5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazoles

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole derivatives of general formula wherein R1, R2, R3 can be identical or different independently means hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, heteroaralkyl (wherein 5- or 6-member N-, O- or S-heteroaromatic cycle), cycloalkyl, 2,2,6,6-tetramethyl-piperidin-4-yl, and also R1+R2 can mean heterocycle specified in optionally substituted pyrrolidine, piperidine, azepane, piperazine, morpholine wherein optional substitutes can be hydroxyl, cyanogroup, halogens, alkyls, lower alkoxy groups, lower alkothio groups, trihalogen methyl, sulphamide, optionally substituted amino groups (amino, dimethyl amino, diethyl amino) provided R1=H, R2 is different from hydrogen or methyl.

EFFECT: there are produced new compounds which can find application in medicine as the substances possessing neuromodulatory activity.

2 cl, 3 ex

 

The invention relates to organic chemistry, specifically to new biologically active compounds derived from 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole of the General formula:

where R1, R2, R3may be the same or different and independently denote hydrogen, possibly substituted alkyl, possibly substituted aryl, possibly substituted aralkyl, heteroalkyl (where the 5 - or 6-membered N-, O - or S-heteroaromatic cycle), cycloalkyl, 2,2,6,6-tetramethyl-piperidine-4-yl, and R1+R2can mean a heterocycle selected from optionally substituted pyrrolidine, piperidine, azepane, piperazine, the research, where the possible substituents may be hydroxyl, cyano, halogen, alkali, low alkoxygroup, low alkariagroup, trihalomethyl, sulfa, optionally substituted amino groups (amino, dimethylamino, diethylamino), provided that when R1=N, then R2is other than hydrogen or methyl.

The term "alkyl" means unsubstituted or substituted alkyl group with straight or branched chain, containing from 1 to 12 carbon atoms. Substituents in the alkyl group can be a halogen (fluorine, chlorine, bromine, iodine), hydroxy - and alkoxygroup (for example, methoxy, ethoxy and the like), cyano, nitro, trihalomethyl (for example, reformer and similar), optionally substituted amino (e.g. amino, dimethylamino, acetylamino, N-piperidino, N-morpholino and the like), acyl groups (e.g. formyl, acetyl, benzoyl and the like), carboxamide (for example, N,N-diethylnitrosamine and similar), carboxypropyl, carbalkoxy and similar.

The term "cycloalkyl" means a cyclic saturated hydrocarbon group with 3-8 ring carbon atoms (for example, cyclopropyl, cyclohexyl and the like).

The term "aryl" means unsubstituted or substituted phenyl group. Substituents in the phenyl group can be a halogen (fluorine, chlorine, bromine, iodine), alkali as described above, the lower alkoxygroup (for example, methoxy, ethoxy and similar), low alkariagroup (for example, methylthio and the like), cyano, nitro, trihalomethyl (for example, trifluoromethyl and the like), optionally substituted amino (e.g. amino, dimethylamino, acetylamino, N-piperidino, N-morpholino and the like), acyl groups (e.g. formyl, acetyl, benzoyl and the like), carboxamide (for example, N,N-diethylnitrosamine and similar), carboxypropyl, carbalkoxy and similar.

The term "aralkyl" means the above aryl, attached to an alkyl group as described above. Examples of suitable Deputy is th include optionally substituted benzyl, phenylethyl, etc.

The term "heteroaryl" means 5 - or 6-membered N-, O - or S-heteroaromatic cycle. Examples of suitable substituents include optionally substituted furan, thiophene, pyrrole, indole, pyridine, piperidine, piperazine, quinoline, etc.

The term "heteroalkyl" means the above heteroaryl, attached to an alkyl group as described above. Examples of suitable substituents include optionally substituted ethylpiperazin-1-yl, ethylindole-3-yl, propyl-3-imidazol-1-yl.

The term "halogen" means chlorine, fluorine, bromine or iodine.

The term "alkoxy" means the group AlkO, in which the alkyl part is as defined above alkyl group (for example, methoxy, ethoxy and similar).

Recently for the creation of new medical drugs used design 5-membered heterocyclic skeleton as the ideal scaffold-pharmacophore with a wide spectrum of biological activity [Krchňák V. et al. Chem. Rev. 2002, 102, 61]. In this aspect thiadiazolyl cycle is one of the privileged structures when creating new libraries "drug-like" compounds [Pal, M. et al. Org. Chem. 2003, 68, 6806]. In particular [1,2,4]thiadiazole used as the primary scaffold for drugs of different therapeutic actions: anti-inflammatory [Y. Song et al. J. Bioorg. Med. Chm. 2004, 12, 5107.], protivosudorozhnogo [Akbarzadeh T. et al. Bioorg. Med. Chem. 2003, 11, 769.], antihypertensive [Tyagi, M. et al. Oriental J. Chem. 2002, 18, 125], neuroprotective [A.Gupta et al. J. Med. Chem. 2009, 44, 1100].

