Phenothiazine-containing 1,2,3,4-tetrahydropyrido[4,3-b]indole derivatives as agent for reducing uncontrolled protein aggregation in nervous system, methods for production thereof, pharmacological agent based thereon and method of reducing uncontrolled protein aggregation in nervous system

FIELD: chemistry.

SUBSTANCE: invention relates to phenothiazine-containing 1,2,3,4-tetrahydropyrido[4,3-b]indole derivatives of general formula 1 and hydrochlorides thereof as an agent for reducing uncontrolled protein aggregation in the nervous system, methods for production thereof, a pharmacological agent based thereon and a method of reducing uncontrolled protein aggregation in the nervous system. In general formula 1: R1=H, (C1-C6)alkyl; R2, R3, R4, R5=H, F, O, Br, (C1-C6)alkyl, (C1-C6)alkoxy, R6, R7= H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2, A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2); CH2CH[((C1-C6)alkyl]C(O)N[(C1-C6))alkyl]CH2CH2), CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: improved properties of derivatives.

9 cl, 2 tbl, 11 dwg

 

The invention relates to the use of chemical compounds in the field of medicine and can be used as a tool in the manufacture of pharmaceutical preparations for the prevention and treatment of neurodegenerative diseases.

Uncontrolled aggregation of certain types of proteins is a key element in the development of neurodegenerative processes underlying the pathogenesis of many neurodegenerative diseases. Accumulation in the nervous system of various intermediate oligomers, protofibrils) and end (fibrillar and amorphous deposits) products, many of which have cytotoxic properties, leading to functional disturbances and, ultimately, to the death of neurons. This type of pathology, called proteopathy, joined in one group of neurological disorders with significantly different clinical manifestations of pathology [Shelkovnikova T.A., Kulikova A.A., Tsvetkov FO, Peter O., Bachurin C.O., Buchman, V.L., Ninkina NN. (2012). Proteinopathy forms of neurodegenerative diseases based on pathological aggregation of proteins. Molecular biology. So 46, No. 3. From:402-415; Shelkovnikova T.A., Ustyugov A.A., Smirnov A.P., V.I. Skvortsova, Buchman, V.L., Bachurin C.O., Ninkina NN. Mutations in the FUS gene associated with hereditary forms of amyotrophic lateral SCR is rose, affect the cellular localization of the encoded protein and its ability to aggregation. DAN, 2011, CH, No. 3, S-426]. In this group of diseases includes such widespread and currently incurable neurodegenerative disorders like Alzheimer's disease (ad), Parkinson's (BP), amyotrophic lateral sclerosis (als), frontotemporal dementia (FTD). To proteinopathy include hereditary diseases, such as Huntington's chorea, as well as a wide group Pranovich diseases.

It is considered that the probable cause of the development of Alzheimer's disease, which is the most common neurodegenerative disease, is associated with the formation of pathological aggregates of Tau protein, forming neurofibrillary tangles and amyloid plaques [M.G. Spillantini and Goedert M. Tau protein pathology in neurodegenerative diseases Trends Neurosci. (1998) 21, 428-433].

Still the treatment of proteinopathy is mainly symptomatic, because not developed effective means, directly affecting the pathogenic process underlying the disease.

Currently, the uncontrolled aggregation of proteins is considered as one of the most important targets to create a new generation of therapeutics that will allow you to modify the processes underlying the development of neurodegeneration, and t is m the slow course of the disease or even to stop the pathological process [J.S. Jacobsen, Reinhart P., M.N. Pangalos NeuroRX. 2005. vol. 2(4). p: 612-626; L.C. Walker, Ibegbu CC, Todd CW, Robinsona H.L., Juckere M., LeVine H 3rd, Gandy S. Biochemical Pharmacology. 2005. vol.69. p:1001-1008; Christensen D.D. CNS Spectrums. 2007. vol.12. p:113-123].

