The method of producing alkanesulfonyl

 

(57) Abstract:

The invention relates to a method of producing alkanesulfonyl General formula 1: where R1is (C1-C6) alkyl, the interaction of the compounds of formula 2 with a Grignard reagent, processing of the received product (C1-C6) alkylsulfonamides reagent and, if necessary, the resulting product of formula 1, where R1represents methyl, are hydrazines in the presence of an amine in a suitable solvent to obtain compounds of formula 3. The described method allows to simplify the process of obtaining alkanesulfonyl by reducing the number of stages, the availability of reagents used and the process is not at ultralow temperatures, as in the known method, and at temperatures higher than minus 20°C. 13 C.p. f-crystals.

The level of technology

The present invention relates to a method for producing derivatives of alkanesulfonyl formula 1:

which are useful as intermediates in the synthesis of pyrazol compounds of formula 5:

where substituent R1represents unsubstituted (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy-, -F3, (C1-C6) alkyl-S-, (C1-C6) alkyl-S(=O)-, (C1-C6) alkyl-SO2-, amino-, (C1-C6) alkylamino-, di[(C1-C6) alkyl] amino, NH2-(C=O)-, (C1-C6) alkyl-NH-(C=O)- and formyl; Deputy Rbrepresents a hydrogen atom, halogen atom or (C1-C6) alkyl; Deputy Rcis a (C1-C6)alkyl, optionally substituted with one to three halogen atoms.

The compounds of formula 5 (“active compound”) is useful in the treatment or alleviation of inflammation and other inflammation diseases, such as arthritis, neurodegeneration, and cancer of the colon, in mammals, preferably humans, dogs, cats or livestock. I believe that active compounds inhibit the biosynthesis of prostaglandins by interference with the action of the enzyme cyclooxygenase on arachidonic acid.

The compounds of formula 5 and other methods of obtaining derivatives of alkanesulfonyl described in which the same is generally as reference. International patent PCT application corresponding to the serial number 09/724446, published June 7, 2001 as WO 01/40216. In the application 09/724446 and WO 01/40216 sulfanilimide receive a two-step process comprising a first stage for receiving sulfide or by nucleophilic substitution using, for example, alkylsulfate, or methylation of mercaptopyridine with the subsequent second stage, which consists in the oxidation of the sulfide group to sulfonyloxy group.

In the present invention alkylsulfonyl group, R1-SO2introducing one stage in metallizovannyj pyridine (i.e. the product of the Grignard reaction), which eliminates the need to stage oxidation of sulfide. In particular, it was found that the use of stage (b) alkylsulfonyl reagents, such as alkanesulfonyl or alkanesulfonyl that are weak electrophiles compared to, for example, disulfides (see Wang et al., (2000), Tet. Lett 41:4335-4338), unexpectedly selectively and with high yield leads to alkanesulfonyl. It is also worth noting that alkylsulfonamides reagents, such as reagents disclosed herein, are cheap and therefore are especially suitable for commercial And, finally, the present invention enables to realize a phase (a) the introduction of the metal atom, and stage (b) - alkylsulfonamides not at very low temperatures, i.e. at temperatures above -20°C. Thus, the present invention provides a direct and regioselective method for obtaining 5-(alkanesulfonyl)-2-bromopyridine.

The invention

The present invention relates to a method for obtaining compounds of formula 1:

which includes the stages of:

(a) interaction of the compounds of formula 2

with a Grignard reagent;

(b) interaction of the product of stage (a) with

(C1-C6)alkylsulfonamides reagent;

where substituent R1represents unsubstituted (C1-C6)alkyl.

In one of the embodiments of the invention, the substituent R1represents unsubstituted (C1-C3)alkyl. In a preferred embodiment of the invention Deputy1represents methyl. In a preferred embodiment of the invention, the substituent R1represents methyl and alkylsulfonamides reagent is methylsulfonium any or branched (C1-C6)alkylacrylate, i.e. the compound of the formula RMgX, where R is a linear or branched (C1-C10)alkyl and X is a halide. In a preferred embodiment of the invention, the Grignard reagent is a (C1-C4)alkylacrylate, such as methylaniline, ethylaniline, propylaniline, isopropylaniline, butylaniline or tert-butylaniline. In a particularly preferred variant of the invention, the Grignard reagent is isopropylaniline.

In another embodiment of the invention stage (a) is carried out in a solvent selected from the group consisting of diethyl ether, tetrahydrofuran (THF), glyme (1,2-dimethoxyethane) or diglyme (bis(2-methoxyethanol) ether). In a preferred embodiment of the invention the solvent at the stage (a) is THF.