Of particular interest are derivatives of 5-amino-[1,2,4]thiadiazole as drugs for the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease [Castro, A. et al. Bioorg. Med. Chem. 2006, 14, 1644.]. Also described the ability of these compounds to inhibit aggregation of β-amyloid in the characteristic senile plaques, which, as you know, are the main neuropathological characteristics of Alzheimer's disease [K. Baumann et al. "Modulators for Amyloid beta", USPatent Application Publication 20090215759 A1].

The biological activity of the synthesized compounds was studied in experiments on the effects on glutamate-dependent capture45Ca2+in synaptosome cortex of rats. It is shown that 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole affect glutamate-induced capture of calcium in synaptosome cortex of rats.

5-Amino-3-(2-aminopropyl)-[1,2,4]thiadiazole General formula 6 were obtained in two ways according to the scheme below.

Method A. 5-N-Monosubstituted 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole General formula 6 (R1=H) were obtained in the following way. To a solution of isothiocyanate (0.01 M) and 50 mg of p-toluenesulfonic acid in 10 ml of acetonitrile at premesis the Institute was bury a solution of 3-amino-5-methylisoxazole (0.01 M) in 10 ml of acetonitrile. Formed isoxazoline thiourea 2 Bolton-Catacomb in situ recyclized [1,2,4]thiadiazole [Boulton A.J., A.R. Katrizky, Hamid A.M. J. Chem. Soc. 1967, 2005]. Upon completion of the addition the mixture is brought to boiling and kept at room temperature until precipitation of 5-amino-3-(2-oxopropyl)-[1,2,4]-thiadiazole 3, which was filtered. If the crystals are not precipitated, the reaction mixture was evaporated and the resulting oil was rubbed out in diethyl ether.

Obtained 5-amino-3-(2-oxopropyl)-[1,2,4]-thiadiazole 3 (0.01 M) and primary amine (0.01 M) was dissolved in 10 ml of methanol and left for a day at room temperature. The precipitate was filtered. According to NMR formed during the reaction Imin 4 programmirovaniya in the appropriate vinylamine 5-amino-3-(2-amino-1-propenyl)-[1,2,4]-thiadiazole 5, which was introduced in the reaction of recovery.

Obtained 5-amino-3-(2-amino-1-propenyl)-[1,2,4]-thiadiazole 5 (0.01 M) suspended in 30 ml of methanol was heated to 50° C. and under vigorous stirring was added in portions sodium borohydride (0.01 M). As the addition of sodium borohydride and the completion of the reaction the precipitate dissolves. Upon completion of the reaction, the methanol was evaporated, was added 50 ml of methylene chloride and washed with water (2×50 ml), the organic layer was separated, dried over sodium sulfate. Dryer was filtered, the filtrate was evaporated and produces the 5-amino-3-(2-oksipropil)-[1,2,4]-thiadiazole 6.

Method B. 5-N,N-Disubstituted amino-3-(2-aminopropyl)-[1,2,4]thiadiazole General formula 6 were obtained in the following way. To a solution of 5-methylisoxazole-3-isothiocyanato 1 (0.01 M) and 50 mg of p-toluenesulfonic acid in 10 ml of acetonitrile under stirring was bury the solution of the corresponding secondary amine (0.01 M) in 10 ml of acetonitrile. Upon completion of the addition the mixture is brought to boiling and kept at room temperature until precipitation of 5-amino-3-(2-oxopropyl)-[1,2,4]-thiadiazole 3, which was filtered. If the crystals are not precipitated, the reaction mixture was evaporated and the resulting oil was rubbed out in diethyl ether.

Subsequent reaction of the condensation of 5-amino-3-(2-oxopropyl)-[1,2,4]-thiadiazole with primary amines and restore the received vinylamine 5 was carried out analogously to method A.

In the following examples, which illustrate but do not limit the invention.

Example 1. {2-[5-(3-Chloro-4-methyl-phenylamino)-[1,2,4]thiadiazole-3-yl]-1-methyl-ethyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine (method A).

To a solution of 3-chloro-4-methylphenylethylamine (9.17 g, 0.05 M) and 50 mg of p-toluenesulfonic acid in 50 ml of acetonitrile under stirring was bury a solution of 3-amino-5-methylisoxazole (4.9 g, 0.05 M) in 50 ml of acetonitrile. Upon completion of the addition the mixture is brought to boiling and kept at room temperature until precipitation that AHP crystal growth is microvilli, recrystallized from isopropanol (30 ml).