It is known that the derived gamma carboline - domestic antihistamine drug Dimebon, shows the ability to block uncontrolled aggregation of some proteins in the nervous system, which is closely associated with the development of a wide range of neurodegenerative diseases. Thus, it was demonstrated that Dimebon selectively inhibits protein aggregation gamma synuclein involved in the pathogenesis of BASS [S.O. Bachurin, A.A. Ustyugov, O. Peter, T.A. Shelkovnikova, V.L. Buchman, NN. Ninkina. Blockade of neurodegenerative processes caused by proteopathy, as a new mechanism of action of neuroprotective and cognitive-stimulating drugs. DAN, 2009, 428(2), 262-265; A.A. Ustyugov, T.A. Shelkovnikova, V.S. Kokhan, I.V. Khritankova, O. Peters, V.L. Buchman, Bachurin S.O., and N.N. Ninkina (2012) Dimebon Reduces the Levels of Aggregated Amyloidogenic Protein Forms in Detergent-Insoluble Fractions In Vivo. Bulletin of Experimental Biology and Medicine, Vol.152, No.6, p.731-733; Bachurin S.O., Shelkovnikova T.A., Ustyugov A.A., Peters O., Khritankova I., Afanasieva M.A., Tarasova T.V., Alentov I.I., Buchman V.L., Ninkina, N. (2012) Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice. Neurotoxicity Research 22(1), 33-42]. However Dimebon had no effect on pathological processes associated with the system of alpha-synuclein [Shelkovnikova T.A., Ustyugov A.A., Millership S., Peters O., Anichtchik O., M.G. Spillantini, Buchman V.L., Bachurin S.O., Ninkina N.N. Dimebon does not ameliorate the pathological changescaused by expression of truncated (1-120) human alpha-synuclein in dopaminergic neurons of transgenic mice. Neurodegenerative Diseases. 2011. T.8, No. 6. P.430-437]. Found that Dimebon is able to improve the condition of the experimental animals with genetically caused increased formation of Tau aggregates characteristic pathological formations in BA [Peters O.M., Connor-Robson N., Sokolov V.B., Aksinenko A.Y., Kukharsky M.S., Bachurin S.O., Ninkina Annalisa Buchman V.L. Chronic administration of dimebon ameliorates pathology in TauP301S transgenic mice. J. Alzheimers Dis. 2013; 33(4): 1041-9].

Recently it was demonstrated that Dimebon may also reduce the formation of pathological aggregates of the protein TDP-43 associated with the development of the BASS and FTD. Moreover, this effect is increased by the simultaneous introduction of Dimebon and drug - methylene blue belonging to the group of derivatives fenotiazina [Makiko Yamashita, Takashi Nonaka, Fuyuki Kametani, Tetsuaki Arai, Haruhiko Akiyama, Vladimir L. Buchman, Natalia Ninkina, Sergey O. Bachurin, Shahin Zibaee, Michel Goedert, Masato Hasegawa. Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Letters, 2009. 583 (2009) 2419-2424]. Many works in recent years shows that methylene blue effectively blocks the development of pathologies associated with the aggregation of the Tau protein, which is important in terms of therapy BA [Congdon E.E., J.W. Wu, Myeku N., Figueroa Y.H., Herman M., Marinec P.S., J.E. Gestwicki, Dickey C.A., W.H. Yu, Duff K.E. Methylthioninium chloride (methylene blue) dosage autophagy and attenuates tauopathy in vitro and in vivo. Autophagy. 2012 Apr;8(4):609-22; Oz m, Lorke D.E., Hasan M., Petroianu GA Cellular and molecular actions of Methylene Blue in the nervous system. Med. Res. Rev. 2011 Jan; 31(1):93-117].

The present invention solves the problem of expansion of the ar is anal funds which can be used as a new effective protectors that protect nerve cells from the formation of abnormal protein aggregates associated with neurodegenerative processes in the Central and peripheral nervous system.

This goal is achieved by applying the following fenotiazinas 1,2,3,4-tetrahydropyrido[4,3-b]indoles of General formula 1 and their clorhidrato as a means for reducing uncontrolled aggregation of proteins in the nervous system.

in which R1=H, (C1-C6)alkyl;

R2, R3, R4, R5=H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy,

R6, R7=H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2;

A=CH2CH2CH=CHCH2CH2CH2CH2CH2CH[(C1-C6)alkyl]C(O)CH2CH2C(O)NHCH2CH2); CH2CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2), CH2CH(OH)CH2CH2CH(OH)CH2NHCH2CH2CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2CH2CHFCH2NHCH2CH2CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido[4,3-b]indoles movetreestate the compounds of General formula 1.1

in which R1, R2, R3, R4, R5, R6, R7have the meanings given above for formula 1;

X=CH2CH2CH=CHCH2CH2CH2CH2CH2CH[(C1-C6)alkyl]C(O)CH2CH2C(O)NHCH2CH2); CH2CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2).

Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido [4,3-b] indoles can also be a compound of General formula 1.2

in which R1, R2, R3, R4, R5, R6, R7have the meanings given above for formula 1;

Y=CH2CH(OH)CH2CH2CH(OH)CH2NHCH2CH2,

CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2.

Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido [4,3-b] indoles can also be a compound of General formula 1.3

in which R1, R2, R3, R4, R5, R6, R7have the meanings given above for formula 1;

Z=CH2CHFCH2NHCH2CH2or

CH2CHFCH2N[(C1-C6)alkyl]CH2CH2,

Another aspect of the invention are methods of producing compounds of the formula 1.1, formulas .2, formula 1.3, as well as their clorhidrato.

Method of producing compounds of the formula 1.1 is that equinology a mixture of gamma-carbolines, which General formula 2

in which R1, R2, R3, R4, R5have the meanings defined above for formula 1;

and acetylisoniazid fenotiazinas General formula 3,

or vinylsamurais fenotiazinas General formula 4,

in which R6, R7have the meanings given above for formula 1;

W=(CH2)nwhere n=0 or 1; C(O); CH[(C1-C6)alkyl]C(O); C(O)NHCH2CH2); C(O)N[(C1-C6)alkyl]CH2CH2; CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2),

heated in dimethyl sulfoxide or dimethylformamide in the presence of a catalyst selected from the range: sodium methylate, tert-butyl potassium, potassium hydroxide or cesium fluoride at a temperature of 120-160°C for 6-24 hours.

The method of obtaining compounds 1.2 is that equinology a mixture of gamma-carbolines, which General formula 2

in which R1, R2, R3, R4, R5have the meanings defined above for formula 1;

and N-epoxydodecane fenotiazinas General formula 5

in which R6, R7have the meanings given above for formula 1;

D=CH2; CH2NHCH2CH2; CH2N[(C1-C6)alkyl]CH2CH2

heated in dimethyl sulfoxide or dimethylformamide in the presence of a catalyst selected from the range: sodium methylate, tert-butyl potassium, potassium hydroxide or cesium fluoride at a temperature of 100-140°C for 2-12 hours.

The method of obtaining compounds 1.3 is that hydroxycobalamin conjugates gamma CARBONYLS and fenotiazinas General formula 6

in which R1, R2, R3, R4, R5, R6, R7have the meanings given above for formula 1;

E=CH2; CH2NHCH2CH2; CH2N[(C1-C6)alkyl]CH2CH2.

foryouth equimolar number of diethylaminosulfur (Et2NSF3) in dimethyl sulfoxide or dimethylformamide at temperatures (-78)-0°C for 1-3 hours.

The method of producing clorhidrato any of the compounds of formulas 1.1, 1.2, 1.3 consists in dissolving the respective compounds of formulas 1.1, 1.2, 1.3 10%solution of HCl in isopropanol.

Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido [4,3-b] indoles of General formula 1, having the claimed properties, obtained by conjugation indole and fanatics the new components, relevant to the claimed composition and the United claimed through a molecular spacer. Synthetic methods for preparing compounds of formula 1 are four General groups, illustrated with examples.

These examples suggest, but do not limit the invention.

The synthesis of compounds of the formula 1.1 (General method)

The process is carried out by heating equimole mixture of gamma-carbolines, which 2 and acetylisoniazid fenotiazinas 3 (scheme 1) or vinylsamurais fenotiazinas 4 (scheme 2) in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) in the presence of a catalyst selected from the range: sodium methylate (MeONa), tert-butyl potassium (tert.-BuOK), potassium hydroxide (KOH) and cesium fluoride (CsF) at a temperature of 120-160°C for 6-24 hours.

Scheme 1.

R1=H, (C1-C6)alkyl;

R2, R3, R4, R5= H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy,

R6, R7=. H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2;

kat=MeONa, tert.-BuOK), KOH, CsF

Scheme 2.

R1=H, (C1-C6)alkyl;

R2, R3, R4, R5=H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy,

R6, R7=. H, F, Cl, Br, (C1-C6)alkyl, (C1 -C6)alkoxy, NH2, NHAlkyl, NAlkyl2;

W= no, CH2; CH[(C1-C6)alkyl]C(O); C(O)NHCH2CH2); C(O)N[(C1-C6)alkyl]CH2CH2; CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2),

X=CH2CH2CH2CH2CH2CH2CH[(C1-C6)alkyl]C(O)CH2CH2C(O)NHCH2CH2); CH2CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2).

kat= MeONa, tert.-BuOK), KOH, CsF

Example 1: a Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-allyl] - N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (I).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and 1 mmol of N,N,N,N-tetramethyl-10-prop-2-inyl-10H-phenothiazines-3,7-diamine. As the catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 140-160°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 82%. An NMR spectrum1H (CDCl3) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH2, J=6.4 Hz); 2.70-2.86 (m 4H, CH2); 2.94 (s, 12H, Me); 3.64 (2H, CH2); 6.3 (d, 1H, CH=, J=12.2 Hz), 6.5 (m, 1H, CH=), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H) 7.30 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=2.2 Hz).