In another embodiment of the invention stage (a) is conducted at a temperature of from about -20°C. to approximately room temperature (approximately 20-25°C). In another embodiment of the invention stage (a) is conducted at a temperature of from about -20 to about 10°C. In another embodiment of the invention stage (a)blithedale 45 minutes

In another embodiment of the invention alkylsulfonamides agent is a (C1-C6) alkanesulfonyl or anhydride (C1-C6) alkanesulphonic acid. In a preferred embodiment of the invention alkylsulfonamides agent is alkanesulfonyl formula R1SO2X, where X represents chlorine or fluorine. In a preferred embodiment of the invention alkanesulfonyl represents unsubstituted (C1-C3) alkanesulfonyl. In a more preferred embodiment of the invention alkanesulfonyl is methansulfonate or methansulfonate. In a particularly preferred variant of the invention alkanesulfonyl is methanesulfonanilide. In another preferred embodiment of the invention alkylsulfonamides agent is an anhydride alkanesulphonic acid of the formula (R1SO2)2O. In the preferred embodiment of the invention the anhydride alkanesulphonic acid is an anhydride unsubstituted (C1-C3) alkanesulphonic acid. In a particularly preferred variant of the invention angina invention stage (b) is carried out in THF.

In yet another variant of the invention the method further includes obtaining the compounds of formula 3

hydrazinolysis the compounds of formula 1 in the presence of an amine in a suitable solvent. In the embodiment of the invention hydrazines carried out using hydrazine, such as hydrazinehydrate. In a variant of the invention the amine is chosen from the group consisting of triethylamine, diisopropylethylamine, 2,6-lutidine and N,N,N’,N’-tetramethylethylenediamine. In a preferred embodiment of the invention the amine is a triethylamine. In another embodiment of the invention suitable solvent for hydrazinolysis selected from the group consisting of water, dichloromethane, dichloroethane and toluene. In a preferred embodiment of the invention the solvent is water.

Compounds obtained by the methods of the present invention, which is basic in nature, for example the compounds of formula 3, can form a large number of different salts with various inorganic and organic acids. Acid additive salts of the basic compounds obtained by the methods of the present invention, is easily obtained by processing the primary connection is orites or in a suitable organic solvent. With careful evaporation of the solvent easily get the desired solid salt. The desired salt may precipitate from a solution of the free base in an organic solvent, adding to the solution of a suitable inorganic or organic acid.

In another embodiment of the invention the method further includes processing the compounds of formula 3 acid in a suitable solvent. In a preferred embodiment of the invention the acid is hydrochloric acid. In the embodiment of the invention the acid additive salt of the compounds of formula 3 obtained by the method according to the invention, is a hydrochloric salt.

In another embodiment, the invention hydrazines carried out at a temperature between room temperature and the temperature of approximately 100°C., preferably at about 70°C. In another embodiment, the invention hydrazines carried out during the period from about 3 to about 24 hours, preferably for about 5 hours.

The present invention also relates to hydrochloric additive salts of the compounds of formula 3 obtained by the method of nagovorena particularly, used regardless of the state of dispersion of its components.

The term “organic solvent”, as used in the description, unless otherwise stated, means a non-aqueous solvent or mixture of non-aqueous solvents.

In a preferred embodiment, the methods described here, the reaction is carried out at approximately atmospheric pressure. In this application, the term “atmospheric pressure” means the pressure within the normal interval meteorological atmospheric pressure for a specific position above sea level, while the term “high pressure” means a pressure above atmospheric pressure. In another embodiment, the described methods, the reaction is carried out at elevated pressure.

Unless otherwise stated, the term “alkyl” used in the description, and the alkyl fragment of the other groups listed in the description (for example, alkoxygroup), may refer to a linear or branched groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl), and can also refer to cyclic groups (such as cyclopropyl or cyclobutyl); optionally substituted 1-3 suitable substituents, to whom lexi-, triptoreline, deformedarse or (C1-C6) alkyl. The phrase “each of these Akilov”, as used in the description applies to any of the preceding alkyl fragments within the group, such as alkoxy-, alkenyl or alkylamino.

Unless otherwise stated, the terms “halogen” and “halogen atom” are used interchangeably to refer to fluorine, chlorine, bromine or iodine or fluorine atoms, chlorine, bromine or iodine, whereas the term “halide” is used to denote fluoride, chloride, bromide or yadidamean.