The resulting oxadiazole (5.62 g, 0.02 M) and 4-amino-2,2,6,6-tetramethylpiperidine (3.12 g, 0.02 M) was dissolved in 10 ml of methanol and left for a day at room temperature. The precipitate was filtered.

Output {2-[5-(3-chloro-4-methyl-phenylamino)-[1,2,4]thiadiazole-3-yl]-1-methyl-vinyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine 7.72 g (calculated on the original isothiocyanate 82%).

Colorless crystals. TPL=70-72°C.

Range PMR (CDCl3), δ, ppm: 8.19 (1H, d, J 8.6 Hz, NH), 7.33 (1H, d, J 2.3 Hz, Harene), 7.26 (1H, d, J 8.4 Hz, Harene), 7.10 (1H, DD, J 2.3, 8.1 Hz, Harene), 5.11 (1H, s, =CH), 3.78 (1H, m, NCH), 2.39 (3H, s, Ph-CH3), 2.08 (3H, s, =C-CH3), 1.96 (2H, DD, J3.5, 12.8 Hz, 2CH), 1.28 (6N, s, 2 CH3), 1.18 (6N, s, 2 CH3), 1.16 (1H, ush. s, NH), 1.11 (2H, t, J 12.3 Hz, 2CH).

{2-[5-(3-chloro-4-methyl-phenylamino)-[1,2,4]thiadiazole-3-yl]-1-methyl-vinyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine (4.20 g, 0.01 M) suspended in 30 ml of methanol was heated to 50° C. and under vigorous stirring was added in portions sodium borohydride (0.38 g, 0.01 M). Upon completion of the reaction, the methanol was evaporated, was added 50 ml of methylene chloride and washed with water (2×50 ml), the organic layer was separated, dried over sodium sulfate. Dryer was filtered, the filtrate was evaporated and received

Output {2-[5-(3-chloro-4-methyl-phenylamino)-[1,2,4]thiadiazole-3-yl]-1-methyl-ethyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine 3.4 g (89%).

Colorless crystals. TPL=76-78°C.

Range PMR (DMSO-d6), δ, ppm: 7.71 (1H, d, J 2.2 Hz, Harene), 7.29 (1H, DD, J 2.2, 8.4 Hz, Harene), 7.17 (1H. d, J 8.4 Hz, Harene), 3.32 (1H, m, NCH), 2.89 (1H, t J 3.5, 11.6 Hz, NCH), 2.71 (2H, DD, J 6.3, 14.2 Hz, CH2), 2.31 (3H, s, Ph-CH3), 1.71 (2H, DD, J 3.5, 12.3 Hz, 2CH), 1.10 (6N, d, J 2.8 Hz, (CH3)2), 1.06 (3H, d, J 6.3 Hz, CLO3), 1.00 (6N, d, J 5.8 Hz, (CH3)2), 0.75 (1H, t, J 12.0 Hz, WithNH), 0.65 (1H, t, J 12.0 Hz, CHN).

Also on the way And we have received the following derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole.

[3-(2-Benzylamino-propyl)-[1,2,4]thiadiazole-5-yl]-(3-chloro-4-fluoro-phenyl)-amine.

Colorless crystals. TPL=77-79°C.

Range PMR (CDCl3), δ, ppm: 10,80 (1H, ush. s, NH), 7,42 (1H, m, NH), 7,30 (5H, s, Harene), 7,17 (2H, m, Harene), 3,80 (2H, DD, J 12.2, CH2), or 3.28 (1H, m, CH), to 2.94 (2H, DD, 14.2 Hz, CH2), to 1.21 (3H, d, J 6.3 Hz, CLO3).

(3-Chloro-4-forfinal)-{3-[2-(4-methoxybenzylamine)-propyl]-[1,2,4]thiadiazole-5-yl}-amine.

Colourless crystals, TPL=93-95°C.

Range PMR (CDCl3), δ, ppm: 7.21 (5H, m, Harene), 6.91 (2H, m, Harene), 3.84 (3H, s, och3), 3.81 and 3.69 (2H, d + d, J 13.0 Hz, ArCHH), 3.25 (1H, Sextus, J 6.3 Hz, CH2NCH3), 3.02 (1H, DD, J 6.7, 14.2 Hz, CHNSNSN3), 2.85 (1H, DD, J 6.0, 14.4 Hz, CHNSNSN3), 1.22 (3H, d, J 6.5 Hz, CH2SNAN3).

3-{1-Methyl-2-[5-(3-methylthio-phenylamino)-[1,2,4]thiadiazole-3-yl]-ethylamino}-benzonitrile.

Butter.

