Novel derivatives of cycloalkanedione, method for their preparing and their using in pharmaceutics

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

 

The technical FIELD

The present invention relates to new chemical compounds, pharmaceutical preparations which contain them and their use in medicine; in particular, the present invention relates to new derivatives of cycloalkanones, which are substances with affinity to the receptor of subtype 5-HT1Aserotonin (5-hydroxytryptamine, 5-HT). Therefore they can be used in the treatment of pathological States in which is shown a substance having affinity to these receptors.

In particular, the compounds according to the present invention can be used as a neuroprotective tools that increase interest in the treatment and prevention of cerebral disorders due to traumatic or ischemic stroke.

The LEVEL of TECHNOLOGY

Pharmacological treatment of acute stroke is very limited; to date moderate effect may have only thrombolytic therapy with tissue plasminogen activator (tPA). Although the primary damage of cells caused by ischemia, no cure, there is a possibility of exposure to secondary necrosis of nerve cells in the zone "penumbra", where the sequence of processes that distribute defeat. Among them, special attention was paid to assalomu the release of excitatory amino acids, and in this sense, drugs that prevent the release of glutamate antagonists to glutamate receptors, these receptors as NMDA and AMPA have proved effective in various experimental models.

Currently known 14 different subtypes of serotonergic receptors. Receptors 5-HT1Aand their localization is both presynaptic and postsynaptic, are the target group of anxiolytics, and perhaps they are also involved in the activities of a specific antidepressants.

In document ES 2052829 substituted aminoacylation and similar heterocyclic compounds are disclosed as selective agonists serotonergic receptor subtype 5-HT1A. One of the products disclosed in the above-mentioned document, BAYx3702, as was proven experimentally in vitro (Suchanek et al., 1998; Ahlemeyer et al., 1999) and in vivo (Schaper et al., 2000; Torup et al., 2000; Kline et al., 2001), has a neuroprotective effect due to its agonistic effect on the receptor 5-HT1A.

Spanish patent application No. 200102113 the same authors, the present invention discloses a group of compounds that behave as pure agonists of the receptors 5-HT1Athough with only moderate force, while their neuroprotective effect can be demonstrated by the use of primary cultures is not the main cells of rats.

Neuroprotective effect of agonists of the receptors 5-HT1Amay result from various mechanisms, among which can be highlighted hyperpolarization by activation of channels To+the inhibition of glutamate release (Matsuyama et al., 1996; Mauler et al., 2001) and the increase in the allocation of neurotrophin BDNF (Gaiter et al., 2000).

The above information allows us to predict new uses for compounds able to activate the receptor 5-HT1Anamely their use in the treatment of lesions of the brain associated with the processes of ischemia/hypoxia or traumatic accidents. So very interested to receive new connections serotonergic agonists of the receptors 5-HT1Athat have a neuroprotective effect and can provide effective treatment of lesions of the brain associated with the processes of ischemia/hypoxia or brain injury.

BRIEF description of the INVENTION

The present invention, as the name implies, relates to new derivatives of cycloalkanones, method of their production and their use as pharmaceuticals.

In the first aspect of the present invention mentioned derivatives of cycloalkanones differ in that they correspond to the General formula I:

where

R1is selected from the group consisting of H, -(CH2 )3-, -(CH2)4-, -CH2-S-CH2, -S-CH2-CH2-;

R2is selected from the group consisting of N, S;

n is 0 or 1;

Z is selected from the group consisting of alkyl, C2-C10alkenyl2-C10, quinil2-C10;

R3is selected from the group consisting of H, alkyl (C1-C10, aryl, aralkyl;

m has a value from 0 to 2;

R4is selected from the group consisting of Oh, CH2;

R5is selected from the group consisting of

where

R6is selected from the group, with Toyama from N, of alkyl, C1-C5, alkoxyl C1-C5HE, F, Cl, Br, I;

X is selected from the group consisting of O, S, NH, NCH3;

Y is selected from the group consisting of Oh, NH;

W is selected from the group consisting of S, NH.

In one of the preferred embodiments of the present invention compounds of formula I are those where Z is alkyl group With2-C10and R5is selected from the group consisting of:

where the definition of R1, R2, R3, n, m, R4and R6similar to the above.

Even more preferred are the compounds of formula (I), where Z is bootrom, R3- N and R5is selected from the group consisting of:

where the definition of R1, R2, n, m, R4and R6similar to the above.

Unless otherwise indicated, the alkyl groups mentioned in the present invention, and alkyl radicals of other groups referred to in the present invention (for example, alkoxyl), can be linear or branched, and may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or a linear or razvetvlenno the mi and contain these cyclic radicals.

Unless otherwise stated, alkeline group referred to in the present invention are linear (for example, 2-butinyl).

The term "aryl" includes any monocyclic aromatic group containing 5 to 12 carbon atoms, optionally broken by one or more heteroatoms selected from N, O and S.

The term "aralkyl" refers to an aryl group having a link to the previously defined alkyl group, such as benzyl or phenethyl.

In the scope of the present invention the compounds according to the present invention can have several asymmetric carbon atoms and, therefore, to have different stereochemical form. Compounds according to the present invention can also be in the form of their salts. In General, you can mention their salts with inorganic or organic acids.

In the scope of the present invention preferred are those salts that are physically compatible. In particular, preferred are, for example, salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultation, o-toluensulfonate, m-toluensulfonate, p-toluensulfonate, benzosulfimide acid, o-naphthalenesulfonate, m-naphthalenesulfonate, p-naphthalenesulfonate, acetic acid, propionic acid, Molo is Noah acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid.

Compounds with strong agonistic effects on the receptor 5-HT1Adisclosed in the present invention are, therefore, effective means to treat diseases of the Central nervous system, including anxiety neurosis, various forms of depression and mixed anxiety anxiety - depression, such as obsessive-compulsive disorder, phobias, bulimia, etc. They are also suitable for the prevention and treatment of damage of the nerve cells in cases of ischemic stroke, with the support of the survival of the cells located in the zone "penumbra"surrounding the ischemic focus.

These new active means can be performed by any known method as conventional drugs, such as tablets, coated tablets, capsules, pills, pellets, granules, aerosols, syrups, emulsions, suspensions and solutions, using a pharmaceutically suitable, non-toxic, inert fillers or solvents. In this case, therapeutically active compound should be present in the medium at a concentration of about 0.5 to 90% by weight of the mixture, i.e. in amounts sufficient to be in it at the specified interval dosing.

Connect the tion, disclosed in the present invention are pure serotonergic receptor agonists 5-HT1Aas has been demonstrated by appropriate functional studies. Therefore, the compounds that are the subject of the present invention have a protective effect on cell death, with natural or necrotic nature, caused by serum deprivation or glutamate in neuronal cultures.

According to another aspect of the present invention, there are two alternative ways to obtain compounds with the General formula I by reaction of the intermediate halogenated derivatives of II (L=Cl, Br) with the appropriate amines III in acetonitrile as the solvent of the reaction (Scheme I, below) or by reaction of intermediate IV with amines suitable halogenated derivatives of V (L=Cl, Br) in acetonitrile as the solvent of the reaction (Scheme II, below).

acetonitrile=acetonitrile

Compounds with R3other than H, can be obtained by alkylation analogues, where R3is hydrogen.

Define R1, R2, R3n, Z, m, R4and R5these schemes are similar to the above for medium according to the present invention.

Intermediate substances of formula II can be obtained by the reaction as diketopiperazine or cyclic imide with the corresponding halogen derivatives in the presence of sodium hydride and N,N-dimethylformamide as the reaction solvent, as shown in Scheme III.

DMF=DMF

Intermediate substances of formula IV can be obtained by the reaction as diketopiperazine or cyclic imide with the corresponding halogenation in the presence of sodium hydride and N,N-dimethylformamide as solvent for the reaction and subsequent catalytic hydrogenation as shown in Scheme IV.

