Derivatives of sulfonamide, their preparing and using as medicaments

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

 

The technical field to which the invention relates.

The present invention relates to new derivatives sulfonamida General formula (I)and their physiologically acceptable salts, methods of obtaining them and their use as pharmaceuticals for the treatment of human and/or veterinary treatment and pharmaceutical compositions that contain them.

New compounds which are the object of the present invention can be used in the pharmaceutical industry as intermediates and to obtain drugs.

The level of technology

The superfamily of serotonin receptors (5-HT) includes 7 classes (5-HT1-5-HT7), including 14 human subclasses [D.Hoyer, et al., Neuropharmacology, 1997, 36, 419]. 5-HT6the receptor is the last of serotonin receptors, identified by molecular cloning as in rats [F.J. Monsma, et al., Mol. Pharmacol., 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193, 268], and in humans [R. Cohen, et al., J. Neurochem., 1996, 66, 47]. Compounds with antagonistic activity at 5-HT6the receptor are useful for treating various diseases of the Central nervous system and gastrointestinal tract, such as irritable bowel syndrome. Compounds with antagonistic activity at 5-HT the receptor are useful in the treatment of anxiety, depression and cognitive disorders, memory [M. Yoshioka, et al., Ann. NY Acad. Sd., 1998, 861, 244; A. Bourson, et al., Br. J. Pharmacol, 1998, 125, 1562; D.C. Rogers, et al., Br. J. Pharmacol. Suppl., 1999, 127, 22P; A. Bourson, et al., J. Pharmacol. Exp. Ther., 1995, 274, 173; A.J. Sleight, et al., Behav. Brain Res., 1996, 73, 245; T.A. Branchek, et al., Annu. Rev. Pharmacol. Toxicol, 2000, 40, 319; C. Routledge, et al., Br. J. Pharmacol., 2000, 130, 1606]. It has been shown that typical and atypical antipsychotic drugs to treat schizophrenia have a greater affinity to 5-HT6receptors [B.L. Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403; C.E. Glatt, et al., Mol. Med., 1995, 1, 398; F.J. Mosma, et al., Mol. Pharmacol., 1993, 43, 320; T. Shinkai, et al., Am. J. Med. Genet., 1999, 88, 120]. Compounds with antagonistic activity at 5-HT6the receptor are useful for the treatment of infantile hyperkinesia (ADHD, attention deficit/ hyperfunctional disorders) [W.D. Hirst, et al., Br. J. Pharmacol., 2000, 130, 1597; C. Gerard, et al., Brain Research, 1997, 746, 207; M.R. Pranzatelli, Drugs of Today, 1997, 33, 379]. In the published international application WO 01/32646 described sulfonamides with antagonistic activity at 5-HT6the receptor, which bicyclic derivatives, where each of bicyclo is a 6-membered aromatic or heteroaromatic. In EP 0733628 described sulfonamides, derivatives of indole, with antagonistic activity at 5-HT1Freceptor useful for the treatment of migraine headaches. Thus, the study of the prior art shows the small structural changes lead to an increase in the number of connections, which are agonists or antagonists of different serotonin receptors, which are useful in the treatment of various diseases depending on which receptor is observed affinity.

After laborious research, the inventors have carried out the synthesis of new compounds of General formula (I)exhibiting interesting biological properties, due to which they are especially useful for use by human and/or veterinary therapy.

A detailed description of the invention

The present invention is to provide new compounds with antagonistic activity against 5-HT6the serotonin receptor useful for the production of pharmaceuticals for the prophylaxis or treatment of various diseases of the Central nervous system and, in particular, anxiety, depression, cognitive memory disorders and senile dementia or other processes of dementia, characterized by an apparent shortage of recognition, psychosis, infantile hyperkinesia (ADHD, attention deficit/hyperfunction disorder) and other diseases associated with 5-HT6the receptor of serotonin in mammals, including humans.