Range PMR (CDCl3), δ, ppm: 7.43 (5H, m, Harene), 7.23 (2H, m, Harene), 6.89 (1H, m, Harene), 3.45 (1H, m, CH2NCH3), 2.95 (1H, m, CHNSNSN3), 2.85 (1H, m,NNSSN3), 2.21 (3H, s, SCH3), 1.23 (3H, d, J 6.5 Hz, CH2SNAN3).

(3-Chloro-4-fluoro-phenyl)-{3-[2-(2-morpholine-4-yl-ethylamino)-propyl]-[1,2,4]thiadiazole-5-yl}-amine.

Colorless crystals. TPL=108-110°C.

Range PMR (DMSO-d6), δ, ppm: 7.90 (1H, DD, J 2.2, 6.5 Hz, Harene), 7.45 (1H, m, Harene), 7.20 (1H, t, J 8.8 Hz, Harene), 3.50 (4H, t, J 4.7 Hz, CH2OCH2), 3.13 (1H, m, NCH), 2.77 (2H, DD, J 76.6, 14.2 Hz, CH2), 2.65 (2H, q, J 5.6 Hz, NCH2), 2.39 (2H, t, NCH2), 2.30 (4H, t, J 4.7 Hz, CH2NCH2), 1.11 (3H, d, J 6.3 Hz, CLO3).

(3-Chloro-4-fluoro-phenyl)-{3-[2-(2-morpholine-4-yl-propylamino)-propyl]-[1,2,4]thiadiazole-5-yl}-amine.

Colorless crystals. TPL=72-74°C.

Range PMR (CDCl3), δ, ppm: 7.37 (1H, m, Harene), 7.18 (1H, s, Harene), 7.10 (1H, m, Harene), 3.61 (4H, t, J 4.7 Hz, CH2OCH2), 3.15 (1H, m, NCH), 2.78 (2H, DD, J 7.1, 14.4 Hz, CH2), 2.62 (2H, m, NCH2), 2.33 (4H, t, J 4.7 Hz, CH2NCH2), 2.30 (2H, t, NCH2), 1.59 (2H, m, NCH2CH2CH2N), 1.06 (3H, d, J 6.4 Hz, CLO3).

{2-[5-(4-trifluoromethyl-phenylamino)-[1,2,4]thiadiazole-3-yl]-1-methyl-ethyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine.

Colorless crystals. TPL=126-128°C.

Range PMR (DMSO-d6), δ ppm: 7.68 (2H, d, J 8.6 Hz, Harene), 7.44 (2H, d, J 8.6 Hz, Harene), 3.32 (1H, m, NCH), 2.89 (1H, TT, J 3.5, 11.6 Hz, NCH), 2.71 (2H, DD, J 6.3, 14.2 Hz, CH2), 2.31 (3H, s, Ph-CH3), 1.71 (2H, DD, J 3.5, 12.3 Hz, 2CH), 1.10 (6N, d, J 2.8 Hz, (CH3)2), 1.06 (3H, d, J 6.3 Hz, CLO3), 1.00 (6N, d, J 5.8 Hz, (CH3)2), 0.75 (1H, t, J 12.0 Hz, WithNH), 0.65 (1H, t, J 12.0 Hz, CHN).

[2-(5-Cyclopropylamino)-[1,2,4]thiadiazole-3-yl-1-methyl-ethyl]-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine.

Colorless crystals. TPL=75-77°C.

Range PMR (CDCl3), δ, ppm: 3.28 (1H, m, NCH), 2.84 (1H, TT, J 3.6, 11.6 Hz, NCH), 2.68 (2H, d, J 6.2 Hz, CH2), 2.54 (1H, m, NCH(CH2)2), 1.73 (2H, d, J 12.3 Hz, 2CH), 1.06 (6N, d, J 2.8 Hz, (CH3)2), 1.04 (3H, d, J 6.3 Hz, CLO3), 1.01 (6N, d, J 5.8 Hz, (CH3)2), 0.80-0.50 (6N, m, NCH(CH2)2WithNN).

2-{2-[5-(4-Fluoro-phenylamino)-thiadiazole-3-yl]-1-methyl-ethylamino}-ethanol.

Colorless crystals. TPL=97-99°C.

Range PMR (DMSO-d6), δ, ppm: 7.56 (2H, DD, J 4.9, 9.1 Hz, 2Harene), 7.07 (2H, t, J 8.7 Hz, 2Harene), 4.20 (1H, ush with IT), 3.49 (2H, t, J 5.3 Hz, CH2OH), 3.16 (1H, m, NCH), 2.75 (2H, DD, J 6.0, 14.0 Hz, CH2), 2.65 (2H, q, J 6.0 Hz, NCH2), 1.10 (3H, d, J 6.3 Hz, CLO3).