DMF=DMF

cat.=catalyst

Some of the intermediates III and V are trademarks. You can also get these intermediate substances according to the processes described in the literature, or conventional synthesis processes.

The structure of the resulting means were determined by IR - and NMR-spectroscopy and quantitative elemental analysis. To facilitate the work, when the final product was not crystalline, it is converted into a pharmaceutically acceptable salt with an inorganic or organic acid.

Affinity in vitro of the compounds of General formula I to cerebral receptors 5-HT1A, 5-HT2A, 5-HT3, 5-HT4, 5-HT7that α1and D2was assessed through inspections radioligand displacement. We used the following specific ligands and fabric:

(a) receptors 5-HT1A, [3H]-8-OH-DPAT, the cerebral cortex of rats;

(b receptors 5-HT 2A, [3H] ketanserin, the cerebral cortex of rats;

(c) receptors 5-HT3, [3N] LY 278584, the cerebral cortex of rats;

(d) receptors 5-HT4, [3H] GR 113808, striatum of rats;

(e) receptors 5-HT7, [3H]-5-CT, the rat hypothalamus;

(f) receptors α1, [3N] prazosin, the cerebral cortex of rats;

(g) receptors D2, [3H] spiperone, striatum of rats.

The functional nature (agonist/antagonist) compounds of the present invention was investigated in vitro by determining the inhibition of the stimulatory effect of Forskolin on adenylate cyclase in cell lines, transfectional receptor 5-HT1Afrom time to time by comparing a result obtained by checking the commit [35S] GTPγS coronary slice of rat brain, as well as hyperpolarize effect on the area CA1 of the hippocampus, further study in vivo agonistic character of the new compounds by analyzing the typical behavioral effects and hypothermia, and evaluation of prevention of these effects selective antagonist WAY-100635.

In addition, the neuroprotective activity of the compounds disclosed in the present invention, with regard to their ability to prevent cell death was natural or necrotic nature, was investigated in primary cultures of neural cells and by studying in vivo predot the stop the death of neurons in area CA1 of the hippocampus of mice gerbils after transient global ischemia, as well as reducing the volume of ischemic stroke after permanent occlusion of the middle artery of the big brain in rats.

The present invention is illustrated using the following non-restrictive examples.

EXAMPLES

EXAMPLE 1: Synthesis of compounds of General formula I. the Usual way.

To 1.5 mmol amine intermediate III or IV, dissolved in 2 ml of acetonitrile, droplets was added a solution of 1.0 mmol halogen derivatives of II or V in 1.5 ml of acetonitrile. The reaction mixture was heated to 60°With stirring for 6-24 hours (under constant control). After cooling, the solvent was removed under reduced pressure, the residue was dissolved in methylene chloride (20 ml) and was washed with an aqueous solution of 20%potassium carbonate. Then the organic phase was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The resulting oil was purified silicagel Packed column chromatography, giving the final product in free base form. The compound was separated in the form of hydrochloride and purified by recrystallization. The data of IR - and NMR-spectroscopy correspond to the free base.

(±)-2-[4-[(chroman-2-yl)methylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole, 1.

Chromatography: toluene/methanol, 9:1. Yield: 35%. IR (CHCl3cm-1): 1772, 1709, 1581, 1489, 1443.1H-NMR (CDC 3that δ): 1,47 is 1.86 (m, 5H), 1.91 a-2,12 (m, 4H), 2,16-of 2.34 (m, 1H), 2,64 of 2.92 (m, 6H), 3,16 of 3.28 (m, 1H), 3,48 (t, J=7,1 Hz, 2H), 3,66 (dt, J=11,2; and 7.3 Hz, 1H), of 4.05 (dd, J=9,1; and 7.3 Hz, 1H), 4,11-4,18 (m, 1H), for 6.81 (t, J=7,6 Hz, 2H), 7,00-7,10 (m, 2H).13C-NMR (CDCl3that δ): 24,6; 25,6; 25,8; 26,9; 27,1; 27,5; 38,7; 45,4; 49,3; 54,1; 63,2; 75,0; 116,7; 120,1; 121,9; 127,1; 129,4; 154,5; 160,8; 173,9. Analysis calculated for C21H24N2O4S·HCl: C, 57,72; N, 5,77; N, 6,41, found: C, 57,64; N, 5,96; N is 6.19.

EXAMPLE 2:

(±)-2-[4-[(chroman-2-yl)methylamine]butyl]-1,3-dioxopyrimidine[1,5-6]thiazole, 2.

Chromatography: toluene/ethanol, and 9.5:0.5 in. Yield: 43%; melting point 149-151°With (ethyl acetate). IR (CHCl3cm-1): 3400, 1770, 1718, 1610, 1558, 1488.1H-NMR (CDCl3that δ): 1,48 is 1.86 (m, 5H), 2,01 is 2.10 (m, 1H), 2,59-3,18 (m, 9H), 3,53 (t, J=7,0 Hz, 2H), 3.95 to 4,27 (m, 1H), 4,49 (dd, 1H, J=12, 0mm; from 6.0 Hz), to 5.08 (s, 1H), 6,56-6,92 (m, 2H), 7.03 is-7,13 (m. 2H).13C-NMR (CDCl3that δ): 23,9; 24,4; 25,5; 25,9; 32,7; 39,1; 48,4; 54,0; 58,3; 63,2; 74,8; 116,7; 120,0; 122,0; 127,1; 129,4; 154,6; 159,6; 171,6. Analysis calculated for C19H24N3About3S·HCl: C, 55,40; N, 6,36; N, 10,20, found: C, 55,38; N, 6,44; N, 9,87.

EXAMPLE 3:

(±)-2-[4-[(chroman-2-yl)methylamine]butyl]-1,3-dioxopyrimidine[1,5-C]-thiazole, 3.

Chromatography: toluene/ethanol, and 9.5:0.5 in. Yield: 38%; melting point 142-144°With (ethyl acetate). IR (CHCl3cm-1): 3400, 3500, 1770, 1716, 1582, 1540, 1508.1H-NMR (CDCl3that δ): 1,49-of 1.74 (m, 5H), to 1.98-2.05 (m, 1H), 2,60-2,84 (m, 6H), 3,12 (dd. J=9.9 Hz, 1H), 4.22-to 4.28 (m, 1H), 4,33 (dd, J=8,5, 5.8 Hz, 1H), free 5.01 (d, J=9.9 Hz, 1H), 6,77-to 6.88 (m, 2H),? 7.04 baby mortality-,13 (m, 2H).13C-NMR (CDCl3δ): 23,8; 24,4; 25,6; 25,9; 32,7; 39,1; 49,2; 54,1; 58,2; 64,4; 74,2; 116,7; 120,3; 122,0; 127,1; 129,5; 154,5; 159,6; 171.9. Analysis calculated for C19H24N3O3S·HCl: C, 55,40; N, 6,36; N, 10,20, found: C, 55,02; N, 6,44; N, 9,85.

EXAMPLE 4:

(±)-3-[4-[(chroman-2-yl)methylamine]butyl]-1,4-dioxothiazolidine, 4.

Chromatography: toluene/ethanol, and 9.5:0.5 in. Yield: 45%; melting point 126-127°With (ethyl acetate). IR (CHCl3cm-1): 3400, 1750, 1683, 1608, 1558, 1508.1H-NMR (CDCl3that δ): 1,47 to 1.76 (m, 5H), 2,01-to 2.06 (m, 1H), 2.57 m-a 3.01 (m, 6H), 3,62 (t, J=7.2 Hz, 2H), 3,92 (s, 2H), 4,10-of 4.25 (m, 1H), 6,74-6,83 (m, 2H), 7,01-was 7.08 (m, 2H).13C-NMR (CDCl3δ): 24,2; 24,5; 25,3; 25,9; 33,7; 41,8; 54,2; 58,4; 74,3; 116,7; 120,3; 122,0; 127,1; 129,5; 154,5; 171,4; 171,8. Analysis calculated for C17H21N2O3S·HCl: C, 55,05; N, Of 6.25; N, 7,55, found: C, 54,98; N, 6,33; N, 7,15.

