6: 8.69 (s, 2H, PY); 8.53 (d, 1H, JHH=9.3 Hz, *CH=CH-C-OMe); 7.80-7.70 (m, 3H, C-C-CH=*CH-C=*CH-C-COOH, CH=*CH-C-OMe); 7.36 (d, 1H, JHH=2.5 Hz, C=*CH-C); 7.20 (d, 1H, JHH=8.7 Hz C-C-*CH=CH-C); 5.00 (s, 2H, *CH2-PY); 3.88 (s, 3H, OMe); 3.85 (s, 3H, OMe).

EXAMPLE 6

Synthesis of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-4-methoxybenzaldehyde (intermediate compound 3)

Intermediate compound 3 was synthesized by acting in the same way as described for compound 1; the substrate used intermediate compound 1 (450 mg, of 1.26 mmol) and 5-formyl-2-methoxyphenylalanine acid (248 g, 1.38 mmol). The reaction mixture was poured into a Varian ChemElut CE100S and washed with dichloromethane (3×10 ml). The filtrate was evaporated under reduced pressure and the product was purified on a Varian Mega Bond ChemElut (SiO2), rinsing with a mixture of CH2Cl2/methanol (in a ratio of from 100:0 to 97:3 volume/volume). The resulting product was recrystallize from methanol; the resulting intermediate compound 3 as a pale yellow solid (214 mg; 0.5 mmol; yield 40%).

MS: 455 [M+H]+

NMR _d6: 9.96 (S, 1H, CHO); 8.71 (s, 2H, PY); 8.54 (d, 1H, JHH=9.2 Hz, C=C-*CH=CH-C-OMe); 8.15 (dd, 1H, JHH=2.3 Hz, 8.5 Hz, CHO-C-*CH=CH); 7.94 (d, 1H, JHH=2.3 Hz, C-*CH=C-CHO); 7.75 (dd, 1H, JHH=2.6 Hz, 9.2 Hz, C=C-CH=*CH-C-OMe); 7.47 (d, 1H, JHH=8.5 Hz, C-*CH=CH-C-CHO); 6.83 (d, 1H, JHH=2.3 Hz, C=*CH-C-OMe); 5.05 (s, 2H, *CH2-PY); 3.83 (s, 3H, OMe); 3.82 (s, 3H, OMe).

EXAMPLE 7

Synthesis of 3-[4-[3,5-dichloropyridine-4-yl-ethyl)-7-methoxypyrazine-1-yl]-4-methoxybenzoic acid (compound 5)

Compound 5 was synthesized acting in the same way as described for compound 4; the substrate used intermediate compound 3 (150 mg, 0.33 mmol). Obtained product was purified on a Varian Mega Bond ChemElut (SiCO2), rinsing with a mixture of CH2Cl2/methanol/acetic acid (in a ratio of 99:1:0,05 volume/volume/volume). The resulting compound 5 as a yellow solid (78 mg; 0.16 mmol; yield 50%).

MS: 470 [M+H]+

NMR _d6: 8.70 (s, 2H, PY); 8.53 (d, 1H, JHH=9.1 Hz, *CH=CH-C-OMe); 8.16 (dd, 1H, JHH=2.2 Hz, 8.7 Hz, CH*CH=C-COOH); 7.90 (d, 1H, JHH=2.2 Hz, C-*CH-C-CO2H); 7.74 (dd, 1H, JHH=2.5 Hz, 9.1 Hz, CH=*CH-C-OMe); 7.36 (d, 1H, JHH=8.7 Hz, *CH-CH=C-COOH); 6.82 (d, 1H, JHH=2.5 Hz, C=*CH-C-OMe); 5.04 (s, 2H, *CH2-PY); 3.81 (s, 3H, OMe); 3.79 (s, 3H, OMe).

EXAMPLE 8

Synthesis of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-methanesulfonylaminoethyl acid (compound 6)

To a suspension of palladium on charcoal (12 mg) in methanol (15 ml) was added 3-carboxy-5-nitrophenylarsonic acid (250 mg; 1.1 mmol) and perform the recovery in the atmosphere of hydrogen (40 psi). After 15 h, the reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. After that, the crude product (200 mg; about 1.1 mol) was dissolved in water (2 ml) and dioxane (1 ml) and added 10 N aqueous sodium hydroxide solution (0.33 ml; 3 EQ). To the resulting mixture dropwise at 0°With obavljale solution methanesulfonanilide (0.1 ml; 1.2 mmol; 1.1 EQ) in dichloromethane (1 ml). Then the reaction mixture was stirred at room temperature for 2 h and acidified with 5% aqueous citric acid solution. The resulting product was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure. Then spent the binding reaction of the crude product (130 mg; 0.5 mmol) intermediate compound 1 (178 mg; 0.5 mmol) under the conditions described Suzuki for compound 1. The product was extracted with ethyl acetate (2×10 ml), dried (Na2SO4) and evaporated under reduced pressure. The product was purified on a Varian Mega Bond ChemElut (SiO2), rinsing with a mixture of CH2Cl2/methanol/acetic acid (in a ratio of 99:1:0,05 volume/volume/volume). The resulting compound 6 as a pale yellow solid (13 mg; 0, 02 mmol, yield 5%).

MS:534[M+H]+

High-performance liquid chromatography/mass spectrometry: install Gilson, equipped with a C18 column Bond SBC18 (3.5 µm, 2.1 a×50 mm), associated with diode UV detector (220 nm)and a mass spectrometer Finnigan Aqa (electronic sputtering, positive ionization). We used the following parameters: flow rate 1 ml/min; column temperature 40°; gradient elution of a/b (eluent A: 0,5% formic acid in water; eluent 0.5% formic acid in acetonitrile); t=0 min, a/b=95:5, t=8 min, a/b=5:95; Rt=4,36.