Compounds corresponding to the present invention have the General formula (I)

where

But a Deputy selected from the

- 5 - or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, optionally substituted by 1 or 2 halogen atoms, C1-C4the alkyl or phenyl, or a 5 - or 6-membered heteroaryl containing 1 or 2 oxygen atom, nitrogen or sulfur;

- bicyclic heteroaromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, optionally substituted by 1 or 2 halogen atoms or C1-C4by alkyl;

group chosen from:

R1represents hydrogen, C1-C4alkyl or benzyl radical;

n has the values 0, 1, 2, 3 or 4;

R2represents-NR4R5or a group of the formula:

,,,,,

,,,,

where the dotted line represents an optional chemical bond;

R 3, R4and R5independently represent hydrogen or C1-C4alkyl;

X, Y and Z independently represent hydrogen, fluorine, chlorine, bromine, C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio, trifluoromethyl, cyano, nitro, and-NR4R5;

W represents a bond between the two rings, CH2, O, S and NR4;

m has the values 0, 1, 2, 3 or 4;

provided that when m=0, And a is a substituted phenyl;

or are one of the physiologically acceptable salts of such compounds.

The term C1-C4alkyl means a linear or branched hydrocarbon chain containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Compounds of the present invention, which correspond to the above formula, can be chosen from:

[1] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[2] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-1-sulfonamida,

[3] hydrochloride of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-1-sulfonamida,

[4] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl] - for 3,5-dichlorobenzenesulfonate,

[5] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-4-vinylbenzenesulfonic,

[6] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chlorothiophene-2-sulfonamida,

[] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[8] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]naphthalen-1-sulfonamida,

[9] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamida,

[10] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[11] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonmethane,

[12] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonamida,

[13] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonmethane,

[14] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chlorothiophene-2-sulfonamida,

[15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-vinylbenzenesulfonic,

[16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamida,

[17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-2-sulfonamida,

[18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonamida,

[19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[20] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-(2-pyridyl)thiophene-2-sulfonamida,

[21] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-2,1,3-benzothiadiazole-4-sulfonamida,

[22] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]quinoline-8-sulfonamida,

[23] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalen-2-sulfonamida,

[24] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-4-phenoxybenzenesulfonyl,

[25] N-[3-(2-dimethy aminoethyl)-1H-indol-5-yl]-4-vinylbenzenesulfonic,

[26] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalen-2-sulfonamida,

[27] N-{3-[2-(morpholine-4-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[28] N-{3-[2-(morpholine-4-yl)ethyl]-1H-indol-5-yl}naphthalen-1-sulfonamida,

[29] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-2-sulfonamida,

[30] N-[3-dimethylaminomethyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[31] N-[3-(2-dipropylamino)-1H-indol-5-yl]naphthalen-1-sulfonamida,

[32] N-[3-(2-dipropylamino)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[33] N-[3-(2-dibutylaminoethanol)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[34] N-[3-(2-dibutylaminoethanol)-1H-indol-5-yl]naphthalen-1-sulfonamida,

[35] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalen-1-sulfonamida,

[36] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-TRANS-β-storycontinued,

[37] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-TRANS-β-storycontinued,

[38] N-[3-(octahedrons-7-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[39] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamida,

[40] N-{3-[2-(morpholine-4-yl)ethyl]-1H-indol-5-yl}naphthalen-2-sulfonamida,

[41] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-α-toluensulfonate,

[42] N-[3-(3-diethylaminopropyl)-1H-indol-5-yl]naphthalen-2-sulfonamida,

[43] N-[3-(3-diethylamino who drank)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[44] N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[45] N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naphthalen-1-sulfonamida,

[46] N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naphthalen-2-sulfonamida,

[47] N-[3-(2-dipropylamino)-1H-indol-5-yl]naphthalen-2-sulfonamida,

[48] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalen-1-sulfonamida,

[49] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]naphthalen-2-sulfonamida,

[50] N-{3-[2-(morpholine-4-yl)ethyl]-1H-indol-5-yl}quinoline-8-sulfonamida,

[51] N-{3-[2-(morpholine-4-yl)ethyl]-1H-indol-5-yl}-4-vinylbenzenesulfonic,

[52] N-[3-(4-methylpiperazin-1-yl)ethyl-1H-indol-5-yl]naphthalen-2-sulfonamida,

[53] N-[3-(4-methylpiperazin-1-yl)ethyl-1H-indol-5-yl]-5-chloronaphthalen-1-sulfonamida.

The present invention also relates to physiologically acceptable salts of the compounds of General formula (I), in particular the additive salts of inorganic acids such as hydrochloric, Hydrobromic, phosphoric, sulphuric, nitric acid, and organic acids such as citric, maleic, fumaric, tartaric acid or their derivatives, p-toluensulfonate acid, methanesulfonate acid, camphorsulfonic acid, and so forth.

New derivatives of General formula (I), where R1, R2, R3, R4, n and a have the meanings indicated above, can be obtained in accordance with CL is blowing ways.