EXAMPLE 5:

(±)-3-[5-[(chroman-2-yl)methylamine]pentyl]-2,4-dioxothiazolidine, 5.

Chromatography: toluene/ethanol, 20:1→8:2. Yield: 38%; melting point 172-174°With (chloroform/ethyl acetate). IR (CHCl3cm-1): 1751, 1682, 1683, 1608, 1581, 1488, 1456.1H-NMR (CDCl3that δ): 1,25-2,04 (m, 8H), to 2.67 (t, J=7,0 Hz, 2H), 2,75-to 2.94 (m, 4H), 3,63 (t, J=7,3 Hz, 2H), 3,92 (s, 2H), 4,08-4,17 (m, 1H), 6,78-6,85 (m, 2H), 7,01-7,11 (m, 2H).13C-NMR (CDCl3that δ): 24,4; 24,6; 25,7; 27,4; 29,4; 33,7; 42,0; 49,6; 54,2; 75,0; 116,7; 120,2; 122,0; 127,2; 129,5; 154,6; 171,4; 171,7. Analysis calculated for C18H24N2O3S·HCl: C, 56,17; N, 6,55; N, 7,28, found: C, 55,49; N, Of 6.49; N, 7,10.

(±)-3-[6-[(chroman-2-yl)methylamine]hexyl]-2,4-dioxothiazolidine, 6.

Chromatography: toluene/ethanol, 20:1. Yield: 30%; melting point 175-177°With (chloroform/ethyl acetate). IR (CHCl3cm-1): 3416, 3321, 1751, 1670, 1608, 1581, 1489, 1456.1H-NMR (CDCl3that δ): 1,25-a 2.01 (m, 10H)to 2.66 (t, J=7,1 Hz, 2H), was 2.76-2.95 and (m, 4H), 3,62 (t, J=7,3 Hz, 2H), 3,93 (s, 2H), 4.09 to 4,19 (m, 1H), 6,78-6,85 (m, 2H), 7,01-7,11 (m, 2H).13C-NMR (CDCl3that δ): 24,6; 25,7; 26,6; 26,8; 27,5, 29,8; 33,7, 42,0; 49,8; 54,2; 75,1; 116,7; 120,2; 122,0; 127,2; 129,5; 154,6; 171,4; 171,7. Analysis calculated for C19H26N2O3S·HCl: C, 57,18; N, PC 6.82; N, 7,02, found: C, 56.78 Has; N, 6,72; N, 6,94.

EXAMPLE 7:

(±)-2-[4-[(naphthas-1-yl)methylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole, 7.

Chromatography: ethyl acetate. Yield: 42%; melting point 150-153°C (chloroform/hexane). IR (CHCl3cm-1): 3300-3500, 1770, 1708, 1696, 1510, 1442, 1416.1H-NMR (CDCl3that δ): 1,48-1,71 (m, 5H), 1,99-of 2.08 (m, 2H), 2,16-of 2.24 (m, 1H), 2,74 (t, J=6.9 Hz, 2H), 3,16-3,24 (m, 1H), 3,47 (t, J=6.9 Hz, 2H), to 3.64 (dt, J=11,1; and 7.8 Hz, 1H), was 4.02 (dd, J=9,3; and 7.8 Hz, 1H), 4,20 (s, 2H,), 7,37-rate of 7.54 (m, 4H), 7,74 (d, J=7.2 Hz, 1H), 7,82-a 7.85 (m, 1H), (d, J=8,4 Hz, 1H).13C-NMR (CDCl3that δ): 25,9; 27,0; 27,2; 27,5; 38,8; 45,5; 49,3; 51,6; 63,3; 123,6; 125,4; 125,9; 126,1; 127,7; 128,7; 131,8; 133,9; 136,0; 160,9; 173,9. Analysis calculated for C21H25N3O2·HCl: C, 65,02; N, 6,76; N, 10,83, found: C, 64,53: N, Of 6.71; N, 10,44.

EXAMPLE 8:

(±)-2-[4-[(naphthas-1-yl)methylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole, 8.

Chromatography: chlorine the product/methanol, 9:1. Output: 25%; melting point 125-127°With (ethyl acetate). IR (CHCl3cm-1): 3417, 1769, 1707.1H-NMR (CDCl3that δ): 1,52-1,80, 1,92-2,23 (m, 3H), 2,80 (t, J=7,1 Hz, 2H), 3,13-of 3.25 (m, 1H), 3,42 (t, J=6.6 Hz, 2H), 3,56-3,74 (m, 1H), 4,06 is 4.13 (m, 3H), 5,19 (sa, 1H), 7,45 is 7.50 (m, 2H). to 7.61 (d, J=8,8 Hz, 1H), 7,78-a 7.92 (m, 4H).13C-NMR (CDCl3that δ): 25,2; 26,8; 27,3; 29,5; 37,8; 45,3; 46,2; 51,5; 63,2; 126,3; 126,4; 126,7; 127,5; 127,8; 128,6; 129,0; 130,0; 132,9; 133,0; 160,5; 173,8. Analysis calculated for C21H25N3O2·HCl·H2O: C, 62,14; N, Of 6.95; N, 10,35, found: C, 62,54; N, 7,06; N, 9,95.

EXAMPLE 9:

2-[4-[2-(naphthas-1-yl)ethylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole, 9.

Chromatography: ethyl acetate/ethanol 1:1. Yield: 48%; melting point 95-97°With (ethyl acetate). IR (CHCl3cm-1): 3400 (NH), 1770, 1710.1H-NMR (CDCl3that δ): 1,56-of 1.78 (m, 5H), 2.00 in 2,28 (m, 3H), of 2.72 (t, J=6,8 Hz, 2H), to 3.02 (t, J=7,1 Hz, 2H), 3,11-to 3.38 (m, 3H), of 3.48 (t, J=7.2 Hz, 2H), 3,63-3,74 (m, 1H), 4,01-4,10 (m, 1H), 7,37-rate of 7.54 (m, 4H), 7,71-7,76 (m, 1H), 7,82-7,86 (m, 1H), 7,08-7,13 (m, 1H).13C-NMR (CDCl3that δ): 27,9; 27,0; 27,1; 27,6; 33,4; 37,8, 45,5; 49,3; 50,4; 63,3; 123,7; 125,5; 125,9; 126,6; 127,0; 128,8: 132,0: 134,0; 136,0; 160,8; 174,0. Analysis calculated for C22H27N3O2·HCl·H2O: C, 62,92: N, 7,20; N, 10,01, found: C, 63,40; N, To 7.09; N, being 9.61.

EXAMPLE 10:

3-[4-[2-(naphthas-1-yl)ethylamine]butyl]-2,4-dioxothiazolidine, 10.