EXAMPLE 9

Synthesis of methyl ester of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-methoxybenzoic acid (intermediate compound 4)

To a suspension of ethyl ether, 3,5-dinitrobenzoic acid (5 g; 0.02 mmol) in methanol (50 ml) was added motility (1.66 g; 0,04 mol; 2.1 EQ); the process is conducted in an inert atmosphere of nitrogen. The reaction mixture was heated to a temperature of distillation for 16 h, and then poured into a cooled with ice water solution of hydrochloric acid (25 ml). The resulting product was extracted with simple ether (3×25 ml), washed with water, dried (Na2SO4) and evaporated under reduced pressure. The product was purified on a Varian Mega Bond ChemElut (SiO2), rinsing with a mixture of cyclohexane/ethyl acetate (ratio 9:1 volume/volume).

The resulting methyl ester of 3-methoxy-5-nitrobenzoic acid (1 g; 5 mmol) was dissolved in methanol (30 ml) and ethyl acetate (20 ml). Added concentrated aqueous solution of hydrochloric acid (0.4 ml) and palladium on charcoal (50 mg). The reaction mixture is left at room temperature under hydrogen pressure of 40 pounds per square inch. After 1 h, the palladium catalyst was filtered through celite, and the filtrate was evaporated under reduced pressure. The resulting methyl ester of 3-methoxy-5-nitrobenzoic acid and is used without further purification. To a suspension of the crude methyl ester of 3-methoxy-5-nitrobenzoic acid (960 mg; 4.4 mmol; 1 EQ) in a mixture of water and concentrated hydrochloric acid (5 ml) in a ratio of 1:1 (volume/volume) is added dropwise at 0°C was added a solution of Na2NO2; (365 mg, 5.3 mmol; 1.2 EQ) in water (5 ml). The mixture was stirred 10 min at 0°C. and Then slowly added a solution of potassium iodide (1.47 g; 8,8 mmol; 2 EQ) in water (3 ml). Simultaneously in the reaction mixture is poured toluene (8 ml). Bath ice was removed and the reaction mixture was stirred for 3 h at room temperature, and then, when the distillation temperature for 1 h was Added water (10 ml) and the product was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine (5 ml), dried (Na2SO4) and evaporated under reduced pressure. Chromatographic purification (SiO2) with elution with a mixture of cyclohexane/ethyl acetate (ratio 9:1 volume/volume) gave the methyl ester of 3-methoxy-5-nitrobenzoic acid (730 mg; 2.5 mmol; output two stage 50%).

In an inert atmosphere of argon methyl ether 3-iodo-5-methoxybenzoic acid (500 mg; 1.7 mmol; 1 EQ) was added to a solution of tetrakis(triphenylphosphine) palladium (20 mg, 4 mol.%) in toluene (25 ml). This reaction mixture is added hexamethylditin (0,41 ml; 2 mmol; 1.2 EQ)and the resulting mixture was heated up to pace atory distillation. After 3 h was added ethyl acetate (10 ml). The reaction mixture is washed aqueous NaOH buffer/KH2PO4having pH=7, dried (Na2SO4) and evaporated under reduced pressure. The resulting product was diluted with toluene (30 ml) and added to a mixture of intermediate compound 1 (610 mg; 1.7 mmol; 1 EQ) and tetrakis(triphenylphosphine) palladium (90 mg; 5 mol.%); the process is conducted in an inert atmosphere of argon. The mixture was heated for 18 h at 110°C. the Resulting product was extracted with ethyl acetate (2×15 ml), dried (Na2SO4), was evaporated under reduced pressure, and then it chromatographic purification (SiO2) with elution with a mixture of cyclohexane/ethyl acetate/methanol (in the ratio 50:50:1 volume/volume/volume) gave the intermediate compound 4 as a pale yellow solid (483 mg; 1 mmol; yield 60%).

MS: 484 [M+H]+

NMR _d6: 8.71 (s, 2H, PY); 8.59 (1H, JHH=9.2 Hz, *CH=CH-C-OMe); 7.84-7.81 [m, 1H, *CH); 7.78 (d, 1H, JHH=2.6 Hz, *CH); 7.64-7.59 (m, 2H, *CH, *CH); 7.31 (d, 1H, JHH=2.5 Hz, C-C=*CH-C); 5.04 (s, 2N, *CH2-PY); 3.90 (s, 3H, OMe); 3.89 (s, 3H, OMe); 3.88 (s, 3H, OMe).

EXAMPLE 10

Synthesis of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-methoxybenzoic acid (compound 7)

To a solution of intermediate compound 4 (430 mg; 0.9 mmol; 1 EQ) in a mixture tetrahydrofuran/water in the ratio 3:1 (volume/volume) was added lithium hydroxide (65 mg; 2.7 mmol; 3 EQ). The reaction to shift the ü was stirred for 4 h, and then poured into cooled by ice water bath (10 ml). The mixture was acidified with 5% aqueous citric acid solution, and the resulting product was extracted with ethyl acetate (2×10 ml). The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure. In the result without further purification was obtained compound 7 as a pale yellow solid (420 mg; 0.9 mmol; yield 100%).

MS: 471 [M+H]+

NMR DMS0_d6: 13.21 (s-broadened, 1H, HE); 8.70 (s, 2H, PY); 8.58 (d, 1H, JHH=9.1 Hz, *CH=CH-C-OMe); 7.82-7.80 (m, 1H, *CH); 7.77 (d, 1H, JHH=2.5 Hz, *CH); 7.63-7.61 (m, 1H, *CH); 7.56-7.54 (m, 1H, *CH); 7.31 (d, 1H, JHH=2.3 Hz, C-C=*CH-C); 5.03 (s, 2H, *CH2-PY); 3.88 (s/ 6H, OMe, OMe).