METHOD AND

By reacting compounds of General formula (II) or one of its suitably protected derivatives

where a has the value given for the General formula (I), and X is an appropriate leaving group including a halogen atom, in particular chlorine; with 5-aminoindole General formula (III) or one of its suitably protected derivatives;

where n, R1, R2and R3matter for the General formula (I);

to obtain the corresponding sulfonamida, with removal if necessary, the protective groups and/or a pharmacologically acceptable salt.

The interaction between the compounds of General formula (II) and (III) is carried out in the presence of an organic solvent, such as Elgiloy ether, particularly diethyl ether or cycloalkenyl ether, in particular tetrahydrofuran or dioxane, halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, in particular methanol or ethanol, a dipolar aprotic solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable solvent.

The interaction is preferably carried out in the presence of a suitable inorganic bases such as hydroxides and ka is bonati alkali metal or in the presence of an organic base, in particular triethylamine or pyridine.

The most suitable temperature range for the reaction is in the range from 0°C to room temperature, and the reaction time is between 5 minutes and 24 hours.

The resulting sulfonamide can be separated by evaporation of the solvent, adding water and, ultimately, regulation of pH so that the sulfonamide was obtained as a solid substance that can be separated by filtration; or it can be extracted with a solvent immiscible with water, such as chloroform and purification using chromatography or recrystallization from a suitable solvent.

Compounds of General formula (II) are commercially available or can be obtained in accordance with conventional methods or by using similar methods described in the prior art [E.E. Gilbert, Synthesis, 1969, 1, 3]. Compounds of General formula (III) can also be obtained in accordance with conventional methods or by using similar methods described in the prior art [J.E. Macor, R. Post, and K. Ryan, Synt Comm., 1993, 23, 1, 65-72.; J. Guillaume, S. Dumont, J. Laurent, and N. Nedelec, Eur. J. Med. Chem., 1987, 22, 33-43; M.L. Saccarello, R. Stradi, Synthesis, 1979, 727].

METHOD IN

Compounds of General formula (I), where R1, R2, R4, n and a have the meanings indicated above and R3represents a C1-C41, R2, R4, n and a have the above significance, and R3represents a hydrogen atom with alkylhalides or diallylsulfide.

The interaction is preferably carried out in the presence of a suitable base, such as hydroxides and carbonates of alkali metals, metal hydrides, alkoxides such as sodium methoxide or tert-piperonyl potassium, ORGANOMETALLIC compounds such as utility or tert-utility, in the presence of an organic solvent, such as Elgiloy ether, particularly diethyl ether or cycloalkenyl ether, in particular tetrahydrofuran or dioxane, a hydrocarbon, in particular toluene, alcohol, in particular methanol or ethanol, a dipolar aprotic solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable solvent. The most suitable temperature range is between 0°and the boiling point of the solvent, and the reaction time is between 1 and 24 hours.

The resulting sulfonamide can be separated by concentration of the filtrate under reduced pressure, adding water and, ultimately, regulation of pH so that the sulfonamide was obtained as a solid substance, which can be selected with what omashu filtering, or it can be extracted with a solvent immiscible with water, such as chloroform and purification using chromatography or recrystallization from a suitable solvent.

WAY

When or compounds of General formula (I), where R1, R3and a have the aforementioned meanings, n=0 and R2represents a hydrogen atom, with an appropriately substituted 4-piperidones, receive a corresponding compound of General formula (I), where R1, R3and a have the meanings specified above, n=0 and R2is an appropriately substituted 1,2,3,6-tetrahydropyridine-4-yl.

The interaction may occur in acidic and basic medium, in a suitable solvent at a temperature lying in the range between 25 and 150°C.

Suitable basic conditions include inorganic bases such as sodium hydroxide or potassium hydroxide, or organic bases, such as pyrrolidin or triethylamine in a solvent such as methanol or ethanol. Preferably, the dissolution of sodium methoxide in methanol is carried out at the boil under reflux. The reaction time is in the range from 1 to 48 hours.

Suitable acid include hydrochloric acid in ethanol or triperoxonane acid in acetic acid at a temperature lying in the range between 50 and 100#x000B0; C and the reaction time in the range from 1 to 48 hours.

The resulting sulfonamide can be isolated by dilution with water and the regulation of pH in such a way as to obtain the sulfonamide in the form of a solid substance which can be separated by filtration; or it can be extracted with a solvent immiscible with water, such as chloroform, and purified by chromatography or recrystallization from a suitable solvent.