Chromatography: ethyl acetate. Yield: 37%; melting point 128-129°With (ethyl acetate). IR (CHCl3cm-1): 1751, 1682, 1682, 1510.1H-NMR (CDCl3 that δ): 1,52-to 1.63 (m, 4H), 2,70 (t, J=6,8 Hz, 2H), 2,94 (s, 1H), 3,03 (t, J=7,3 Hz, 2H), 3,32 (t, J=7,6 Hz, 2H), 3,62 (t, J=6,8 Hz, 2H), 3,93 (s, 2H), 7,33-of 7.55 (m, 4H), 7,71 to 7.75 (m, 1H), 7,83-7,88 (m, 1H), 8,04-8,08 (m, 1H).13C-NMR (CDCl3that δ): 25,4; 26,3; 32,7; 33,8; 41,7, 48,7; 49,9, 123,7; 125,7; 125,8; 126,1; 126,8; 127,3; 128,9; 131,0; 134,0; 135,4; 171,0; 171,5. Analysis calculated for C19H22N2O2S·HCl: C, 60,82; N, 6,85; N, 7,09, found: C, 62,87; N, Of 6.45; N, 6.90 to.

EXAMPLE 11:

2-[4-[2-(naphthas-2-yl)ethylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 11.

Chromatography: ethyl acetate/ethanol 9:1. Output: 25%; melting point 130-132°With (ethyl acetate). IR (CHCl3cm-1): 3421, 1769, 1705.1H-NMR (CDCl3that δ): 1,59-1,89, (m, 5H), 2,03-of 2.27 (m, 3H), 2,98 (t, J=7.8 Hz, 2H), 3,01-of 3.32 (m, 5H), 3,47 (t, J=6.6 Hz, 2H), 3,57-of 3.77 (m, 1H), of 4.05 (dd, J and 9.3; and 7.3 Hz, 1H), 6,29 (sa, 1H), 7,32-of 7.48 (m, 3H), 7.68 per-7,80 (m, 4H).13C-NMR (CDCl3that δ): 25,4; 27,1; 27,5; 31,2; 33,1; 37,9, 45,5; 47,1; 49,1; 63,4; 125,5; 125,8; 126,2; 126,9; 127,4; 127,6; 128,6; 131,8; 133,5; 139,5; 160,7; 174,1. Analysis calculated for C22H27N3O2·HCl·H2O: C, 62,92; N, 7,20; N, 10,01, found: C, 63,34; N, 7,46; N, 9,65.

EXAMPLE 12:

2-[4-[2-(phenoxy)ethylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 12.

Chromatography: toluene/ethanol, and 9.5:0.5 in. Yield: 54%; melting point 145-147°With (ethyl acetate). IR (CHCl3cm-1): 3315, 1770, 1709, 1599, 1587, 1497.1H-NMR (CDCl3that δ): 1,47-to 1.77 (m, 6H), 1,98-to 2.29 (m, 3H), 2,70 (t, J=6,8 Hz, 2H), 2,99 (t, J=4.9 Hz, 2H), 3,23 (ddd, J=11,2; 7,6; and 5.2 Hz, 1H), 3,49 (t, J=7,3 Hz, 2H), to 3.67 (dt, J=11,2; and 7.6 Hz, H), as 4.02-4,10 (m, 3H), 6.87 in-6,98 (m, 3H), 7.23 percent-to 7.32 (m, 2H).13C-NMR (CDCl3that δ): 26,0; 27,1; 27,3; 27,7; 38,9; 45,7, 48,9; 49,4; 63,4; 67,3; 114,7; 121,0; 129,6; 158,3; 160,7; 174,0. Analysis calculated for C18H25N3O3·HCl: C, 58,77; N, 7,12; N, 11,42, found: C, 58,79; N,? 7.04 baby mortality; N, 11,16.

EXAMPLE 13:

-3-[4-[2-(phenoxy)ethylamine]butyl]-2,4-dioxothiazolidine, 13.

Chromatography: ethyl acetate→ethyl acetate/ethanol 9:1. Yield: 37%; melting point 173-174°With (ethyl acetate). IR (CHCl3cm-1): 3413, 3327, 1751, 1685, 1599, 1587, 1497.1H-NMR (CDCl3, 8): 1,48-1,72 (m, 4H), 2,70 (t, J=7,1 Hz, 2H), 2,99 (t, J=7.9 Hz, 2H), 3,65 (t, J=7,1 Hz, 2H), 3,93 (s, 2H), 4,06 (t, J=5,1 Hz, 2H), 6,88-6,98 (m, 3H), 7.23 percent-to 7.32 (m, 2H).13C-NMR (CDCl3that δ): 25,4; 27,1; 33,7; 41,8; 48,8; 49,1; 67,1; 114,5; 120,8; 129,4; 158,8; 171,4; 171,5. Analysis calculated for C15H20N2O3S·HCl: C, 52,17; N, 6,14; N, 8,12, found: C, 51,77; N, 6,04; N, 8,10.

EXAMPLE 14:

2-[4-[2-(naphthas-1-hydroxy)ethylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 14.

Chromatography: ethyl acetate→ethyl acetate/ethanol 9:1. Yield: 43%; melting point 163-164°With (ethyl acetate). IR (CHCl3cm-1): 3354, 1771, 1707, 1582, 1508.1H-NMR (CDCl3that δ): 1,58-to 1.77 (m, 5H), 1.93 and-2,30 (m, 3H), of 2.86 (t, J=7,1 Hz, 2H), 3,15-of 3.27 (m. 3H), 3,49 (t, J=6,8 Hz, 2H), 3,60-to 3.73 (m, 1H), of 4.05 (dd, J=9,0; and 7.3 Hz, 1H), 4,30 (t, J=4.9 Hz, 2H), 6,80 (dd, J=8,5; 1.2 Hz. 1H), 7,31-7,53 (m, 4H), 7,75-7,83 (m. 1H). 8.22-of 8.28 (m, 1H).13C-NMR (CDCl3that δ): 25,7; 26,3; 27,0; 27.5; 38,5; 45,5; 48,3; 48,8; 63,3; 66,7; 104,9; 120,6; 121,9; 125,3; 125,8; 126,4; 127,5; 125,5; 134,5; 154,3; 160,8; 174,0. EN is Liz, calculated for C22H27N3O2·HCl·N2O: C, 60,61; N, 6,94; N, for 9.64, found: C, 61,00; N, To 6.57; N, 9,46.

EXAMPLE 15:

-3-[4-[2-(naphthas-1-hydroxy)ethylamine]butyl]-2,4-dioxothiazolidine, 15.

Chromatography: ethyl acetate→ethyl acetate/ethanol 9:1. Yield: 46%; melting point 149-151°With (ethyl acetate). IR (CHCl3cm-1): 3332, 1684, 1582, 1508.1H-NMR (CDCl3that δ): 1,58 is 1.70 (m, 4H), of 2.81 (t, J=6,8 Hz, 2H), 3,17 (t, J=5.4 Hz, 2H), 3,65 (t, J=6,8 Hz, 2H), 3,92 (s, 2H), 4,27 (t, J=5,1 Hz, 2H), for 6.81 (dd, J=7,1; 1.5 Hz, 1H), 7,30-7,56 (m, 4H), 7,75-7,83 (m, 1H), they were 8.22 is 8.38 (m, 1H).13C-NMR (CDCl3that δ): 25,3; 26,7; 33,7; 41,7; 48,5; 48,9; 67,1; 104,9; 120,5; 121,9; 121,2; 125,8; 126,4; 127,5; 125,6; 134,5; 154,4; 171,4; 171,5. Analysis calculated for C19H22N2O3S·HCl: C, 57,79; N, By 5.87; N, 7,09, found: C, 57,75; H, 5,79; N, 6,59.

EXAMPLE 16:

2-[4-[(benzimidazole-2-yl)methylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 16.

Chromatography: toluene/ethanol, and 9.5:0.5 in. Yield: 50%; melting point 208-210°With (ethyl acetate). IR (CHCl3cm-1): 3400, 1775, 1714.1H-NMR (COCl3that δ): 1,42 is 1.70 (m, 5H), 1,92-of 2.28 (m, MN), 2,63 (t, J=6.5 Hz, 2H), 3,13-of 3.25 (m, 1H). of 3.43 (t, J=6.5 Hz, 2H), 3,55-to 3.64 (m, 1H), 4.00 points (m, 2H), 7,10-to 7.18 (m, 2H), 7,47-7,53 (m, 2H).13C-NMR (CDCl3that δ): 25,4; 26,2; 27,0; 27,5; 38,4; 45,4; 47,6; 48,5; 63,3; 115,0; 122,0; 139,0; 154,0; 160,8; 174,0.