In this description, the term “halogen-substituted alkyl” refers to the alkyl radical, as described above, which is substituted by one or more Halogens including, but not limited to, chloromethyl, dichloromethyl, vermeil, deformity, trifluoromethyl, 2,2,2-trichloroethyl and the like, optionally substituted by 1-3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C1-C6) alkoxy-, (C6-C10) aryloxy, triptoreline, deformedarse or (C1-C6) alkyl.

In this description, the term “alkenyl” means a linear or branched unsaturated radical of 2-6 carbon atoms, VK-butenyl and the like, optionally substituted by 1-3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C1-C10) alkoxy-, (C6-C10) aryloxy, triptoreline, deformedarse or (C1-C6) alkyl.

In this description, the term “quinil” means linear or branched hydrocarbon radical of 2-6 carbon atoms, containing one triple bond including, but not limited to, ethinyl, PROPYNYL, butynyl and the like, optionally substituted by 1-3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C1-C6) alkoxy-, (C6-C10) aryloxy, triptoreline, deformedarse or (C1-C6) alkyl.

Used in the description of the term “alkoxy” refers to O-alkyl groups, in which alkyl has the meanings given above.

Used in the description, the term “alkoxycarbonyl” refers to the CNS radical, as defined above, linked to the carbonyl group (>C=O), which in turn serves as the attachment point.

The term “pharmaceutically acceptable (s) salt (s)” used in the description, unless otherwise stated, includes salt obtained by the methods of the present invention, which are basic in nature are capable of forming a large number of salts with various inorganic and organic acids. Acids which can be used to obtain a pharmaceutically acceptable acid additive salts of such basic compounds of the present invention are acids which form non-toxic acid additive salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, pamoate [i.e 1,1’-methylene-bis-(2-hydroxy-3-aftout)]. Compounds obtained by the methods of the present invention, which contain an amino group, can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above.

The present invention also includes methods for obtaining the compounds of formula 1, in which one or a few m is generated as diagnostic tools in the study of metabolism, pharmacokinetics and binding. Examples of isotopes that can be used in the methods of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N18O,17O,35S 18F and36Cl respectively. The methods of the present invention, using the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Some isotope-labeled compounds obtained by the methods of the present invention, for example compounds which are introduced such radioactive isotopes, as3N and14With, useful in the study of distribution in the treatment of drug and/or substrate tissue. Tritium,3N and carbon-14, that is,14With, are the preferred isotopes because of the simplicity of their production and detection. In addition, the substitution of heavier isotopes such as deuterium, i.e2H, may provide some therapeutic benefit due to the higher metabolic stability, for example a higher half-life in vivo or the need for lower doses, and therefore, in some cases moreout to be obtained by implementing techniques described below in the schemes and/or examples, by the replacement of the reagent without isotopic labels on readily available isotope-labeled reagent.

Detailed description of the invention

The method of the present invention can be carried out in accordance with scheme 1 and described below.

Scheme 1

Scheme 2

Schemes 1 and 2 above are only illustrative and are described in more detail below and in the examples below. The substituents R1and Ra-Rcin schemes 1 and 2 have the following meanings: R1is a (C1-C6) alkyl; Rarepresents phenyl, optionally substituted by 1-3 substituents, independently selected from the group consisting of halogen atom, hydroxy-, cyano-, mercapto-, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy-, -F3, (C1-C6) alkyl-S-, (C1-C6) alkyl-S (=O)-, (C1-C6) alkyl-SO2-, amino-, (C1-C6) alkylamino-, di [(C1-C6) alkyl] amino, NH2-(C=O)-, (C1-C6) alkyl-NH-(C=O)- and formyl; Deputy Rbrepresents a hydrogen atom, halogen atom or (C1-C6

The first stage in figure 1 represents direct alkylsulfonamides 2,5-dibromopyridine. The compound of formula 2, 2.5-dibromopyridin, (1) is treated with a Grignard reagent and then (2) enter into reaction with alkylsulfonamides agent with obtaining the compounds of formula 1. The Grignard reagent, that is, RMgX, where R is a (C1-C6) alkyl and X represents a halogen atom, preferably represents sawn or botilony the Grignard reagent, such as propylaniline or isopropylaniline, most preferably isopropylaniline. The metallation reaction (Grignard reagent) is preferably carried out at a temperature from about -20°C. to about room temperature over a period of time from about 0.5 hours to about 4 hours, preferably for about 45 minutes Suitable solvent for the Grignard reaction include, but are not limited to, diethyl ether, tetrahydrofuran (THF), glyme (1,2-dimethoxyethane) or diglyme (bis (2-methoxyethoxy) ether). The preferred solvent is THF.