Compounds of General formula (I), where R1, R3and a have the meanings specified above, n=0 and R2represents a hydrogen atom, can be obtained according to method a from 5-aminoindole.

METHOD D

Compounds of General formula (I), where R1, R3and a have the meanings specified above, n=0 and R2represents a suitably substituted 4-piperidinyl can be obtained by restoring the compounds of General formula (I), where R1, R3and a have the meanings specified above, n=0 and R2is an appropriately substituted 1,2,3,6-tetrahydropyridine-4-yl, obtained in accordance with method C.

The hydrogenation takes place using a metal catalyst, such as palladium, platinum or rhodium, on a substrate, such as coal, aluminum oxide or barium sulfate, predpochtite is) palladium on coal, with an initial pressure of hydrogen in the range between 1 and 10 atmospheres, preferably between 2 and 5 atmospheres, in a solvent such as methanol or ethanol. The reaction time ranges from 1 hour to 3 days.

The resulting sulfonamide can be isolated by filtering off the catalyst and concentrating the filtrate under reduced pressure. The isolated product can be used as such or it can be purified by chromatography or recrystallization from a suitable solvent.

METHOD E

Pharmacologically acceptable salts of the compounds of General formula (I) traditionally can be obtained by the reaction with an inorganic acid, such as hydrochloric, Hydrobromic, phosphoric, sulphuric, nitric acid, or with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluensulfonate acid, methanesulfonate acid, and so forth, in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, and selected using conventional deposition or crystallization of the corresponding salts.

During any of the described ways of synthesis or getting used intermediates may be necessary and/or desirable in order to protect sensitive or reactive groups in some of the molecules used. This can be done using a conventional protective groups such as described in the prior art [Protective groups in Organic Chemistry, ed J. F.W. McOmie, Plenum Press, 1973; T.W. Greene &P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & sons, 1991]. Protective groups can be removed at a suitable last stage using known methods.

The invention provides for obtaining pharmaceutical compositions which contain in addition to acceptable pharmaceutical excipient, at least one compound of General formula (I) or one of its physiologically acceptable salts. The invention also relates to the use of compounds of General formula (I) and its physiologically acceptable salts when getting drugs with antagonistic activity against T6the serotonin receptor useful for the prophylaxis or treatment of various diseases of the Central nervous system, and, in particular, anxiety, depression, cognitive disorders, memory and processes associated with senile dementia, and other dementias, dominated by the deficiency of recognition, psychosis, infantile hyperkinesia (ADHD, attention deficit/ hyperfunctional disorder) and other diseases associated with 5-HT6the receptor of serotonin in mammals, including humans.

The following examples demonstrate new connection is s in accordance with the invention. Also described an affinity for NT6the serotonin receptor and glenavy formulations acceptable for connections in accordance with the present invention. The examples below are given only for illustration purposes and should not to in any way limit the scope of the invention.

METHOD AND

Example 7. Obtaining N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamida

To a solution of 3.05 g (15 mmol) of 5-amino-3-(2-dimethylaminoethyl)-1H-indole in 100 ml of pyridine is added dropwise at room temperature the solution is 4.21 g (15 mmol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonylchloride in 20 ml of pyridine. The reaction mixture was stirred at room temperature for 20 hours. Then it is evaporated to dryness, slightly alkalinized diluted with ammonia and dissolved in ethyl acetate. The organic phase is washed with water and saturated sodium bicarbonate solution, separated and dried over calcined sodium sulfate. The organic phase is evaporated to dryness and the resulting solid is washed again with ethyl ether, giving at the output of 5.5 g (82%) of N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamida in the form of a solid substance with a melting point = 226-227 of the°C.

METHOD IN

Example 26. Obtaining N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethylnaphthalene-2-sulfonamida

A mixture of 285 mg (0.7 mmol) of N-[-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-2-sulfonamida (example 17) and 80 mg (0.7 mmol) of tert-butoxide potassium in 3 ml of DMSO is stirred for 30 minutes at room temperature. Then add 105 mg (0.7 mmol) of ethyliodide, and the mixed solution is kept for 3 hours. Water is added and the solution extracted with ethyl acetate. The organic solution is evaporated to dryness and the resulting crude product was then purified using chromatography on silica gel, using as eluent a mixture of methylene chloride /methanol/ammonia, which in turn yields N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethylnaphthalene-2-sulfonamide as a solid substance with a melting point = 49-50°C.