(4-Chloro-phenyl)-[3-(2-methylamino-propyl)-[1,2,4]thiadiazole-5-yl]-amine.

Colorless crystals. TPL=92-94°C.

Range PMR (DMSO-d6), δ, ppm: 7.56 (2H, d, J 8.7 Hz, 2Harene), 7.20 (2H, d, J 8.7 Hz, 2Harene), 3.04 (1H, m, NCH), 2.75 (2H, DD, J 6.2, 14.1 Hz, CH2), 2.35 (3H, s, NCH3), 1.06 (3H, d, J 6.4 Hz, CLO3).

4-(2-{2-[5-(3-Chloro-4-methyl-phenylamino)-[1,2,4]thiadiazole-3-yl]-1-methyl-ethylamino}-ethyl)-phenyl sulphonamide.

Colorless crystals. TPL=143-145°C.

Range PMR (CD3CN), δ, ppm: 7.93 (1H, DD, J 2.8, 6.7 Hz, Harene), 7.78 (2H, d, J 8.2 Hz, 2Harene), 7.45 (1H, m, Harene), 7.39 (2H, d, J 8.2 Hz, 2Harene), 7.29 (1H, t, J 8.8 Hz, Harene), 3.26 (1H, m, NCH), 2.97 (1H, m, NCH), 2.85 (4H, m, NCH2CH2Ph), 1.15 (3H, d, J 6.3 Hz, CLO3).

Example 2. [5-azepin-1-yl-[1,2,4]thiadiazole-3-yl)-1-methyl-vinyl]-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine (method B).

5-Methylisoxazole-3-isothiocyanate 1.

To a cooled to 0°C. a mixture of 42.2 ml (0.55 M) of thiophosgene, 92.4 g (1.1 M) of sodium bicarbonate in 200 ml of water with vigorous stirring for one hour bury solution 49.05 g (0.5 M) 3-amino-5-methylisoxazole in 300 ml of methylene chloride. Upon completion of addition the reaction mixture was stirred for another 30 minutes. The organic phase was separated, washed with a saturated solution of sodium chloride (2×100 ml), dried with sodium sulfate and evaporated. The resulting oil was distilled, selecting a fraction of 39-41°C/1 mm Hg

Yield 36.8 g (52.6%).

Range PMR (CDCl3, M.D., b): 2,50 (3H, s, CH3), 6,00 (1H, s, CH).

An NMR spectrum13With (CDCl3, ppm, b):172,9 (C5), 153,1 (C3), 145,4 (C7), 100,1 (C4), and 13.2 (C6). The assignment of the signals is performed in proton-coupled spectra PITS the 13C.

To a solution of 5-methylisoxazole-3-isothiocyanato 1 (1.4 g, 0.01 M) and 50 mg of p-toluenesulfonic acid in 10 ml of acetonitrile under stirring was bury solution hexamethylenimine (0.99 g, 0.01 M) in 10 ml of acetonitrile. Upon completion of the addition the mixture is brought to boiling and kept at room temperature until precipitation [3-(2-oxopropyl)-[1,2,4]-thiadiazole-5-yl]-azepane 3, which was filtered. The resulting oxadiazol 3 (2.39 g, 0.01 M) and 4-amino-2,2,6,6-tetramethylpiperidine (1.70 g, 0.01 M) was dissolved in 10 ml of methanol and left for a day at room temperature. The precipitate was filtered.

Output {2-[5-azepin-1-yl-[1,2,4]thiadiazole-3-yl]-1-methyl-vinyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine 3.86 g (78%).

Yellow crystals. TPL=86-88°C.

Range PMR (CDCl3), δ, ppm: 8.22 (1H, d, J 8.7 Hz, NH), 5.10 (1H, s, =CH), 3.74 (1H, m, NCH), 2.06 (3H, s, =C-CH3), 1.96 (2H, DD, J 3.5, 12.8 Hz, 2CH), 1.88 (4H, m, CH2NCH2), 1.64 (8H, m, (CH2)4), 1.28 (6N, s, 2 CH3), 1.18 (6N, s, 2 CH3), 1.16 (1H, ush. s, NH), 1.07 (2H, t, J 12.2 Hz, 2CH).

Received {2-[5-azepin-1-yl-[1,2,4]thiadiazole-3-yl]-1-methyl-vinyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine 5 (3.91 g, 0.01 M) was suseptible in 30 ml of methanol was heated to 50 and under vigorous stirring was added in portions sodium borohydride (0.38 g, 0.01 M). Upon completion of the reaction, the methanol was evaporated, was added 50 ml of methylene chloride and washed with water (2×50 ml), the organic layer was separated, was dried over sodium sulfate. Dryer was filtered, the filtrate was evaporated and obtained [5-azepin-1-yl-[1,2,4]thiadiazole-3-yl)-1-methyl-vinyl]-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine 6.