EXAMPLE 17:

2-[4-[(o-methoxyphenyl)methylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 17.

Chromatography: ethyl acetate/hexane. Yield: 42%; oil. IR (CHCl 3cm-1): 3016-2837, 1770, 1706, 1600, 1492, 1442, 1415, 1242.1H-NMR (CDCl3that δ): 1,47-1,72 (m, 3H), 1,95-of 2.09 (m, 2H), 2,17-of 2.28 (m, 1H), 2,59 (t, J=7,1 Hz, 2H), 3,18-3,26 (m, 1H), 3.45 points (t, J=7,1 Hz, 2H), 3,65 (dt, J=11,1; 7.9 Hz, 1H), 3,76 (s, 2H), 3,82 (s, 3H), Android 4.04 (dd, J=9,3; 7.9 Hz, 1H), 6,83-6,91 (m, 2H), 7,20-7,25 (m, 2H).13C-NMR (CDCl3that δ): 24,4; 26,0; 27,0; 27,5; 38,9; 45,5; 47,1; 53,3; 63,3; 110,1; 120,3; 127,1; 130.3; 157,5; 160,9; 174,0. Analysis calculated for C18H24N2About3·HCl·3/2H2O: C, 54,88; N, 7,16; N, 10,67, found: C, 54,52; N, To 7.09; N, 10,52.

EXAMPLE 18:

2-[4-[2-(o-methoxyphenyl)ethylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 18.

Chromatography: ethyl acetate/hexane. Output: 25%; melting point 160-162°C (chloroform/hexane). IR (CHCl3cm-1): 3018-2899, 1770, 1709, 1495, 1443, 1418, 1244.1H-NMR (CDCl3that δ): 1,60-1,7·7 (m, 5H), 1,96-of 2.27 (m, 3H), of 2.75 (t, J=6,8 Hz, 2H), 2,92 (s, 4H), 3,15-of 3.27 (m, 1H), 3.45 points (t, J=6.6 Hz, 2H), 3,65 (dt, J=11,0; and 7.6 Hz, 1H), 3,79 (s, 3H), of 4.05 (dd, J=9,0; 7,3 Hz, 1H), 4,62 (sa, 1H), 6,80-6,89 (m. 2H), 7,13-7,22 (m, 2H).13C-NMR (CDCl3that δ): 25,6; 27,0; 27,5; 27,5; 29,7; 38,4; 45,5; 48,3; 48,7; 55,2; 63,3; 110,3; 120,5; 127,2; 127,7; 130,4; 157,5; 160,7; 173,9. Analysis calculated for C19H26N3O3·HCl·N2About: With, 57,20; N, 7,33; N, 10,53, found: C, 57,43; N, 7.03 Is; N, 10,41.

EXAMPLE 19:

2-[4-[3-(o-methoxyphenyl)Propylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 19.

Chromatography: toluene/methanol. Yield: 52%; oil. IR (CHCl3cm-1): 3018-2700, 1772, 1709, 1492, 1418, 1244.1H-NMR (CDCl3that δ): 1,0-of 1.81 (m, 5H), 1.93 and-of 2.34 (m, 5H), to 2.67 (t, J=6,8 Hz, 2H), 2,77 (m, 4H), 3,16 of 3.28 (m, 1H), 3.46 in (t, J=6.6 Hz), to 3.67 (dt, J=11,1; and 7.6 Hz, 1H, in), 3.75 (s, 3H), 4,07 (dd, J=9,3; and 7.3 Hz, 1H), for 6.81-6.90 to (m, 2H), 7,10-7,21 (m, 2H).13C-NMR (CDCl3that δ): 24,9; 25,6; 27,1; 27,5; 27,6; 27,9; 38,3; 45,6; 48,1; 48,4; 55,4; 63,4; 110,4; 120,6; 127,4; 129,3; 130,0; 157,4; 160,8; 174,0. Analysis calculated for C20H28N3About3·HCl·3/2H2O: C, 56,93; N, Of 7.64; N, to 9.93, found: C, 57,23; N, 7,21; N, 9,40.

EXAMPLE 20:

2-[4-[4-(o-methoxyphenyl)butylamine]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole, 20.

Chromatography: chloroform/methanol, and 9.5:0.5 in. Yield: 27% (oil). IR (CHCl3cm-1): 3700, 1770, 1709, 1601, 1443, 1495, 1585, 1215.1H-NMR (CDCl3that δ): 1,58-of 1.74 (m, 9H), 2,01-2,11 (m, 2H), 2,17-of 2.27 (m, 1H), 2,60 (t, J=7,3 Hz, 2H), 2,65-2,570 (m, 4H), 3,18-3,26 (m, 1H), 3.46 in (t, J=6,8 Hz, 2H). 3,66 (dt, J=11,2; and 7.6 Hz, 1H), 3,79 (s, 3H), of 4.05 (dd, J=9,0; and 7.6 Hz, 1H), 6,80-6,87 (m, 2H), 7,09-7,17 (m, 2H).13C-NMR (CDCl3that δ): 23,4; 25,2; 26,3; 27,0; 27,4; 29,6; 37,8; 45,4; 47,1; 47,8; 55,1; 63,4; 110,1; 120,3; 127,1; 129,7; 129,9; 157,2; 160,6; 173,9. Analysis calculated for C21H31N3About3·HCl·3/2H2About: With, 60,31: N, Of 7.95; N, of 10.05, found: C, 60,70; N, 7,56; N, 9,77.

EXAMPLE 21:

2-[3-[3-(o-methoxyphenyl)Propylamine]propyl]-1,3-dioxopiperazinyl[1,2-C]imidazol, 21.

Chromatography: chloroform/methanol, and 9.5:0.5 in. Yield: 27% (oil). IR (CHCl3cm-1): 3700, 1770, 1707, 1601, 1587, 1493, 1445, 1215.1H-NMR (CDCl3that δ): 1,62-to 1.86 (m, 5H), 2,02 of-2.32 (m, 3H), 2,56-to 2.67 (m, 6H), 3,24 (m, 1H), 3,54 (t, J=6,8 Hz, 2H), to 3.67 (dt, J=11,2; and 7.6 Hz, 1H), 3,81 (s, 3H), 4,06 (dd, 7=9,0; and 7.3 Hz, 1H), for 6.81-6,91 (m, 2H),7,10-7,22 (m, 2H).13C-NMR (CDCl3that δ): 26,9; 27,5; 27,8; 28,4; 30,0; 36,9; 45,5; 46,7; 49,5; 55,2; 63,3; 110,2; 120,3; 127,0; 129,8; 130,5; 157,4; 160,9; 174,0. Analysis calculated for C18H25N3About3·HCl·3H2O: C, 51,24; N, Of 7.64; N, 9,96, found: C, 51,26; N, Of 7.25; N, to 9.57.

EXAMPLE 22: Determination of the affinity for the receptor

Biochemical studies to determine the affinity of the synthesized compounds was carried out by experiments on radioligand displacement, and the experiments were carried out to determine the affinity to the receptors 5-HT1A, 5-HT2A, 5-HT3, 5-HT4, 5-HT7that α1and D2.

Conditions for each of the investigated receptor are summarized in table 1 below, while data on affinity receptors are summarized in table 2, below.