WAY

Example 18. Obtaining N-[3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonamida

To a solution of 712 mg (13,2 mmol) of sodium methoxide in 100 ml of methanol, add 850 mg (2,64 mmol) N-[1H-indol-5-yl]naphthalen-1-sulfonamida, then 596 mg (5,28 mmol) of 1-methyl-4-piperidone, and the resulting solution was heated to boiling for 48 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue purified via chromatography on silica gel, using as eluent a mixture of methylene chloride /methanol/ammonia, which gives at the output of 573 mg (52%) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonamida in the form of a solid substance with a melting point = 244-245°C.

METHOD D

Example 12. Obtaining N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonamida

To a solution of 417 mg (1 mmol who) N-[3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonamida in 50 ml of methanol was added 100 mg of 5% palladium on coal. The mixture hydronaut at room temperature under an initial hydrogen pressure of 3 bar for 20 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to obtain the crude product is mixed with ethyl ether, obtaining at the output of 272 mg (65%) of N-[3-(1-methyl-piperidine-4-yl)-1H-indol-5-yl]naphthalen-1-sulfonamida in the form of a solid substance with a melting point = 254-256°C.

METHOD E

Example 3. Obtain hydrochloride of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-1-sulfonamida

1,05 g (2.5 mmol) of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-1-sulfonamida (example 2) dissolved in 10 ml of ethanol and add 0.6 ml of 4.2 N hydrochloric acid in ethanol. The reaction mixture is allowed the opportunity to crystallize at room temperature. Receive hydrochloride N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalen-1-sulfonamida in the form of a solid substance with a melting point = 255-257°C.

Melting point and spectroscopic data for the identification of some compounds, as an object of the present invention, shown in the following table:

BIOLOGICAL TESTS

LINKING NC6RECEPTOR SEROTONIN

The cell membrane of SOME 293 cells expressing recombinant NT6receptor human, were obtained using the technique of receptor biology. In these membranes, the concentration of the receptor is 2,18 pmol/mg protein, and the protein concentration is 9,17 mg/ml of the Experimental Protocol consists in a method .L.Roth et at. [.L. Roth, S.. Craigo, M.S. Choudhary, A. Uluer, F.J. Monsma, Y. Shen, H.Y. Meltzer, D.R. Sibley: Binding of Typical and Atypical Antipsychotic Agents to 5-Hydroxytryptamine-6 and Hydroxytriptamine-7 Receptors. The Journal of Pharmacology and Experimental Therapeutics, 1994, 268, 1403] with slight modifications. Commercial membrane diluted (1:40 dilution) binding buffer: 50 mm Tris-HCl, 10 mm MgCl2, 0.5 mm EDTA (pH 7.4). Used radioligand is a [3H]-LSD at a concentration of 2.7 nm with a final volume of 200 μl. Incubation is initiated by adding 100 μl of membrane suspension (≈22,9 μg of membrane protein) and held for 60 minutes at a temperature of 37°C. Incubation finish quick filtering in a Brandel Cell Harvester through glass fiber filters, made the diversified firm Schleicher & Schuell GF 3362, treated with 0.5% solution of polyethylenimine. The filters are washed three times in three milliliters of buffer Tris-HCl 50 mm pH 7.4. The filters move in flasks and each flask add 5 ml of Ecoscint H of liquid scintillation cocktail. Give the opportunity to achieve balance in flasks for several hours before counting with a scintillation counters Wallac Winspectral 1414. Nonspecific affinity determined in the presence of 100 μm serotonin. Testing is carried out three times. The inhibition constants (Kinm) calculated using the analysis of nonlinear regression using the program EBDA/LIGAND [Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220]. The following table shows the results of affinity for some of the compounds of the present invention.

/tr>
Table
Example% inhibition of 10-6MToi(nm)
198.1±4.00.28
396.6±5.23.5
496.2±0.69.3
5101.2±0.11.0
697.6±1.88.7
7103.0±7.90.13
894.5±7.00.76
996.8±3.72.2
11101.30.98
1398.34.7
1495.7±3.424.3
1597.4±0.86.8
1694.4±8.621.2
17102.05.3

Daily dose for treatment is in the range of 1 milligrams to 500 milligrams of the product, which you can enter once or reusable. The compositions have in forms compatible with your way of introduction, the type of tablets, pills in sweet wafers, capsules, suppositories, solutions or suspensions. These compositions are prepared using known methods, and they contain from 1 to 60 wt.% active ingredient (compound of General formula (I) and (40-99 wt.% suitable pharmaceutical excipient compatible with the active ingredient and the physical form of the composition. The example shows the formula of the tablets containing the product according to the invention is:

An example of the composition of the tablets:

Example 15 mg
Lactose60 mg
Crystalline cellulose25 mg
To 90 povidone 5 mg
Reptitiously starch3 mg
Colloidal silicon dioxide1 mg
Magnesium stearate1 mg
The total weight pills100 mg

Method C. Obtaining N-[3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamida.