EXAMPLE 11

Synthesis of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-diplomaticaly-1-yl]-benzoic acid (compound 8)

To a mixture of 4-chloro-1-(3,5-dichloropyridine-4-yl-methyl)-6-diftormetilirovaniya (5 g; 12.8 mmol; 1 EQ)obtained by the method, which was described (application for international patent WO 00/05218, example 99, p.45), 3-carboxybenzeneboronic acid (2,34 g; 14 mmol; 1.1 EQ) and tetrakis(triphenylphosphine)palladium (450 mg; 5 mol.%) in an inert atmosphere of nitrogen was added a solution of potassium carbonate (5.3 g; 39 mmol; 3 EQ) in water (30 ml), DME (100 ml) and ethanol (10 ml), previously flushed with nitrogen. The process was carried out at room temperature, and the resulting reaction mixture was stirred 16 h at 80°C. Then the mixture was evaporated under reduced is the t and added water (250 ml). The excess reagents were extracted with ethyl acetate (3×50 ml)and the aqueous layer was acidified with concentrated hydrochloric acid to pH=3. The mixture was stirred for 1 h and the precipitate was collected by filtration and dried it at 50°C. the resulting compound 8 as a pale yellow solid. After further recrystallization from chloroform was received more than a pure compound 8 (3,9 g; 8,7 mmol; yield 68%).

MS: 477 [M+H]+

NMR _d6: 8.77 (d, 1H, JHH=9.0 Hz, *CH=CH-C-O-CHF2); 8.72 (s, 2H, PY); 8.24 (m, 1H, *CH=C-SON); 8.19-7.97 (m, 3H, *CH=CH-CH=C-COOH, CH=*CH-C-COOH, CH=*SN-C-OCHF2); 7.74 (m, 1H, CH-*CH=CH); 7.61 (d, 1H, JHH=2.4 Hz, CHF2-O-C-*CH=C); 7.51 (t, 1H, JHF=73.4 Hz, *CHF2); 5.10 (s, 2H, *CH2-Ru).

EXAMPLE 12

Synthesis of methyl ester 1-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-carboxylic acid (intermediate compound 5)

To a suspension of intermediate 1 (9.7 g; 27 mmol) in dimethyl sulfoxide (80 ml) and methanol (40 ml) was added potassium carbonate (7.4 g; 54 mmol), palladium acetate (0.31 g; 1.4 mmol) and 1,3-misdefinition (0.75 g; 1.8 mmol). Within a few hours the reaction mixture was stirred in an atmosphere of carbon monoxide (8,5 bar) and heated to 50°and then poured into water (1 liter). The product was extracted with ethyl acetate (4×200 ml), washed with saturated saline (300 ml), dried and evaporated in vacuum. Chromatographic purification (SO 2) with elution with a mixture petroleum ether/ethyl acetate (ratio 1:1 volume/volume) gave the intermediate compound 5 as a white solid (5.0 g; 13 mmol; yield 49%).

NMR CDCl3: 8.42 e 7.97 (2s, 2H, PY); 7.90 (d, 1H, JHH=8.6 Hz, *CH=CH-C-OMe); 7.31-7.23 (m, 2H, Ar); 7.19 (dd, 1H, CH-*CH=P-OMe); 7.11-7.09 (m, 2H, Ar); 7.02 (d, 1H, JHH=2.3 Hz, C=*CH-C=CH); 5.62 (s, 1H, CH); 5.08 (s, 1H, CH); 3.95 (s, 4H, OCH2CH2O); 3.91 (s, 3H, OCH3); 3.42 (bs, 1H, OH).

EXAMPLE 13

Synthesis of 1-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl-4-carboxylic acid (intermediate compound 6)

To a suspension of intermediate 5 (750 mg; to 1.98 mmol) in methanol (27 ml) and water (3 ml) was added 85% potassium hydroxide (210 mg, 3 mol). After 1 h the reaction mixture was evaporated, added water (10 ml) and washed with dichloromethane (2×5 ml). Then was acidified with a concentrated aqueous solution of hydrochloric acid. Resulting precipitate was filtered and washed with water (2×5 ml). The resulting intermediate compound 6 as a white solid (0.66 g; 1.8 mmol; yield 92%).

NMR _d6: 10.13 (s, 1H, Cho); 8.70 (s, 2H, PY); 8.57 (d, 1H, JHH=9.0 Hz, *CH=CH-C-OMe); 8.29-7.80 (m, 4H, Ar-CHO; 7.82-7.76 (dd, 1H, CH*CH=C-Ome); 7.28 (d, 1H, JHH=2.65 Hz, MeO-C-*CH=C); 4.96 (s, 2H, *CH2-PY); 3.88 (s, 3H, OMe).

EXAMPLE 14

Synthesis of 2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-oxazol-4-carboxylic acid (compound 9)

In the solution of hydrochloride serine ethyl ester (233 mg; 1.4 to what they say; 1 EQ) in dimethylformamide (3 ml) was added a solution of intermediate compound 6 (500 mg; 1.4 mmol; 1 EQ) in dichloromethane (15 ml)and triethylamine (0,22 ml; 1.5 mmol; 1.1 EQ) and 1-hydroxybenzotriazole (200 mg; 1.5 mmol; 1.1 EQ). The reaction mixture was cooled to 0°and within 10 min was added 1,3-dicyclohexylcarbodiimide (310 mg; 1.5 mmol; 1.1 EQ). The reaction mixture was heated to room temperature and was stirred for 36 h, and then was acidified with 5% aqueous citric acid solution. The resulting layers were separated, and the organic layer washed with 5% aqueous sodium bicarbonate solution (5 ml) and water (2 ml). The organic layer was dried (Na2SO4), was evaporated under reduced pressure, and then it chromatographic purification (SiO2) with elution with a mixture of cyclohexane/ethyl acetate/methanol (ratio 60:40:1 volume/volume/volume) as a result gave the intermediate compound (350 mg; 0.75 mmol; yield 55%). The specified connection (300 mg; 0.6 mmol; 1 EQ) was dissolved in tetrahydrofuran (10 ml) in an inert nitrogen atmosphere. Added Burgess reagent (160 mg; 0.7 mmol; 1.1 EQ) and the reaction mixture was heated to a temperature of distillation for 3 hours was Added water (5 ml). The product was extracted with ethyl acetate (2×15 ml), dried (Na2SO4), was evaporated under reduced pressure. Chromatographic purification (SiO2) with elution with a mixture of cyclohexane/ethyl acetate/meth is Nol (in the ratio 50:50:1 volume/volume/volume) gave the ethyl ester of 2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-4,5-dihydrooxazolo-4-carboxylic acid. This intermediate ester (100 mg; 0.22 mmol; 1 EQ) was dissolved in dichloromethane (3 ml)and the resulting solution was cooled to 0°C. Then was added dropwise to 1.8-diazabicyclo[5,6]undec-7-ene (0.036 ml; 0.24 mmol; 1.1 EQ) and bromotrichloromethane (0,024 ml; 0.24 mmol; 1.1 EQ). The reaction mixture was stirred for 6 h at 0°C. was Added a saturated aqueous solution of ammonium chloride (10 ml), and the resulting layers were separated. The combined organic layer was washed with brine (5 ml), dried (Na2SO4) and evaporated under reduced pressure. After that, the obtained ester (85 mg; 0.18 mmol; 1 EQ) was dissolved in a mixture of tetrahydrofuran/water (6 ml) in a ratio of 3:1 (volume/volume) and added lithium hydroxide (14 mg; 0.5 mmol; 3 EQ). After 2 h introduced an aqueous solution of 5% citric acid (5 ml). The product was extracted with ethyl acetate (2×15 ml), dried (Na2SO4) and evaporated under reduced pressure. Then subsequent recrystallization from methanol gave compound 9 as a solid substance of white color (65 mg; 0.14 mmol; yield 80%).