Table 1.
The conditions used to determine affinity receptors
ReceptorRadioligandClothNonspecific connectionConditions of incubation
WednesdayTemperatureTime
5-HT1A[3H]-8-OH-DPATThe cerebral cortex of rats5-HT 10 Ámol 137°15 min
5-HT2A[3N] CiancariniThe cerebral cortex of ratsCinanserin 1 Ámol237°15 min
5-HT3[3N]LY 278584The cerebral cortex of rats5-HT 10 Ámol325°30 min
5-HT4[3H]GR 113808Striatum of rats5-HT 30 Ámol437°30 min
5-HT7[3H]-5-CTThe rat hypothalamus5-HT 10 Ámol523°120 min
α1[3H] prazosinThe cerebral cortex of ratsPhentolamine 10 Ámol625°30 min
D2[3N] spiperoneStriatum of rats(±) Butaclamol 1 Ámol737°15 min
Incubation medium:
1. MgSO45 mmol and EDTA 0.5 mmol in Tris-HCl 50 mmol, pH 7.4
2. MgSO45 mmol EDTA 0.5 mmol, ascorbic acid 0.1% and pargyline 10 Ámol in Tris-HCl 50 mmol, pH 7.4
3. Pargyline 10 Ámol, ascorbic acid 0.6 mmol and CaCl25 mmol of Tris-HCl 50 mmol, pH 7.4
4. N-2-hydroxyethylpiperazine-N-2-econsultancy acid 50 mmol, pH 7.4
5. CaCl24 mmol, ascorbic acid 1 mg/ml, pargyline and 0.01 mmol (-)pindolol 3 Ámol in Tris-HCl 50 mmol, pH 7.4
6. MgCl22.5 mmol of Tris-HCl 50 mmol, pH 7.4
7. NaCl 120 mm, KCl 5 mm, CaCl21 mmol of ascorbic acid 5.7 mmol of Tris-HCl 50 mmol, PH 7.4

EXAMPLE 23: Determination of functional characteristics in vitro

The functional nature of the new compounds originally identified by examining their effects on adenylate cyclase in He-La cells, transfection human receptor 5-HT1Awith measuring their inhibitory effect on the stimulation of enzyme-induced Forskolin (table 3, below). Compounds included in this table, in all cases behave as pure agonists, to reach values close to 100% inhibition of activation-induced Forskolin. The mean effective concentration (CE50) - con who entrace, which provides 50% inhibition of the increase of enzyme activity sledstvie actions of Forskolin, were in the nanomolar range. The action of new compounds in this test was softened receptor 5-HT1Aas you can see from the blocking effect of all investigated compounds selective antagonist of 5-HT1AWAY-100635 (10-8mol).

Table 3.
Test on the adenylate cyclase in the cell He-La
Connection # CE50(nanomoles)% maximum inhibition
116,394,6
218,994,5
331,589,3
4the 11.689,6
1276,287,4

Agonistic nature in vitro of new compounds were also evaluated in some cases by checking the commit [35S]-GTPγS coronary slices of rat brain. In this test, the results obtained for the compounds No. 1 and No. 3 at a concentration of 10 Microm, were especially similar to the results obtained with 5-HT1Aprototype agonist 8-OH-DPAT. On autoradiogram increase in signal intensity was observed in hippona the PE (CA1, CA2, CA and dentate gyrus), the thalamic nuclei of cells, almond-shaped complex, cerebral cortex and nuclei mediobasal hypothalamus. The increase in the intensity of labeling in these cerebral areas were reduced to achieve reference levels when carrying out the incubation in the presence of the studied molecules and selective antagonist WAY-100635) (1 Microm) receptor 5-HT1A.

Five compounds listed in table 3, similarly created hyperpolarization potential of neurons in area CA1 of the hippocampus. As a result of performance curves "dose-effect" was observed that the effect of the compounds No. 1 and No. 2 in this test was indistinguishable by force from the action of 5-HT1Athe agonist 8-OH-DPAT.

EXAMPLE 24: the Determination of functional in vivo

All connections previously investigated in vitro as agonists 5-HT1A(table 3), were introduced by subcutaneous injection to mice in order to quantify the hypothermia associated with the promotion of this subtype serotonergic receptor. In all cases, mice were observed decrease in rectal temperature of various lengths in the range from 30 to 120 minutes. In table 4, below, shows the minimum effective dose for each investigated compound and the degree of hypothermia achieved at this dose. Maximum hypothermic the ski effect was achieved at doses of 4-8 times more than specified in table 4, and in some cases, the temperature drop was 4°C.

Table 4.
Check hypothermia in mice
Connection # The minimum effective dose(mg/kg)Hypothermic effect (°)
12,51,4
21,251,5
31,251,3
40,32,0
122,51,4

EXAMPLE 25: the Definition of neuroprotective action in vitro

Neuroprotective effect of the considered compounds were studied in experimental models in vitro using primary cultures of hippocampus of rats subjected to serum failure to toxic concentrations of glutamate or incubated in hypoxia and absence of glucose.

In the model of natural death of nerve cells induced by incubation of mixed cultures of nerve cells and glial cells for 24 hours in medium without serum, it is necessary to allocate the neuroprotective effect of compound No. 1, which was observed effects, depending on concentration, which was even pain is e (protection of over 40%), than the effect obtained with agonist 8-OH-DPAT. Other compounds were also effective, such as # 4 and # 12, although in both cases the degree of protection was slightly lower at various concentrations used in the experiments.

In the model exitotoxicity death of nerve cells due to the addition to the cultures of neural cells 1 mmol glutamate junction 1 of the most effectively prevented (37%) corresponding death. In addition, this compound showed a neuroprotective effect (>20%) in the model the death of nerve cells due to exposure to the culture of transient hypoxia in the absence of glucose and subsequent incubation in an atmosphere of 5% CO2.

EXAMPLE 26: the Definition of neuroprotective action in vivo

The neuroprotective effect was evaluated in vivo as a model of transient global ischemia in mice, gerbils, and on the model of permanent focal ischemia in rats.

In a model of transient ischemia in mice gerbils induced by temporary occlusion of both carotid arteries, the introduction of compounds No. 1 and No. 12 for 30 minutes before induction of ischemia and after 24 and 48 hours later were significantly prevented the defeat caused by ischemic process in area CA1 of the hippocampus, which was estimated by threadname spot. Neuroprotective effect was dose dependent, comprising 1-5 mg/kg and injected by subcutaneous injection, temperature is in the case of compound No. 1 degree complete protection against electric shock in about half of the animals at the dose of 5 mg/kg This protection was accompanied by a hypothermic effect is also dependent on the administered dose.

In models of focal ischemia induced by permanent occlusion of the middle artery of the big brain in rats, the introduction of compound No. 1 by intravenous injection significantly reduced the volume of necrosis area. Specifically, at the dose of 2 mg/kg the volume of necrosis was reduced by more than 25%.

1. The compound of General formula I

where R1is selected from the group consisting of H, -(CH2)3-, -(CH2)4-, -CH2-S-CH2, -S-CH2-CH2-;

R2is selected from the group consisting of N, S;

n is 0 or 1;

Z is selected from the group consisting of alkyl With2-C10;

R3is selected from the group consisting of H;

m has a value from 0 to 2;

R4is selected from the group consisting of Oh, CH2;

R5is selected from the group consisting of

where R6is selected from the group consisting of H, alkyl With1-C5-alkoxyl, HE;

W is selected from the group consisting of NH;

each "alkyl" may be linear or branched and may be cyclic or linear or branched and contain such cyclic residues and each "aryl" includes monocyclic aromatic group containing 5 to 12 carbon atoms, connected with one or more heteroatoms selected from the series N, O or S;

and their salts and solvate.

2. The compound according to claim 1, wherein R5is selected from the group consisting of

where R6is selected from the group consisting of H, C1-C5-alkoxyl, HE.