To a solution of 712 mg (13,2 mmol) of sodium methoxide in 100 ml of methanol add 852 mg (2,64 mmol) N-[1H-indol-5-yl]quinoline-8-sulfonamida then adding 596 mg (5,28 mmol) of 1-methyl-4-piperidone, and the resulting solution was refluxed for 48 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel, using as eluent a mixture of methylene chloride/methanol/ammonia, obtaining 552 mg (50%) N-[3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamida in the form of solids.

Method D. Obtaining N-[3-(1-methyl-piperidine-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamida.

To a solution of 418 mg (1 mmol) N-[3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamida in 50 ml of methanol was added 100 mg of 5% palladium on coal. The mixture hydrogenizing at room temperature under hydrogen pressure of 3 ATM for 20 hours. The reaction mixture is filtered and the filtrate concentrated in ponie nom pressure to provide the crude product, which is suspended in ethyl acetate, to obtain 256 mg (61%) of N-[3-(1-methyl-piperidine-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamida in the form of solids.

1. Derived sulfonamida General formula (I)

where And is a Deputy selected from the

5 - or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, optionally substituted by 1 or 2 halogen atoms, C1-C4alkyl or phenyl radical or a 5 - or 6-membered heteroaryl radical containing 1 or 2 oxygen atom, nitrogen or sulfur;

bicyclic heteroaromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, optionally substituted by 1 or 2 halogen atoms or C1-C4alkyl radical;

R1represents hydrogen, C1-C4alkyl or benzyl radical;

n is 0, 1, 2, 3 or 4;

R2represents-NR4R5or a group of the formula

where the dotted line represents an optional chemical bond;

R3, R4and R5independently represent hydrogen or C1-C4alkyl,

or one of its physiologically acceptable salts.

2. The compound according to claim 1, selected from

[1] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[6]] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chlorothiophene-2-sulfonamida,

[7] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[9] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamida,

[10] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[11] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonmethane,

[14] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chlorothiophene-2-sulfonamida,

[16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamida,

[19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[20] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-(2-pyridyl)thiophene-2-sulfonamida,

[21] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-2,1,3-benzothiadiazole-4-Sul is Onamia,

[22] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]quinoline-8-sulfonamida,

[27] N-{3-[2-(morpholine-4-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[30] N-[3-dimethylaminomethyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[32] N-[3-(2-dipropylamino)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[33] N-[3-(2-dibutylaminoethanol)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[38] N-[3-(octahedrons-7-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[39] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamida,

[43] N-[3-(3-diethylaminopropyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[44] N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamida,

[50] N-{3-[2-(morpholine-4-yl)ethyl]-1H-indol-5-yl}quinoline-8-sulfonamida.

3. The method of deriving sulfonamida General formula (I) according to claim 1, characterized in that conduct the reaction of interaction of the compounds of General formula (II) or one of its suitably protected derivatives

where a has the value given for the General formula (I) and X is an appropriate leaving group including a halogen atom, in particular chlorine;

5-aminoindole formula (III) or one of its suitably protected derivatives

where n, R1, R2and R3have the meanings mentioned for the General formula (I),

to obtain the corresponding sulfonamida and, if necessary, followed by removal of protective groups.

4. The method of deriving sulfonamida General formula (I) according to claim 1, where R1, R2, R4, n and a have the meanings indicated in claim 1 and R3represents a C1-C4alkyl, wherein conducting the reaction of interaction of the compounds of General formula (I), where R1, R2, R4, n and a have the meanings indicated in claim 1, and R3represents a hydrogen atom, a C1-C4alkylhalides or diallylsulfide.

5. The method of deriving sulfonamida General formula (I) according to claim 1, where R1, R3, and a have the meanings indicated in claim 1, n=0 and R2is a 1,2,3,6-tetrahydropyridine-4-ilen radical substituted in position 1 by the radical R1, characterized in that conduct the reaction of compounds of General formula (I), where R1, R3and a have the meanings indicated in claim 1, n=0 and R3represents a hydrogen atom, 4-piperidone, substituted in position 1 by the radical R1.