Output: 3.32 g (85%).

Oil. Range PMR (DMSO-d6), δ, ppm: 3.26 (1H, m, NCH), 2.88 (1H, TT, J 3.5, 11.6 Hz, NCH), 2.71 (2H, DD, J 6.3, 14.2 Hz, CH2), 1.83 (4H, m, CH2NCH2), 1.73 (2H, DD, J 3.5, 12.3, 2CH), 1.63 (8H, m, (CH2)4), 1.12 (6N, d, J 2.3 Hz, (CH3)2), 1.03 (3H, d, J 6.3 Hz, CLO3), 1.03 (6N, d, J 2.6 Hz, (CH3)2), 0.75 (1H, t, J 12.1 Hz, WithNH), 0.65 (1H, t, J 12.1 Hz, CHN).

Also according to the method B yielded the following derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole.

Dibenzyl-[3-(2-benzylamino-propyl)-[1,2,4]thiadiazole-5-yl]-amine. Colorless crystals. TPL=103-105°C.

Range PMR (CDCl3), δ, ppm: 7.31 (15 NM, m, Narene), 4.67 (4H, s, N(CH2)2), 3.91 and 3.79 (2H, d + d, J 13.0 Hz, ArCHH), 3.25 (1H, Sextus, J 6.3 Hz, CH2NCH3), 2.97 (1H, DD, J 6.5,14.2 Hz, CHNSNSN3), 2.85 (1H, DD, J 5.8, 14.2 Hz, WithNNSSN3), 1.21 (3H, d, J 6.3 Hz, CH2SNAN3).

Furan-2-ylmethyl-{1-methyl-2-[5-(4-methyl-piperidine-1-yl)-[1,2,4]thiadiazole-3-yl}-ethyl)-amine.

Butter.

Range PMR (CDCl3), δ, ppm: 7.44 (1H, m, Harene), 6.58 (1H, m, Harene), 6.38 (1H, m, Harene), 4.09 (2H, m, NCH2), 3.85 (2H, m, N(CHH)2), 3.25 (1H, Sextus, J 6.3 Hz, CH2NCH3), 3.13 (2H, m, N(CHH)2), 2.99 (1H, is d, J 6.5, 14.2 Hz, CHNSNSN3), 2.87 (1H, DD, J 5.8, 14.2 Hz, WithNNSSN3), 1.75 (1H, m, (NN)2SNSN3), 1.66 (1H, m,NCH3), 1.30 (1H, m, (CHN)2SNSN3), 1.20 (3H, d, J 6.3 Hz, CH2SNAN3), 1.00 (3H, d, J 6.3 Hz, SNAN3).

Cyclohexyl-[1-methyl-2-(5-morpholinyl-4-yl-[1,2,4]thiadiazole-3-yl)-ethyl]-amine.

Colorless crystals. TPL=93-95°C.

Range PMR (CDCl3), δ, ppm: 3.77 (4H, t, J 5.5, O(CH2)2), 3.47 (4H, t, J 5.5, N(CH2)2), 3.39 (1H, Sextus, J 6.3 Hz, CH2NCH3), 2.95 (1H, DD, J 6.3, 14.2 Hz, CHNSNSN3), 2.81 (1H, DD, J 6.3, 14.2 Hz, WithNNSSN3), 2.58 (1H, m, NCH), 1.91 (2H, m, NCH(CHH)2), 1.71 (2H, m, NCH(CHH)2), 1.18 (6H, m, CH2CH2CH2), 1.13 (3H, d, J 6.3 Hz, CH2SNAN3).

2-[5-(Cyclopropyl-thiophene-2-instil-amino)-[1,2,4]thiadiazole-3-yl]-1-methyl-ethyl}-]-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine.

Butter.

Range PMR (DMSO-d6), δ, ppm: 7.25 (1H, DD, J 1.4, 5.5 Hz, Harene), 7.06 (1H, DD, J 1.2, 3.5 Hz, Harene), 6.94 (1H, DD, J 3.5, 5.1 Hz, Harene), 4.95 (2H, s, CH2), 3.29 (1H, m, NCH), 2.93 (1H, TT, J 3.5, 11.6 Hz, NCH), 2.70 (2H, DD, J 6.3, 14.2 Hz, CH2), 2.64 (1H, m, NCH), 1.71 (2H, DD, J 3.5, 12.3, 2CH), 1.12 (6H, d, J 2.3 Hz, (CH3)2), 1.05 (3H, d, J 6.5 Hz, CLO3), 1.03 (6H, d, J 4.0 Hz, (CH3)2), 0.91 (4H, m, (CH2)2), 0.76 (1H, t, J 12.1 Hz, WithNH), 0.67 (1H, t, J 12.1 Hz, CHN).