3. The compound according to claim 1, characterized in that Z is bootrom, R3is hydrogen, and R5is selected from the group consisting of

where R6is selected from the group consisting of H, C1-C5-alkoxyl, HE.

4. The compound according to claim 1, selected from

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopyrimidine[1,5-b]thiazole;

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopyrimidine[1,5-C]-thiazole;

(�B1; )-3-[4-[(chroman-2-yl)methylamino]butyl]-2,4-dioxothiazolidine;

(±)-3-[5-[(chroman-2-yl)methylamino]pentyl]-2,4-dioxothiazolidine;

(±)-3-[6-[(chroman-2-yl)methylamino]hexyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-2-yl)methylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

2-[4-[2-(naphthas-1-yl)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

3-[4-[2-(naphthas-1-yl)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-2-yl)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

2-[4-[2-(phenoxy)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

3-[4-[2-(phenoxy)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-1-oxy)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

3-[4-[2-(naphthas-1-oxy)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[3-(o-methoxyphenyl)propylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole; and

2-[4-[4-(o-methoxyphenyl)butylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole.

5. The compound according to claim 2, selected from

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopyrimidine[1,5-b]thiazole;

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopyrimidine[1,5-C]-thiazole;

(±)-3-[4-[(chroman-2-yl)methylamino]butyl]-2,4-dioxothiazolidine;

(±)-3-[5-[(chroman-2-yl)methylamino]pentyl]-2,4-dioxothiazolidine;

(±)-3-[6-[(chroman-2-yl)methylamino]hexyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-2-yl)methylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

2-[4-[2-(naphthas-1-yl)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

3-[4-[2-(naphthas-1-yl)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-2-yl)ethylamino]butyl]-1,3-dioxopiperazinyl [1,2-C]imidazole;

2-[4-[2-(phenoxy)ethylamino]butyl]-1,3-dioxopiperazinyl [1,2-C]imidazole;

3-[4-[2-(phenoxy)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-1-oxy)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

3-[4-[2-(naphthas-1-oxy)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[3-(o-methoxyphenyl)propylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole; and

2-[4-[4-(o-methoxyphenyl)butylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole.

6. The compound according to claim 3, selected from

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopiperazinyl [1,2-C]imidazole;

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopyrimidine[1,5-b]thiazole;

(±)-2-[4-[(chroman-2-yl)methylamino]butyl]-1,3-dioxopyrimidine[1,5-C]-thiazole;

(±)-3-[4-[(chroman-2-yl)methylamino]butyl]-2,4-dioxothiazolidine;

(±)-3-[5-[(chroman-2-yl)IU is ylamino]pentyl]-2,4-dioxothiazolidine;

(±)-3-[6-[(chroman-2-yl)methylamino]hexyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-2-yl)methylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

2-[4-[2-(naphthas-1-yl)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

3-[4-[2-(naphthas-1-yl)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-2-yl)ethylamino]butyl]-1,3-dioxopiperazinyl [1,2-C]imidazole;

2-[4-[2-(phenoxy)ethylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole;

3-[4-[2-(phenoxy)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[2-(naphthas-1-oxy)ethylamino]butyl]-1,3-dioxopiperazinyl [1,2-C]imidazole;

3-[4-[2-(naphthas-1-oxy)ethylamino]butyl]-2,4-dioxothiazolidine;

2-[4-[3-(o-methoxyphenyl)propylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole; and

2-[4-[4-(o-methoxyphenyl)butylamino]butyl]-1,3-dioxopiperazinyl[1,2-C]imidazole.

7. A method of obtaining a compound according to any one of claims 1 to 6, characterized in that the intermediate halogenated derivatives II are produced by the reaction, where L denotes Cl, Br, with suitable amines III in acetonitrile within 6-24 hours at a temperature of 60°according to scheme I, reaction

where the definition of R1, R2n, Z, m, R4and R5this scheme is described in claims 1 to 6.

8. Pharmaceutical composition having neuropro the active activity characterized in that it contains a therapeutically effective amount of any of the compounds defined in the preceding claims 1 to 6, together with a pharmaceutically acceptable carrier or excipient.

9. The use of compounds according to any one of preceding claims 1 to 6 for the manufacture of a medicinal product for the treatment and/or prevention of pathological conditions in which it is shown agonists of the receptor 5-HT1A.

10. The use of compounds according to any one of preceding claims 1 to 6 for the manufacture of a medicinal product for the treatment and/or prevention of cerebral disorders caused thromboembolic attack or traumatic brain injuries.



 

Same patents:

FIELD: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds of formula I , or stereoisomers, or pharmaceutically acceptable salts thereof, wherein Q is SO2; n = 2 or 3; each R1 and R2 is independently H, halogen, OR22 or C1-C6-alkyl; each R3 and R4 is H; each R5 and R6 is independently H or C1-C6-alkyl optionally substituted with phenyl or R5 and R6 together with together with atom to which they are attached may form 5-7-membered ring optionally containing N as the second heteroatom optionally substituted with COOH or C1-C6-alkyl; R7 is H; R7 is optionally substituted 8013-membered bicyclic or tricyclic ring system, containing N in bridge bond and optionally 1, 2 additional heteroatoms selected from N, S wherein substituent represent 1 or 2 halogen atoms; R22 is H or C1-C6-phenyl optionally substituted with C1-C6-alkyl. Compounds of present invention specifically bond to 5-HT6 receptor and are useful in pharmaceutical compositions.

EFFECT: compounds with specific bonding to 5-HT6 receptor.

10 cl, 3 tbl, 45 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to bicyclic 1,4-piridotiazine-1,1-dioxides of general formula I wherein R1 is chlorine or fluorine; R2 is linear or branched alkyl, cycloalkyl, optionally reduced aryl or heteroaryl, etc. Method for production of said compounds includes reaction of acyclic sulfones with primary alcohols, preferably in presence of inorganic or organic such as carbonates or alkali metal hydroxides tertiary organic amines or base mixtures, preferably in aprotic bipolar media without solvents, or mixture thereof with water.

EFFECT: safe method for production of new compounds useful as drugs.

2 cl, 2 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, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole of formula useful in liver protection from poisoning with carbon tetrachloride. Said compound has boiling point of 174-175°C (decomposition) and LD50 of 1950±180 mg/kg. Method for production of claimed compound also is disclosed.

EFFECT: new compound for liver protection from poisoning with carbon tetrachloride.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the general formula (I): wherein R0 represents hydrogen atom; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and each represents independently hydrogen atom, halogen atom, perhalogenalkyl, substituted or unsubstituted groups, such as linear or branched (C1-C12)-alkyl, (C3-C7)-cyclaoalkyl, (C1-C12)-alkoxy, cyclo-(C3-C7)-alkoxy group, hydroxyalkyl; R13 and R14 can be similar or different and each represents independently hydrogen atom, substituted or unsubstituted groups, such as linear or branched (C1-C4)-alkyl, (C3-C7)-cycloalkyl, optionally, R13 and R14 in common with nitrogen atom can form 5-6-membered heterocyclic ring wherein heterocycle can be substituted also, and it can comprise one, two or three double bonds or "additional heteroatoms" chosen from nitrogen atom (N); "n" means a whole number in the range 1-6, and pharmaceutical compositions based on its. Indicated compounds are ligands of 5-HT (serotonin) and can be used in treatment in cases if modulation of activity of 5-HT and melatonin is desirable.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

21 cl, 31 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to novel hydrogenated pyrrolo[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers, pharmaceutically acceptable salts and/or hydrates that can be used, for example, in treatment and prophylaxis of different neurodegenerative diseases, such as Alzheimer's syndrome. In the general formula (1): a dotted line with accompanying unbroken line represents ordinary or double bond; R1 and R2 represent independently of one another substitutes of amino group chosen from hydrogen atom, possibly substituted (C1-C6)-alkyl substituted possibly with aryl, possibly substituted phenyl, possibly substituted carbonylamino or thiocarbonylamino group, substituted acyl, possibly substituted aryl sulfonate wherein substituted in indicated R1 and R2 are chosen from (C1-C6)-alkyl, halogen atoms, nitro, carboxy, alkoxy group, aryl; R1n represents one or some similar or different substituted of cyclic system chosen from hydrogen atom, alkyl, aryl, cyano group, halogen atom, 5-6-membered nitrogen-containing heteroaryl. Also, invention relates to methods for synthesis of these compounds, pharmaceutical compositions and their using, and to using compounds in libraries with their using.