MS: 431 [M+H]+

NMR DMSO_d6: 9.08 (s, 1H, O-*CH=C); 8.86 (d, 1H, JHH=2.5 Hz, C=*CH-C); 8.71 (s, 2H, PY); 8.63 (d, 1H, JHH=9.3 Hz, *CH=CH-C-OMe); 7.87 (dd, 1H, CH=*CH-C-OMe); 5.08 (s, 2H, *CH2-PY); 4.04 (s, 3H, OMe).

EXAMPLE 15

Synthesis of 2-[4-(3,5-dichloropyridine-4-yl-methyl-7-methoxypyrazine-1-yl]-thiophene-3-carboxylic acid (compound 10)

Compound 10 was obtained by acting thus, as e is about described for compounds 1, the substrate used intermediate compound 1 (500 mg, 1.4 mmol)and 3-formyl-2-tiefenbronn acid (220 g; 1.4 mmol). Product binding assays were extracted with ethyl acetate (2×15 ml), dried (Na2SO4) and evaporated under reduced pressure. This was followed by chromatographic purification (SiO2), which is when elution with a mixture of cyclohexane/ethyl acetate/methanol in a ratio of 60:40:1 (volume/volume/volume) gave the intermediate compound 2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-thiophene-3-carboxaldehyde (150 mg; 0.35 mmol; yield 25%). Then the specified intermediate aldehyde (80 mg, 0.18 mmol) was oxidized to the corresponding acid, at the same time acted as it was described for compound 5. This was followed by chromatographic purification (SiO2), which is when elution with a mixture of dichloromethane/methanol/acetic acid in the ratio 95:5:95 (volume/volume/volume) and subsequent recrystallization from a mixture of dichlorethane/methanol in a ratio of 99:1 (volume/volume) gave compound 10 in the form of a solid white color (40 mg; 0.09 mmol; yield 50%).

MS: 446 [M+H]+

NMR _d6: 8.70 (s, 2H, PY); 8.58 (d, 1H, JHH=9.1 Hz, *CH=CH-C-OMe); 7.97 (d, 1H, JHH=4.1 Hz, CH-S); 7.85-7.80 (m, 2H, S-CH=*CH, CH=*CH-C-OMe); 7.75 (d, 1H, JHH=2.5 Hz, C-*CH=C); 5.02 (s, 2H, *CH2-PY); 4.03 (s, 3H, OMe).

EXAMPLE 16

Synthesis of N-methyl-P-glutaminol salt of compound 2 (compound 11)

To with whom spencie compound 2 (500 mg; 1,136 mmol) in methanol (5 ml), heated to a temperature of distillation in an inert atmosphere of nitrogen was added a solution of N-methyl-D-glucamine (233 mg; 1,19 mmol) in methanol (1.2 ml) and water (1.5 ml). After complete dissolution of the above-mentioned mixture was evaporated under reduced pressure at room temperature. Added ethanol (10 ml) and the resulting solution was kept for 4 days at 4°C. the Formed precipitate was filtered and washed with ethanol (5 ml) and diethyl ether (5 ml). The product was dried for 15 h in vacuum at 50°With, receiving a connection 11 in the form of solid light yellow (400 mg; 0.61 mmol; yield 54%).

NMR _d6: 8.68 (s, 2H, PY); 8.54 (d, 1H, JHH=8.7 Hz, *CH=CH-C-OMe); 8.17 (s-broadened, 1H, C=*CH-C-CO2H); 8.06 (d-broadened, 1H, JHH=8.1 Hz, *CH), 7.78 (d-broadened, 1H, JHH=8.1 Hz, *CH); 7.72 (dd, 1H, CH=*CH-C-OMe); 7.58-7.50 (m, 1H, CH=*CH-CH); 7.29 (d, 1H, JHH=2.3 Hz, C=*CH-C); 5.04 (s, 2H, *CH2-PY); 3.91-3.82 (m, 4H, OMe, *CHH-OH); 3.58-3.33 (m, 5H, HO-*CHH-*CH(OH)-*CH(OH)-*CH(OH)-*CH(OH)), 3.06-2.84 (m, 2H, CH2-NH), 2.09 (s, 3H, NHMe).

EXAMPLE 17

Synthesis of 2-amino-2-hidroximetilpropan-1.3-Volovoi salt of compound 2 (compound 12)

To a suspension of compound 2 (500 mg; 1,136 mmol) in ethanol (5 ml), heated to a temperature of distillation in the inert atmosphere of nitrogen was added 2-amino-2-hydroxymethylpropane-1,3-diol (138 mg; 1.13 mmol). After complete dissolution, the temperature was decreased to room. After 2 h the precipitate was filtered and washed with ethanol (5 ml) and diethyl shall FYROM (5 ml). The product was dried in vacuum for 15 h at 50°With, receiving a connection 12 in the form of solid light yellow (400 mg; 0.71 mmol; yield 63%).