6. The method of deriving sulfonamida General formula (I) according to claim 1, where R1, R3, and a have the meanings indicated in claim 1, n=0 and R2pre is is a 4-piperidinyloxy radical, substituted in position 1 by the radical R1, characterized in that carry out the restoration of compounds of General formula (I), where R1, R3and a have the meanings indicated in claim 1, n=0 and R2is a 1,2,3,6-tetrahydropyridine-4-ilen radical substituted in position 1 by the radical R1.

7. The method of obtaining physiologically acceptable salts of the compounds of General formula (I) according to claim 1, characterized in that conduct the reaction of compounds of General formula (I) with inorganic or organic acid in a suitable solvent.

8. Pharmaceutical composition having antagonistic activity against 5-HT6receptor, serotonin, characterized in that it contains, in addition to pharmaceutically acceptable excipients, at least one compound of General formula (I) or one of its physiologically acceptable salts according to claim 1 or 2.

9. The compound according to claim 1 for the prophylaxis or treatment of anxiety, depression, cognitive impairment and memory processes associated with senile dementia, and other dementias, dominated by the deficiency of recognition, psychosis, infantile hyperkinesia (ADHD, attention deficit (hyperfunctional disorder) and other disorders mediated by the 5-HT6the receptor of serotonin in mammals, including humans.

10. The use of a derivative is sulfonamide General formula (I)

where And is a Deputy selected from the

5 - or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulphur, optionally substituted by 1 or 2 halogen atoms, C1-C4alkyl or phenyl radical or a 5 - or 6-membered heteroaryl radical containing 1 or 2 oxygen atom, nitrogen or sulfur;

bicyclic heteroaromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, optionally substituted by 1 or 2 halogen atoms or C1-C4alkyl radical;

R1represents hydrogen, C1-C4alkyl or benzyl radical;

n has the values 0, 1, 2, 3 or 4;

R2represents-NR4R5or a group of the formula

where the dotted line represents an optional chemical bond;

R3, R 4and R5independently represent hydrogen or C1-C4alkyl,

or one of its physiologically acceptable salts for the preparation of drugs for prevention or treatment of anxiety, depression, cognitive impairment and memory processes associated with senile dementia, and other dementias, dominated by the deficiency of recognition, psychosis, infantile hyperkinesia (ADHD, attention deficit, hyperfunctional disorders and other diseases mediated by 5-HT6the receptor of serotonin in mammals, including humans.



 

Same patents:

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

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

SUBSTANCE: invention describes novel derivatives of N-triazolylmethylpiperazine of the general formula (I): , wherein R1 means hydrogen atom or (lower)-alkyl; R2 means (lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, cycloalkyl with 5-6 carbon atoms in cycle, pyridinyl-(lower)-alkyl, possibly bi-substituted phenyl-(lower)-alkyl, phenyloxy-(lower)-alkyl substituted with halogen atom in phenyl ring; R3 means (lower)-alkyl, (lower)-alkyloxycarbonyl-(lower)-alkyl or (C5-C6)-cycloalkyl, or both R2 and R3 in common with nitrogen atom to which they are bound form substituted pyrrolidine ring or cyclic group of the formula (a): , wherein A means nitrogen, oxygen atom, methylene or methylidene group wherein its double bond is formed in common with adjacent carbon atom at position 3 of the group (a), and if A means nitrogen atom then this nitrogen atom has substitute R4', and in this case n means 2 or 3, and R4' means (lower)-alkyl, possibly substituted phenyl-(lower)-alkyl, possibly substituted pyridyl, pyridyl-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, pyrimidyl-(C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(lower)-alkyl or morpholinyl-(lower)-alkyl; R4 and R5 mean hydrogen atom and in all cases n means a whole number from 1 to 2; R4 means hydrogen atom, (lower)-alkyl, (lower)-alkoxy-(lower)-alkyl, (lower)-alkoxycarbonyl, (lower)-alkoxycarbonyl-(lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, phenyl, pyrrolidinyl, pyrrolidinyl-(lower)-alkyl, pyridyl or piperidinyl, cyclohexyl, cyclohexyl-(lower)-alkyl, phenyl-(lower)-alkyl, pyridyl monosubstituted with (lower)-alkyl, phenyl-(lower)-alkyl monosubstituted with (lower)-alkyl, pyrimidyl, pyridyl-(lower)-alkyl, morpholinyl-(lower)-alkyl; R5 means hydrogen atom, (lower)-alkyl or (lower)-alkoxy-(lower)-alkyl, or R4 and R5 taken in common mean spiroethylenedioxy-group bound with carbon atom of the group (a), (C3-C4)-alkylene bound with two adjacent atoms of the group (a) or phenyl anellated by two adjacent carbon atoms of the group (a), and their physiologically acceptable acid-additive salts also. Also, invention relates to methods for synthesis of these compounds, a medicinal agent based on thereof and intermediate compound in synthesis of novel compounds. Novel compounds are antagonists of neurokinin receptors and display effect in peripheral region preferably and can be used in treatment of functional and inflammatory disorders of digestive tract.