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

20 cl, 2 tbl, 12 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to 1,4,5,6-tetrahydro-6-oxo-5-(2-piperazinoethyl)-4-phenyl-3-(4-chlorophenyl)pyrrolo[3.4]pyrazole dihydrochloride of the formula (I): . This compound is synthesized by interaction of 1-(2-piperazinoethyl)-5-phenyl-4-(4-chlorobenzoyl)-3-hydroxy-3-pyrrolin-2-one dihydrochloride with hydrazine hydrate. Synthesized compound can be used in medicine as agent decreasing arterial blood pressure and blood coagulation. Invention provides synthesis of a novel compound not described early that possesses hypotensive and anti-coagulant effect simultaneously.

EFFECT: valuable medicinal properties of compound.

3 tbl, 1 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

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

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): or their pharmaceutically acceptable salts possessing the inhibitory effect on activity of tyrosine kinase. Proposed compounds can be used in treatment of proliferative disease, such as tumor. In the formula (I) each R1 and R2 means independently of one another hydrogen atom, methyl, ethyl, isopropyl, hydroxyethyl, piperidine-1-ylmethylcarbonyl, pyrrolidine-1-ylmethylcarbonyl, morpholine-4-ylmethylcarbonyl, 4-methylpiperazine-1-ylmethylcarbonyl, N,N-dimethylaminomethylcarbonyl, 4-ethylpiperazine-1-ylmethylcarbonyl, piperidine-1-ylethylcarbonyl, N,N-diethylaminoethylcarbonyl, N,N-dimethylaminopropylcarbonyl, 2-pyridylcarbonyl, tetrahydropyrane-4-yl, morpholine-4-ylethyl, N,N-diethylaminoethyl, tert.-butyl; or R1 and R2 in common with nitrogen atom to which they are bound form 4-ethylpiperazine-1-yl, pyrrolidine-1-yl, 4-methylpiperazine-1-yl, piperidine-1-yl, morpholine-4-yl, 3,5-dimethylpiperazine-1-yl; R3 is chosen from 3-chloro-4-fluorophenyl, phenyl, 4-benzyloxyphenyl, 3-hydroxy-4-methylphenyl, 3-hydroxy-4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,5-dichlorophenyl, 3-methoxyphenyl, benzo[1,3]dioxol-5-yl, 6-methoxypyridine-3-yl, 2-methoxypyridine-4-yl, pyridine-2(1H)-one-5-yl, pyridine-2(1H)-one-4-yl, 3-methoxyphenyl, 3-methylphenyl, pyridine-2(1H)_one-4-yl; G means -CH2-; Q means -NH-; X absents or means -CH(CH3)-, -CH2- under condition that if X absents then R3 is bound by ring carbon atom. Also, invention relates to variants of methods for synthesis of compounds of the formula (I), preparing a pharmaceutical composition and using compounds proposed.

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

13 cl, 147 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): that are antagonists of CRF receptors and wherein Ar means optionally substituted phenyl or monocyclic 6-membered heteroaryl comprising one heteroatom chosen from nitrogen, oxygen or sulfur atoms; R1-R4 have values given in the invention claim, or to their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of indicated compounds and to pharmaceutical compositions containing these compounds that are useful for administration to a patient suffering from diseases that are relived in therapy using antagonists of CRF receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 tbl, 17 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of 1-[(indole-3-yl)carbonyl]piperazine of the formula (I): wherein R means substitute chosen from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkyloxy-group (optionally substituted with halogen atom), halogen atom, -OH, -NH2, -CN and -NO2; R1 means (C5-C8)-cycloalkyl or (C5-C8)-cycloalkenyl; R2 means H, methyl or ethyl; radicals R3, R'3, R4, R'4, R5, R'5 and R'6 means independently hydrogen atom or (C1-C4)-alkyl optionally substituted with halogen atom or -OH; R6 means hydrogen atom or (C1-C4)-alkyl optionally substituted with (C1-C4)-alkoxy-group or halogen atom; or R6 in common with R7 forms 5-6-membered saturated heterocyclic ring; R7 means H, (C1-C4)-alkyl optionally substituted with -OH, halogen atom or (C1-C4)-alkoxy- group, or (C3-C5)-cycloalkyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) possess agonistic activity with respect to CB1 receptors. Also, invention describes pharmaceutical composition possessing agonistic activity with respect to CB1 receptors and using compound of the formula (I) for preparing a drug used in pain treatment.

EFFECT: valuable medicinal and pharmacological properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 21 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

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

SUBSTANCE: invention describes novel derivatives of triazolo[4,5-d]pyrimidine of the general formula (I): wherein R1 means (C3-C5)-alkyl that can be substituted with halogen atom; R2 means phenyl that can be substituted with fluorine atom; R3 and R4 are similar and mean hydroxy-group; R means XOH wherein X means -CH2, -OCH2CH2 or a bond, or their pharmaceutically acceptable salt or solvate of solvate of such salt under condition that when X means -CH2 or a bond then R1 doesn't mean propyl group; when X means -CH2 and R1 means -CH2CHCF3, butyl or pentyl groups then phenyl group at R2 must be substituted with fluorine atom; when X means -OCH2CH2 and R1 means propyl then phenyl group at R2 must be substituted with fluorine atom. Also, invention describes a pharmaceutical composition based on these compounds, method for their synthesis and novel intermediate compounds of the formula (II) , (V) and R-(R*,R*)-2,3-dihydroxybutanedioate (1:1) of compound of the formula (III): . Also, invention relates to a method for treatment of diseases mediated by P2T-receptors, such as myocardium infarction, prophylaxis or propagation of tumors and others.

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

15 cl, 9 ex

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

SUBSTANCE: invention relates to novel hydrogenated azepino[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers and their pharmaceutically acceptable salts and/or hydrates. In the general formula (1) a dotted line with accompanying unbroken line represents a simple or double bond; R1 and R2 represent independently of one another substitutes of amino-group chosen from hydrogen atom, possibly substituted (C1-C8)-alkyl possibly substituted with aryl, 5-6-membered azaheterocyclyl, (C1-C8)-alkoxycarbonyl, possibly substituted phenyl, possibly substituted carbonylamino- or thiocarbonylamino-group, substituted acyl, (C1-C8)-alkylsulfonyl, possibly substituted arylsulfonyl and wherein substitutes in indicated R1 and R2 are chosen independently from (C1-C8)-alkyl, halogen atoms, nitro-, carboxy-, alkoxy-group, aryl; Rin represents one or some similar or different substitutes of cyclic system chosen from hydrogen atom, (C1-C8)-alkyl, (C6-C10)-aryl, halogen atom, 5-6-membered azaheterocyclyl. Also, invention relates to methods for synthesis of these compounds, their using and pharmaceutical composition and libraries of compounds. Synthesized compounds possess neuroprotective, cognitive-stimulating and anti-histaminic properties and can be used in treatment of different neurological disorders, allergic and autoimmune diseases, for example, for memory improvement.

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

25 cl, 2 tbl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

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