NMR _d6: 8.68 (s, 2H, PY); 8.54 (d, 1H, JHH=8.7 Hz, *CH=CH-C-OMe); 8.17 (s-broadened, 1H, C=*CH-C-CO2H); 8.05 (d-broadened, 1H, JHH=8.1 Hz, *CH), 7.79 (d-broadened, 1H, JHH=8.1 Hz, *CH); 7.77-7.70 (m, 1H, CH=*CH-C-OMe); 7.60-7.51 (m, 1H, CH=*CH-CH); 7.29 (d, 1H, JHH=2.3 Hz, C=*CH-C); 5.01 (s, 2H, *CH2-PY); 3.86 (s, 3H, OMe), 3.46 (s, 6H, C(CH2)3).

Example 18

Inhibition of the enzyme PDE 4

a) Purification of the enzyme PDE 4

The enzyme PDE 4 was isolated from cell line U937. using the method Nielson et al. (J. Allergy Clin. Immunol, 1990, vol.86, pages 801-807), partially modified for liquid Express chromatography of proteins (FPLC).

Cell line U-937 (Istituto Zooprofilattico Sperimentale. Brescia. Italy) was maintained in RPMI 1640 with 10% fetal bovine serum and 2 mm glutamine, density was (1·106-8×106) cells per ml, the process was performed in an incubator at 37°C, With 5% CO2.

Suspension of U937 cells homogenized in a buffer with a pH of 7.8, containing 10 mm Tris (tri-(hydroxymethyl)-aminomethan), 5 μm MgCl2, 4 μm EGTA (ethylene glycol-bis-(β-aminoacylase ether)-N,N,N′N′-tetraoxane acid), 5 μm β-mercaptoethanol, 1 μm leupeptin, 1 μm of pepstatin And 1% Triton x-100, and 100 μm of phenylmethylsulfonyl (PMSF).

Homogenized centrifuged, and superna the ant used for purification of the enzyme PDE 4; enzyme sowed column attached to a chromatographic system for biological objects (FPLC, BIO RAD).

The enzyme PDE 4 was suirable acetate sodium when it is a linear gradient from 50 mm to 1 M, siourounis fractions were collected for subsequent determination of the enzymatic activity of PDE 4

Combined fractions containing the active PDE 4, and after overnight dialysis (for separation of sodium acetate), was evaporated to 30% of the volume; for the latter procedure used filter system with Amicon YM10 membrane filter.

Added ethylene glycol (30% volume/volume), and the obtained sample was kept at 20°in the form of single aliquots until use.

b) analysis of the activity of PDE 4

The enzyme activity was analyzed in the device Scintillation Proximity Assay (SPA) (Amersham), which consisted of [3H]camp as a label, the buffer for the analysis of PDE (10× solution: 500 mm Tris/HCl pH 7,5; 83 μm MgCl2and 17 µm EGTA), and the granules PDE Yttrium SPA (containing 18 μm zinc sulfate).

The radioactivity of these granules was determined using a scintillation counter (Packard model MINAXI β TRI-CARB 4000 SERIES).

The values of the IC50was calculated by the curve of the dependence of inhibition on the concentration, was used for nonlinear regression analysis program ORIGIN 3.5 (MICROCAL SOFTWARE INC.). Each parameter was represented by actually testing the giving ± the arithmetic mean of values obtained in 3 experiments using different preparations of PDE 4.

The compounds of formula I of the present invention demonstrated selective inhibition of the enzyme PDE 4.

The results are shown in table 1.

Table 1
ConnectionIC50(nm)
125% at 10-7
237
347% at 10-7
416% at 10-7
5for 91.3
645
754% at 10-7
823
914% at 10-7
1048

Example 19

The release of TNFa in whole human blood

Blood samples obtained from healthy volunteers was collected in heparinized tubes and diluted in RPMI 1640 at a ratio of 1:5, with no additives serum is not produced.

The analysis was carried out on plates with 96 wells. Samples containing 150 ál of diluted blood and 150 μl of RPMI 1640 with control medium or with various concentrations of the compounds of the present invention were incubated with the ri 37° C for 30 min in a humid atmosphere with 5% CO2.

Whole blood samples for analysis were diluted in the ratio 1:10 (volume/volume).

Samples were treated with LPS (lipopolysaccharide from E. coli: serotype 0:55, Sigma) in an amount of 0.25 microgram/ml, and then incubation was performed within 24 hours

After centrifugation supernatant were collected for determination of concentration of TNFa; used for the analysis of commercially available device ELISA (Biosource).

The test objects were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10-2M, and then dissolved in RPMI 1640.

The final concentration of DMSO did not exceed 0.1%, and it had no effect on the release of TNFa.

For each of the 9 levels of compounds analysis was performed twice. The resulting data were then confirmed using blood samples obtained from different donors.

Estimate the inhibition of production of TNFafor each concentration, and the value of the IC50were determined using 4-paratroopa equation logistics (Origin calculation program, Microcal Software Inc.).

It turned out that the compounds of formula I of the present invention inhibit the release of TNFa.

The following table 2 shows the results, expressed as IC50at two different concentrations.

Table 2
ConnectionIC50(nm)IC50(nm)
2247033000
8123014300
1018000

EXAMPLE 20

Inhibition of enzymes PDE 3 and re 5

a) Purification of enzymes PDE 3 and PDE 5

Enzymes PDE 3 and PDE 5 was purified from plasma rich in platelets (PBT), obtained from healthy volunteers.

Purification of enzymes PDE 3 and PDE 5 was carried out using Simpson's method A.W.M. et al. (Biochem. Pharmacol, 1988, 37, 2315-2320), partially modified for liquid Express chromatography of proteins (FPLC).