{1-Methyl-2-[5-(4-methyl-n is perazin-1-yl)-[1,2,4]thiadiazole-3-yl]-ethyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine.

Butter.

Range PMR (DMSO-d6), δ, ppm: 3.54 (4H, t, J 5.1 Hz, CH2NCH2), 3.35 (1H, m, NCH), 2.95 (1H, TT, J 3.5, 11.6 Hz, NCH), 2.78 (2H, d, J 6.0, CH2), 2.54 (4H, t, J 5.1 Hz, CH2NCH2), 2.36 (3H, s, CH3), 1.83 (2H, DD, J 3.5, 12.3, 2CH), 1.18 (6H, d, J 2.3 Hz, (CH3)2), 1.13 (3H, d, J 6.3 Hz, CLO3), 1.10 (6H, d, J 2.6 Hz, (CH3)2), 0.80 (1H, t, J 12.1 Hz, CH), 0.70 (1H, t, J 12.1 Hz, CH).

(2-{5-[(4-Diethylamino-benzyl)-pyridine-3-ylmethyl-amino]-[1,2,4]thiadiazole-3-yl}-1-methyl-ethyl)-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine.

Butter.

Range PMR (DMSO-d6), δ, ppm: 8.42 (2H, m, 2Py-α), 7.60 (1H, DD, J 1.9,7.9 Hz, Ru-gamma), 7.25 (1H, dt, J 0.7, 4.7, 7.7 Hz, PY-β), 7.04 (2H, d, J 8.8 Hz, 2Harene), 6.56 (2H, d, J 8.8 Hz, 2Harene), 4.67 (2H, s, NCH2), 4.43 (2H, s, NCH2), 3.33 (4H, HF, CH3CH2NCH2CH3), 3.27 (1H, m, NCH), 2.91 (1H, TT, J 3.5, 11.6 Hz, NCH), 2.65 (2H, d, J 6.0 Hz, CH2), 1.69 (2H, DD, J 3.5, 12.3, 2CH), 1.15 (6H, t, CH3CH2NCH2CH3), 1.12 (6H, d, J 4.2 Hz, (CH3)2), 1.05 (3H, d, J 6.3 Hz, CLO3), 1.01 (6H, d, J 4.2 Hz, (CH3)2), 0.73 (1H, t, J 12.1 Hz, CH), 0.63 (1H, t, J 12.1 Hz, CH).

Example 3. Neyromoduliruyuschim activity of 5-amino-3-(2-aminopropyl)-(1,2,4]thiadiazolo.

Neyromoduliruyuschim the action of the new compounds were tested for P2-fraction synaptosomes structures of the cerebral cortex of rats. 5-Amino-3-(2-aminopropyl)-[1,2,4]thiadiazole was studied in the test on glutamate-induced seizure isotope45Ca2+ in synaptosome. {2-[5-(3-Chloro-4-methyl-phenylamino)-[1,2,4]thiadiazole-3-yl]-1-methyl-ethyl}-(2,2,6,6-tetramethyl-piperidine-4-yl)-amine at a concentration of 100 μm stimulated seizure45CA2+in synaptosome at 213±12.4% compared to control.

1. Derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole of the General formula:
,
where R1, R2, R3may be the same or different and independently denote hydrogen, possibly substituted alkyl, possibly substituted aryl, possibly substituted aralkyl, heteroalkyl (where the 5 - or 6-membered N-, O - or S-heteroaromatic cycle), cycloalkyl, 2,2,6,6-tetramethyl-piperidine-4-yl, and R1+R2can mean a heterocycle selected from optionally substituted pyrrolidine, piperidine, azepane, piperazine, the research, where the possible substituents may be hydroxyl, cyano, halogen, alkali, low alkoxygroup, low alkariagroup, trihalomethyl, sulfa, optionally substituted amino groups (amino, dimethylamino, diethylamino), provided that, when R1=H, then R2is other than hydrogen or methyl.

2. Derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole according to claim 1, having neyromoduliruyuschim activity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, where Ar denotes a phenyl group substituted with piperazine or benzo[d]thiazole, with a phenyl part bonded to B, where the piperazine or benzo[d]thiazole can be unsubstituted or substituted with substitutes selected from alkyl or acetyl; B denotes -O-; R1 denotes hydrogen; R2 denotes S(O)2R4 or C(O)(CH2)n-C(O)OR5; R3 denotes halogen; R4 denotes an aryl which can be unsubstituted or substituted with substitutes selected from a group comprising halogen, alkyl, fluoroalkyl, alkoxy and trifluoromethoxy; R5 denotes hydrogen; n is a whole number from 1 to 3. The invention also relates to a method of producing said compounds and a pharmaceutical composition for treating metabolic disorders associated with insulin resistance or hyperglycaemia, based on said compounds.