Alkylsulfonamides agent preferably is alkanesulfonyl (that is, R1SO2X, where X is preferably, alkanesulfonyl represents unsubstituted (C1-C3) alkanesulfonyl. More preferably alkylsulfonamides agent is methansulfonate or methansulfonate. Especially preferred is methanesulfonanilide. The preferred anhydride alkanesulphonic acid anhydride is unsubstituted (C1-C3) alkanesulphonic acid. Particularly preferred anhydride alkanesulphonic acid anhydride is methanesulfonic acid.

The second optional step is hydrazinolysis the compounds of formula 1 to obtain the compounds of formula 3. The compound of formula 1 is reacted with hydrazine, such as hydrazinehydrate, in the presence of an amine, such as triethylamine, diisopropylethylamine, 2,6-litein, N,N,N’,N’-tetramethylethylenediamine, preferably triethylamine, in the presence of a solvent, such as water, dichloromethane, dichloroethane, toluene, preferably in water, at a temperature between room temperature and 100°C., preferably at about 70°C for a period of time from about 3 to about 24 hours, preferably 5 hours, to obtain the compounds of formula 3.

Active compounds, obtained by using the compounds of formula 1 and formula 3 obtained by the methods of the present invention, can be administered orally, parenterally, locally or rectally in the treatment or alleviation of inflammation and other disorders associated with inflammation, such as arthritis, neurodegeneration, and cancer of the colon, in mammals, preferably humans, dogs, cats and livestock.

In General, the active compounds are most preferably administered in doses in the range from approximately 0.2 to 200 mg per kg of body weight per day (mg/kg/day in single or split the weight and condition of the subject, undergoing treatment, and selected specific way of introduction. However, most desirable to use the level of doses, which is in the range of from about 4 to about 50 mg/kg/day. However, there may be different ways depending on the type of mammal that is being treated and its individual response to the specified medication, and depending on the type of the selected pharmaceutical product and time period and frequency of drug administration. In some cases it may be more acceptable level of dose below the lower limit of the above interval, while in other cases still larger doses may be used without any harmful side effects, provided that such higher doses of first divided into several small doses for administration throughout the day.

The active compounds may be introduced separately or in combination with pharmaceutically acceptable carriers or diluents as described previously, and such introduction can be carried out in the form of single or multiple doses. More specifically, the active compounds may be introduced in the form of a large number of different dosage forms, aunts, capsules, pellets, lozenges, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc. Such carriers are solid diluents or fillers, sterile aqueous media, various non-toxic organic solvents, and others. In addition, the oral pharmaceutical compositions can be appropriately podkosheny and/or flavored. In General, the active compounds are present in such dosage forms at concentration in the range of from about 5.0 to about 70 wt.%. Various examples of suitable carriers, diluents, excipients, disintegrants, lubricating agents, sweetening and flavouring agents, colouring matter or dyes, with emulsifying agents, suspendida agents, diluents, buffers, creams, jellies, gels, pastes, plasters, ointments, etc. that can be used to obtain pharmaceutical compositions and formulations known in the art, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18thEdition, Gennaro, ed. (1990), pp.1545-1580. Obtaining all of these compositions in sterile conditions easily S="ptx2">

With the introduction of animal, but not human, such as livestock or Pets, such as cats or dogs, the active compounds can be introduced into food for animals or orally in the form of medicines for animals.

The active compounds can also be introduced in the form of liposomal delivery systems, such as small manelmellado vesicles, large manelmellado vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

The active compounds can also be connected with soluble polymers as a carrier, the sending drugs to the target. Such polymers can include polyvinylpyrrolidone, peranovic copolymer, polyhydroxyethylmethacrylate, polyricinoleate-phenol or a polyethylene oxide-polylysin, substituted palmitoleate remains. In addition, the active compounds can be connected to a class of biodegradable polymers useful for achieving controlled release of the drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyaminopropyl the AMI and sewn or amphiphilic copolymers of hydrogels.

The following additional examples illustrate the method and intermediate compounds of the present invention. Examples 1(i)-(iii) are preferred embodiments of the invention, however, it should be understood that the present invention is not limited to the specific details of the examples presented below.