PBT was diluted in the ratio 1:1 and centrifuged at room temperature for 15 min at a rotation speed of 2000 rpm/min

Platelets suspended in 10 ml lisanova solution (155 mm NH4Cl, 10 mm knso3and 0.1 mm sodium salts of ethylenediaminetetraacetic acid (ATDC) pH 7.4). To remove impurities erythrocytes held incubation for 10 min in an ice bath.

After centrifugation, the platelets suspended in 10 ml of 20 mm bis-Tris (2 ml add, 5 mm β-mercaptoethanol, 50 mm sodium acetate, 2 mm benzamidine), and then homogenized in an ice bath in the homogenizer transmitter station.

The homogenate was centrifuged, and the floor is built supernatant was transferred to a column UNO Q12, attached to the system for chromatography of biological objects (FPLC, Bio-Rad).

Enzymes PDE 3 and PDE 5 was suirable sodium acetate with a linear gradient of 0.05-1M, and erwerbende fraction was collected for further analysis of the activity of enzymes PDE.

Combined fractions having the activity of the enzyme PDE, during the night spent their dialysis against distilled water and using Amicon filtration system (with membrane YM10 filter), conducted a 10-fold thickening.

Added ethylene glycol to obtain a 30% concentration (volume/volume) and the resulting solution was kept at -20°C.

Under these conditions, enzyme activity remained stable.

b) analysis of the activity of PDE 3 and PDE 5

Enzyme activity was analyzed in the device Scintillation Proximity Assay (SPA) (Amersham), which included3H-camp for PDE 3 or3H-for cGMP PDE 5, the buffer for the analysis of PDE (10× solution: 500 mm Tris/HCl pH 7,5; 83 μm MgCl2and 17 µm EGTA), and the granules PDE Yttrium SPA (containing 18 μm zinc sulfate).

The radioactivity of these granules was determined using a scintillation counter (Packard model MINAXI β TRI-CARB 4000 SERIES).

The following table 3 shows the results, expressed as the value of the IC50some of the compounds which are representative of the entire class of compounds.

Table 3
ConnectionPDE 3-5 IC50(nm)
2>10000
8>10000
10>10000

EXAMPLE 21

Inhibition of the enzyme PDE 2

a) Purification of the enzyme PDE 2

PDE 2 was purified from mouse cells RS according to the method described in the work Whalin et al. (Molecular Pharmacol. 1991, 39, 711-717).

Cells RS obtained from the Istituto Zooprofilattico Brescia (Italy), kept in containers with a capacity of 150 cm3at 37°C and 5% CO2in a medium containing 5% fetal bovine serum, 15% horse serum, 1% penicillin, 1% streptomycin and 1% glutamine.

Cells were increased in volume, however, attention was drawn to the fact that their cleavage occurred only on the achievement of the merger.

After washing cells were separated using a mixture of 0.05% trypsin/0.02% of add, and then collected in a clean tube.

After centrifugation cells suspended in a buffer with pH 6.5, containing bis-Tris (20 mm), edtk (2 μm), 2-mercaptoethanol (5 μm), leupeptin (1 μm), pepstatin A (1 μm), phenylmethylsulfonyl (100 μm), and then homogenized using a homogenizer transmitter station.

Obtained by centrifugation of the supernatant was transferred to a column UNO Q12 connected to the system for chromatography of biological objects (FPLC, Bio-Rad).

The enzyme PDE 2 suirou and sodium acetate with a linear gradient of 0.05-1M, erwerbende fraction was collected for further analysis activity of the enzyme PDE 2.

Combined fractions having the activity of the enzyme PDE 2, during the night spent their dialysis against distilled water and using Amicon filtration system (with membrane YM10 filter), conducted a 10-fold thickening.

Added ethylene glycol (30%, volume/volume) and the resulting solution was kept at -20°C.

Under these conditions, enzyme activity remained stable for several weeks.

b) analysis of the activity of PDE 2

The activity of the enzyme PDE 2 was analyzed in the device Scintillation Proximity Assay (SPA) (Amersham), which included tag3H-camp, the buffer for the analysis of PDE (10× solution: 500 mm Tris/HCl pH 7,5; 83 μm MgCl2and 17 µm EGTA), and the granules PDE Yttrium SPA (containing 18 μm zinc sulfate).

The radioactivity of these granules was determined using a scintillation counter (Packard model MINAXI β TRI-CARB 4000 SERIES).

The following table 4 contains the results, expressed as the value of the IC50some of the compounds which are representative of the entire class of compounds.

Table 4
ConnectionPDE 2 IC50(nm)
2>10000
8>10000
1 >10000

EXAMPLE 22

Inhibition of the enzyme PDE 1

a) Purification of the enzyme PDE 1

Dried and partially purified enzyme PDE 1 was purchased from the company Sigma (P0520).

The specified enzyme contained a fraction P1 reported in the work But et al. (Biochim Biophys Acta, 1976, vol.429 (2), 461-473).

Liofilizovannye enzyme was recovered 30% volume/volume of a glycol with a concentration of 500 g/ml, and kept at t -20°C.

b) analysis of the activity of PDE 1

The activity of the enzyme PDE 1 was analyzed in the device Scintillation Proximity Assay (SPA) (Amersham), which included tag3H-camp, the buffer for the analysis of PDE (10× solution: 500 mm Tris/HCl pH 7,5; 83 μm MgCl2and 17 µm EGTA), and the granules PDE Yttrium SPA (containing 18 μm zinc sulfate).

The radioactivity of these granules was determined using a scintillation counter (Packard model MINAXI β TRI-CARB 4000 SERIES).

The following table 5 contains the results, expressed as the value of the IC50some of the compounds which are representative of the entire class of compounds.

Table 5
ConnectionPDE 1 IC50(nm)
2>10000
8>10000
10>10000

EXAMPLE 23

Are Yes the data on the solubility of the compounds of formula I of the present invention in comparison with the same data, specified in the application for international patent WO 00/05218.

To test the solubility of the used liquid chromatography with high resolution (URGH).