EFFECT: novel compounds are obtained, which can be used in medicine to treat type 2 diabetes, obesity, glucose intolerance, dyslipidaemia, hyperinsulinaemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension or non-alcoholic fatty liver disease.

28 cl, 3 dwg, 4 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing amide-containing 1,3,5-dithiazinanes of general formula , where R=H (Ia), CH3 (Ib). The method is realised by reacting hydrogen sulphide-saturated aldehyde (formal or acetic) with a mixture of isonicotinic acid hydrazide - BuONa (1:3, pH>11.5). The process is carried out at ratio hydrazide: aldehyde: H2S equal to 1:3:2, at temperature 40°C while stirring constantly for 4 hours, followed by neutralisation with a calculated quantity of dilute HCl and purification via column chromatography on SiO2. The substances obtained using the disclosed method can be used as radiation protection, antitumour and diuretic agents, as well as selective sorbents and extractants of noble and precious metals.

EFFECT: obtaining amide-containing 1,3,5-dithiazinanes of general formula (I).

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3,4-thiadiazolines (I), thiadiazinones (II) and thiadiazepines (III), obtained based on thiohydrazides of oxamic acids, which can be used to inhibit pathogenic bacteria, and can particularly affect type III secretion system in pathogens, having general formula:

, , ,

where R denotes H; R1 denotes H, pyridinyl; phenyl, substituted with alkyl C1-C5, Hal, CF3; a group , where X denotes S, substituted with alkyl C1-C5, COOR4; R2, R3 denotes alkyl C1-C5, pyridinyl, phenyl, substituted Hal, OH, OR4, a R4 denotes unsubstituted alkyl C1-C4.

EFFECT: obtaining compounds which can be used to inhibit pathogenic bacteria.

2 cl, 2 dwg, 6 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel compounds of formula (I), where R1 represents hydroxymethyl; R2 is selected from -C(O)NR4R5; HET-1 represents 5- or 6-member heteroaryl ring, bound by atom C; R3 represents halogeno; R4 and R5 together with nitrogen atom, to which they are bound, can form heterocyclyl ring system, as it is defined for HET-3; HET-3 represents possibly substituted azetidinyl; m equals 1; n equals 0, 1 or 2; or their pharmaceutically acceptable salt, which can be applied as glucokinase (GLK) activators or active ingredient of pharmaceutical compositions, also described are methods of obtaining them.

EFFECT: creation of novel compounds applied as glucokinase (GLK) activators in treatment of diabetes.

13 cl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns improved method of obtaining 3,5-diamino-1,2,4-thiadizol applied in synthesis of medicines, macroheterocyclic compounds, bioactive substances etc. Invention claims method of obtaining 3,5-diamino-1,2,4-thiadizol by reaction of 2-imino-4-thiobiuret with equimolecular quantity of hydrogen peroxide of 26-35% concentration in boiling alcohol for 20-30 minutes.

EFFECT: increased output to by 86% of target product with melting temperature of 172-174°C and reduced general process duration from 60 to 2 hours.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel derivatives of 1,2,4-thiadiazole-2-il formula (I), , where R1, R2 and R4 present the radicals containing cyclic fragments, R3 designates hydrogen, alkyl, alkenyl or alkinyl that can be used as the agonists and antagonists of melanokortin receptors. Also, in this invention, the pharmaceutical composition, which shows the activity of modulator of melanokortin receptors, and the method of its preparation, are described. The purpose of this invention is to obtain the pharmaceutical compositions, which contain the therapeutically effective amount of compounds, as well as the pharmaceutically acceptable carrier, which are administered to the subject that suffers the melanokortin-mediated diseases, from the group with metabolic disturbances, abnormalities related to CNS and dermatologic abnormalities.

EFFECT: compounds can be used in treatment of CNS and dermatologic diseases.

21 cl, 13 ex, 13 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 1,2,4-thiadiazole of the formula (II): wherein R1, R2 and R4 represent radicals comprising cyclic fragments that can be used as agonists or antagonists of melanocortin receptors. Invention provides preparing pharmaceutical compositions comprising the claimed compounds taken in the therapeutically effective dose that can be used in treatment of diseases mediated by melanocortin receptors, for example, such as metabolic disorders, disorders associated with the central nervous system, and dermatological disorders.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

20 cl, 13 tbl, 5 sch, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

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