Example 1

2-Bromo-5-(methanesulfonyl)pyridine

(i) To a solution of 2,5-dibromopyridine (50 g, 211 mmol) in tetrahydrofuran (175 ml) at 0°C, add 2.0 M isopropylaniline (274 mmol) at such a speed that the temperature remained below 8°C. the Reaction mixture was stirred at 0°C for 45 min, then cooled to -15°C. To the reaction mixture add a solution of methanesulfonamide (32,2 g, 281 mmol) in tetrahydrofuran (40 ml) with such speed, to ensure that the temperature remained below 5°C. the Reaction mixture is allowed to warm to room temperature and then the reaction quenched with water (500 ml) and tert-butylmethylamine ether (300 ml). The layers separated, the aqueous layer was extracted twice tert-butylmethylamine ether (2200 ml). The combined organic extracts washed with water (200 ml) and concentrated. The crude product is crystallized from toluene (110 ml), the solids filtered, gain of 29.4 g (yield 59%) of 2-bromo-5-(metasul the>2.7 Hz, 1H), 8,91 (d, J=2.5 Hz, 1H).

(ii) In the reaction described above in paragraph (i), using methanesulfonamide as sulfonylurea agent gives the product with a yield of 53%.

(iii) In the reaction described above in paragraph (i), the use of anhydride methanesulfonic acid, that is, (CH3SO2)2O, as sulfonylurea agent gives the product with a yield of 50%.

Example 2

2 Hydrazino-5-(methanesulfonyl)pyridine

A suspension of 2-bromo-5-(methanesulfonyl)pyridine (27.5 g, 116 mmol), triethylamine (14,7 g, 145 mmol) and hydrazine hydrate is added (7,26 g, 145 mmol) in water (205 ml) was heated to 70°C. Before the mixture the product starts to precipitate (after 90 min), the reaction mixture becomes homogeneous. The reaction mixture was stirred at 70°C in just 5 hours, then allowed to cool to room temperature and stirred for 18 hours. Precipitated precipitated product is filtered off, dried and triturated with hot ethanol, receive 2 hydrazino-5-(methanesulfonyl)pyridine with the release of 86%. Range1H NMR (300 MHz, Dl3, M. D.): 3,12 (s, 3H), of 4.44 (ush.s, 2H), 6,80 (ush.D., J=8.7 Hz, 1H), 7,81 (DD, J1=9,0 Hz, J2=2.4 Hz, 1H), scored 8.38 (d, J=2.3 Hz, 1H), 8,57 (ush.s, 1H).

1. The method of obtaining the compounds of formula 1

(a) interaction of the compounds of formula 2

with a Grignard reagent;

(b) interaction of the product of stage (a) with (C1-C6) alkylsulfonamides reagent; and, if necessary, the resulting product of the formula (I), where R1represents methyl, are hydrazines in the presence of an amine in a suitable solvent to obtain compounds of formula 3

2. The method according to p. 1, in which R1represents methyl.

3. The method according to p. 1, in which the Grignard reagent is a linear or branched (C1-C10) alkylacrylate.

4. The method according to p. 3, in which the Grignard reagent is a linear or branched (C1-C4)alkylacrylate.

5. The method according to p. 4, in which the Grignard reagent is isopropylaniline.

6. The method according to p. 1, in which stage (a) is carried out in a solvent selected from the group consisting of diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or bis(2-methoxyethanol) ether.

7. The method according to p. 6, in which the solvent is a tetrahydrofuran.

8. The method according to p. 1, in which alkylsulfonamides agent p is in which alkylsulfonamides agent is alkanesulfonyl formula R1SO2X, where X represents fluorine or chlorine.

10. The method according to p. 9, in which alkanesulfonyl is methanesulfonanilide.

11. The method according to p. 8, in which alkylsulfonamides agent is an anhydride alkanesulphonic acid of the formula (R1SO2)2O.

12. The method according to p. 11, in which the anhydride alkanesulphonic acid is an anhydride methanesulfonic acid.

13. The method according to p. 1, in which stage (b) is carried out in tetrahydrofuran.

14. The method according to p. 1, in which hydrazines performed using hydrazine hydrate is added.

 

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20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes compound of the general formula (3): wherein R15 represents a heterocyclic group chosen from 3-7-membered saturated or 4,7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom, or 7-14-membered polycyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R16 represents a cycloalkyl group comprising 3-7 carbon atoms, monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms, or heterocyclic group chosen from 3-7-membered saturated or 4-7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R17 represents a monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms or heterocyclic group chosen from 4-7-membered saturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R18 represents hydrogen atom or (C1-C)-alkyl group; X represents -S-, -SO- or -SO2; or N-oxide or S-oxide of this compound; their salt; or solvate of above described compound. Proposed compounds possess the inhibitory activity against producing/secretion of β-amyloid protein and can be used in treatment of such diseases as Alzheimer's disease, Down's disease and other diseases associated with amyloid deposition.

EFFECT: valuable medicinal properties of inhibitors.

7 cl, 1 tbl, 410 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

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