Test solubility relative to the benchmark was performed using the analysis method URGH (column 4,6×15 mm; gradient: water/0.1%of TRA-CH3CN/IS 0.06% TFA).

Was prepared in a 10 M solution of analyte, dissolved in dimethyl sulfoxide (DMSO).

For preparation of the sample to 10 μl of the above solution was added to 190 μl of phosphate-saline buffer (FSB; pH 7.4). For making reference to other 10 μl of the above solution was added to 190 μl of DMSO.

The results obtained for the compounds of formula I, are listed in table 6.

Table 6
ConnectionMolecular weightSolubility (mg/ml)Solubility (μm)
24480,216482,14
14400,218495,45
65330,271508,44
34850,298614,43
44700,226480,85
547 0,23489,36
74700,235500,00
84760,47987,39
94310,202468,68
104460,253567,26

The results obtained for the compounds of the application for international patent WO 00/05218

in which R represents a group-CH3(if it is not specifically mentioned); below in table 7.

Table 7
YSolubility (μm)Connection
H301
H, N1-ox402
H, N1-ox, N3-ox523
Ethyl374
Phenyl245
4-phenyl-butyl<16
Triazole-2-yl<126
Phenylethynyl627
Pyrrolidin-1-he13028
Triazole-1-yl12 29
Morpholine-4-yl8738
Propylamino5239
Dimethylamino5844
Imidazol-1-yl2045
Triazole-2-yl-amimo346
Phenoxy647
4-methylpiperazin7148
Triazole-1-yl, R=-CHF21054
Morpholine-4-yl, R=-CHF28255
Morpholine-4-yl-methyl3956
Pyrrolidin-1-yl-methyl3757
3-morpholine-4-yl-PROPYNYL1358
2-methyl-buten-2-ol3359
Ethinyl3260
-CONH2761
Carbonitril562
Carboxypropanoyl>20075
pyrrolidin
Triazole-2-yl, N3-ox<185

The connection indicated in the application for international is natural patent WO 00/05218 at number 75, has inhibitory activity against PDE 4, which is below the value set for the compounds of the present invention.

EXAMPLE 24

Pharmakinetics case studies of rats

Rats injected with a mixture containing 3-5 compounds from work K.W. Ward et al. (Drug Metab. Dispos. 2001, vol.29, 82-88), the dose was 10 mg/kg and was administered orally (1 mg/ml in 77% N-methylglucamine 25 microns and 20% PG, containing 3% tween 80), or intravenously at a dose of 3 mg/kg (3 mg/ml in 15% DMSO/85% PEG).

During the study, animals were treated once.

Rats with long-term implanted catheter (SilasticRDow Corning) were analyzed mixture in the form of intravenous bonus (via the implanted catheter) or orally through a feeding tube.

Blood samples were collected via the catheter at different points in time up to 6 h after injection of the mixture.

Analysis of blood samples was performed after deposition of proteins using two volumes of CH3CN; concentration of plasma was determined by methods of liquid chromatography/mass spectrometry.

The results obtained for several compounds of formula I listed in table 8.

Table 8
ConnectionRK rats t/2 (min)RK rats % F
213243%
86641%
10217%

The increase in the solubility of the compounds of the present invention has enabled to study the biological availability using physiological media, typically used in conventional pharmaceutical compositions.

The study of compounds with the General formula of the application for international patent WO 00/05218, which was carried out using physiological media, showed that the magnitude of the biological availability of 0.

Because compounds with the General formula of the application for international patent WO 00/05218 have a low solubility, pharmakinetics study was to be conducted with use of a solution of 15% DMSO/85% PEG for connections, input and intravenously and orally (i.e. used absolutely nefiziologichnoe media).

In table 9 is given in the specified conditions results in the biological availability.

td align="center"> 0%
Table 9
ConnectionRK rats %F
529%
2011%
150%
178%
2927%
60
499%

Thus, the compounds of formula I, which is the subject of the present invention, when administered in physiological media show good bioavailability, values which are comparable, and in many cases higher than that of the compounds of comparable applications. It is stressed that the bioavailability of the latter compounds above only if it is measured in nefiziologichnoe solution of DMSO/PEG.

1. Derivatives phthalazine formula

in which R predstavljaet metallinou or deformational group; R1represents phenyl, or oxazolyl, or thiophenyl associated chemical bond with phthalazinone cycle through carbon-carbon link, and as phenyl and said heterocycle substituted by carboxyl group, and optionally on a second functional group selected from methoxy-, nitro-, N-acetylamino-, N-methanesulfonylaminoethyl,

and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, wherein R1represents phenyl, substituted at carboxypropyl, and not necessarily on the second functional group selected from methoxy-, nitro-, N-acetylamino-, N-methanesulfonylaminoethyl.

3. Connection is about to claim 2, wherein R1represents phenyl, substituted at carboxypropyl and this carboxypropyl is in the meta position relative to phthalazinone cycle.

4. Compounds according to claim 1, wherein R1represents oxazolyl or thiophenyl associated with phthalazinone cycle through carbon-carbon links, substituted carboxyl group, and optionally on a second functional group selected from methoxy-, nitro-, N-acetylamino-, N-methanesulfonylaminoethyl.

5. The compound according to claim 1, chosen from:

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

4-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-nitrobenzoic acids;

5-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-2-methoxybenzoic acids;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-4-methoxybenzoic acids;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-5-methanesulfonylaminoethyl acids;

3-acetylamino-5-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxy-phthalazine-1-yl]-benzoic acid;

3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-gift methoxypyrazine-1-yl]-benzoic acid;

2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-oxazol-4-carboxylic acid;

2-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-thiophene-3-carboxylic acid;

(2-amino-2-hydroxymethylpropane-1,3-diol salt of 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

N-metilglyukaminovoy salt 3-[4-(3,5-dichloropyridine-4-yl-methyl)-7-methoxypyrazine-1-yl]-benzoic acid;

6. A method of obtaining a compound according to claim 1 by reaction of nucleophilic aromatic substitution or binding reaction in the presence of palladium catalyst between the compound of formula II

in which R has the meanings specified for compounds of formula I,

and reagent type derived tin or Bronevoy acid suitable for substitution of the halogen atom that is directly associated with phthalazinone cycle, phenyl, or oxazolyl, or thiophenyl placed on carboxypropyl, and not necessarily in a second functional group that is specified for values of R1in formula I.