EFFECT: improved preparing method, valuable medicinal properties of derivatives.

10 cl, 4 tbl, 4 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of amide of the general formula (I)

wherein X means -CH; Y means -CH or nitrogen atom (N); m = 1 or 2; R1 means (C1-C6)-alkyl, (C1-C)-alkoxy-group, N,N-di-[(C1-C6)-alkyl]-amino-group, heterocyclyl-(C1-C6)-alkyl wherein heterocyclyl represents piperazinyl or homopiperazinyl; n = 3; R2 means halogen atom, (C1-C6)-alkyl; R3 means hydrogen atom; Q means phenyl optionally substituted with cyano-group, or pyridyl optionally substituted with morpholino-group, or their pharmaceutically acceptable salts, to methods for synthesis of indicated compounds, pharmaceutical compositions containing thereof and their using in treatment of diseases or states mediated by cytokines.

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

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to anthranylamide derivative selected from compound of formula I or N-oxides thereof, wherein R1 represents methyl, F, Cl, Br; R2 represents F, Cl, Br, I, CF3; R3 represents CF3, Cl, Br, OCH2CF3; R4a represents C1-C4-alkyl; R4b represents H, CH3; and R5 represents Cl, Br, and agriculturally acceptable salt thereof. Also disclosed are composition for pest controlling containing biologically effective amount of formula I and at least one additional component selected from group comprising surfactants, solid and liquid diluents; composition for invertebrate insect controlling containing biologically effective amount of formula I and at least one additional biologically active compound or agent. Also disclosed are method for insect controlling as well as intermediates such as benzoxazinone and parasolocarboxylic acid derivatives.

EFFECT: compounds with insecticide activity, useful in insect controlling.

20 cl, 16 tbl, 33 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel C-2'-methylated derivatives of paclitaxel of the formula (I): wherein R represents trifluoromethyl group, phenyl, 2-furyl, 2-thienyl; R1 represents tert.-butoxycarbonyl or benzoyl group; R2 represents hydroxy-group; R3 means hydrogen atom or in common with R2 forms residue of cyclic carbonate of the formula: under condition that when R3 means hydrogen atom then R is not phenyl. Also, invention relates to a pharmaceutical composition based on thereof and using for preparing medicinal agents possessing an antitumor activity. Invention provides preparing novel derivatives of paclitaxel that possess antitumor activity.

EFFECT: valuable medicinal property of derivatives and pharmaceutical composition.

4 cl, 1 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, chemical technology, medicine, veterinary science.

SUBSTANCE: invention describes the compound R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula (I) and its salts, in particular, its mononitrate. Also, invention relates to a method for preparing compound of the formula (I) possessing antifungal effect based on compound of the formula (I), and using compound of the formula (I) as an active component of the antifungal composition. Compound of the formula (I) can be used in compositions for treatment of fungal infections in humans or animals and against diseases of agricultural crops.

EFFECT: improved preparing method, valuable properties of compound and composition.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of diphenylazathedinone of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another (0-C30)-alkylene-L wherein one or some C-atoms of alkylene residue can be substituted with -O-, -(C=O)- or -NH- and, except for, R1-R6 can represent hydrogen atom (H), fluorine atom (F), and L represents compound of the formula: , and their pharmaceutically tolerated salts also. Compounds of the formula (I) elicit hypolipidemic effect and can be used in therapeutic aims. Also, invention describes a medicinal agent and its using.

EFFECT: valuable medicinal properties of compounds.

7 cl, 31 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

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

28 cl, 10 tbl, 16 ex

Up!