7. The method according to claim 6, characterized in that the binding reaction between the compounds of formula II and the appropriate Bronevoy acid occurs in the presence of palladium triphenylphosphine, and an aqueous solution of potassium carbonate.

8. Pharmaceutical Sortavala treatment of allergic and inflammatory diseases, containing a therapeutically effective amount of a compound according to claim 1 in a mixture with a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 for the treatment of respiratory diseases.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

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

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to nonhygroscopic crystalline 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,2-dimethyl-1H-pyrrol-3-carboxamide maleate salt that possesses inhibitory effect on tyrosine kinase receptors. Also, invention relates to a pharmaceutical composition and to a method for treatment of cancer in mammals using such compositions.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

12 cl, 12 tbl, 17 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to a new method of obtaining derivatives of N-phenyl-2-pyrimidineamine (2-anilinopyrimidine) with general formula (I), which have a wide spectrum of biological effects and can be used mainly, for treating various types of tumours, leucaemia, cerebral ischemia, vascular stenosis and other diseases. In general formula (I) , R1 represents a pyridyl or its oxide bonded to a carbon atom, which can be substituted with a low alkyl or alkoxy, each of R2 and R3 independently represents hydrogen, branched of unbranched low alkyl, phenyl, unsubstituted of substituted with a haloid, R4 represents hydrogen, unbranched or branched low alkyl, R5 represents hydrogen, low alkyl, possibly substituted with halogen atoms. Other representations of radical are given in the formula of invention. The method involves the following stages: A) reaction of urea, mainly in a basic medium with N,N-dialkyamino-1-(3-pyridyl)-2-propene-1-ono with general formula II: with obtaining of the corresponding dihydropyrimidinone with general formula (III) B) oxidation of compound (III) by proton oxidation, with obtaining of the corresponding hydroxypyrimidine with formula IV , C) activation of the hydroxy group in the obtained compound IV , for example, treatment using sulphohalide R'SC2Hal or anhydride R'(SO2)2O, with obtaining of a compound with general formula V , where R' represents aryl of low alkyl, D) reaction of the obtained compound V with the corresponding aromatic amino compound with formula VI , with obtaining of compound with formula (I) and subsequent possible conversion of the obtained compounds to other compounds with general formula (I).

EFFECT: method allows for excluding use of toxic compounds and simplifies the process.

13 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of quinoline with general formula Ia or Ib their stereoisomers and pharmaceutical salts, where X represents oxygen or sulphur, Z-CH2, Y-NO2, -C(O)OR5, -NR5SO2R5, -SO2R5 (for Ia) and -NO2 or -C(O)OR5 (for Ib). Description is also given of the method of obtaining Ia and Ib compounds, pharmaceutical compositions based on them, and their use when making medicinal preparations.

EFFECT: compounds can be used for treating lesions, related to inhibition of migration of magrophage, for example, during treatment of septic shock or arthritis.

175 cl, 16 tbl, 22 ex, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA): or the formula (IB): wherein B means hydrogen atom or lower alkyl; A means an unsubstituted or substituted cyclic group chosen from compounds of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) and (k) wherein R1-R4 mean independently of one another hydrogen atom, halogen atom, -CF3, -CHF2, -C(CH3)F2, (C3-C6)-cycloalkyl, lower alkoxy-group, lower alkyl, -OCF3 or phenyl; R5-R10 means independently of one another hydrogen atom, halogen atom, lower alkoxy-group, lower alkyl or -CHF2; R11-R16 mean independently of one another hydrogen atom, halogen atom, alkoxy-group or lower alkyl; R17 means halogen atom or -CHF2; R18-R20 mean independently of one another hydrogen atom, lower alkoxy-group or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicinal agent possessing the selective effect of blockers of NMDA receptors of subtype 2B. Invention provides synthesis of novel biologically active compounds and medicinal agents based on thereof.

EFFECT: valuable medicinal properties of compounds and drugs.

6 cl, 180 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.

SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.

EFFECT: improved method of synthesis, valuable medicinal property of compounds.

2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: description is given benzimidazole derivatives with general formula I , where Z is chosen from O=; R1 is chosen from C1-10alkyl, R5 R6 N-C1-6alkyl, R5O-C1-6alkyl, R5C(=O)N(-R6)-C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, C3-6heterocycloalkyl-C1-6alkyl C3-6heterocyclyl-C(=O)-C1-6alkyl, C1-10hydrocarbylamino, R5R6N-, R5O-, R5C(=O)N(-R6)-, R5R6NC(=O)N(-R7)-, C3-10cycloalkyl, C3-6heterocyclyl and C3-6heterocyclyl-C(=O)-; R2 is chosen from a group consisting of C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6 alkyl, C3-6heterocycloalkyl-C1-6alkyl, R5R6N- and C3-6heterocycloalkyl; R3 and R4 are independently chosen from -H, -OH, R and -0-R , where R3 and R4 simultaneously do not represent -H. The indicated C1-6alkyl or bivalent C1-6group in definition of R8 are possibly substituted with one or more groups, chosen from halogen, methoxy, ethoxy, hydroxy and -NR5R6; or R3 and R4 together with the nitrogen atom to which they are bonded, form part of a 5- or 6-member ring. The indicated ring is possibly substituted with one or more groups, chosen from methyl, ethyl, halogen, methoxy, ethoxy, hydroxyl and -NR5R. Description is given of a method of obtaining an intermediate product, as well as pharmaceutical compositions, containing formula I compounds.

EFFECT: proposed benzimidazoles relate to therapeutic compounds, which are ligands of receptor CB1 and can be used in making pain killers.

11 cl, 23 ex

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