Example 2: a Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-allyl]-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (I).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 1 mmol of substituted N,N,N,N-tetramethyl-10-prop-2-inyl-10H-phenothiazines-3,7-diamine as a catalyst took 300 mg of MeONa in 1.5 ml DMF. Was heated under stirring at 130-140°C for 8 hours and Then DMF was removed in vacuum of 3 mm RT. Art. of residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 78%. An NMR spectrum1H (CDCl3) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH2, J=6.4 Hz); 2.70-2.86 (m 4H, CH2); 2.94 (s, 12H, Me); 3.64 (2H, CH2); 6.3 (d, 1H, CH=, J=12.2 Hz), 6.5 (m, 1H, CH=), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H) 7.30 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=2.2 Hz).

Example 3: the Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-allyl]-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (I).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol N,N,N,N-tetramethyl-10-prop-2-inyl-10H-phenothiazines-3,7-diamine as a catalyst took the 300 mg of tert.-BuOK in 1.5 ml of DMSO. Was heated under stirring at 120-130°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 80%. An NMR spectrum1H (CDCl3) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH2, J=6.4 Hz); 2.70-2.86 (m 4H, CH2); 2.94 (s, 12H, Me); 3.64 (2H, CH2); 6.3 (d, 1H, CH=, J=12.2 Hz), 6.5 (m, 1H, CH=), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H) 7.30 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=2.2 Hz).

Example 4: Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-allyl]-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (I).

As starting substances took 1 Mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmole of N,N,N,N-trimethyl-10-prop-2-inyl-10H-phenothiazines-3,7-diamine as a catalyst took 100 mg of KOH in 1.5 ml of DMF was heated under stirring at 120-140°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. Yellow solid, yield: 79%. An NMR spectrum1H (CDCl3) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH2, J=6.4 Hz); 2.70-2.86 (m 4H, CH2); 2.94 (s, 12H, Me); 3.64 (2H, CH2); 6.3 (d, 1H, CH=, J=12.2 Hz), 6.5 (m, 1H, CH=), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H) 7.30 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=2.2 Hz).

Example 5: the Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-ethyl]N,N,N,N-tetramethyl-10H-Phenothiazines-3,7-diamine (II).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 10-allyl-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine as a catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 140-150°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 86%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH2, J=6.4 Hz); 2.60-2.86 m (6H, CH2); 2.96 (s, 12H, Me); 3.64 (2H, CH2); 3.68 (t, 2H, J=6.5 Hz), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H), 7.31 (d, 2H, J=8.8 Hz), 7.55 (d, 2H, J=2.2 Hz).

Example 6: the Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)ethyl]-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (II).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 10-allyl-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine as a catalyst took 300 mg of MeONa in 1.5 ml DMF. Heat the Ali under stirring at 150-160°C for 8 hours DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 82%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH2, J=6.4 Hz); 2.60-2.86 m (6H, CH2); 2.96 (s, 12H, Me); 3.64 (2H, CH2); 3.68 (t, 2H, J=6.5 Hz), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H), 7.31 (d, 2H, J=8.8 Hz), 7.55 (d, 2H, J=2.2 Hz).

Example 7: a Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-ethyl]-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (II).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 10-allyl-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine, 300 mg of tert.-BuOK in 1.5 ml of DMSO. Was heated under stirring at 140-150°C for 18 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform = 1/5. The resulting product is a yellow solid, yield: 85%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH2, J=6.4 Hz); 2.60-2.86 m (6H, CH2); 2.96 (s, 12H, Me); 3.64 (2H, CH2); 3.68 (t, 2H, J=6.5 Hz), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H), 7.31 (d, 2H, J=8.8 Hz), 7.55 (d 2H, J=2.2 Hz).

Example 8: the Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-ethyl]-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (II).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 10-allyl-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine as a catalyst took 100 mg of KOH in 1.5 ml DMF. Was heated under stirring at 150-160°C for 12 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 78%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH2, J=6.4 Hz); 2.60-2.86 m (6H, CH2); 2.96 (s, N, Me); 3.64 (2H, CH2); 3.68 (t, 2H, J=6.5 Hz), 6.70-7.00 (m, 3H), 7.00-7.25 (m, 2H), 7.31 (d, 2H, J=8.8 Hz), 7.55 (d, 2H, J=2.2 Hz).

Example 9: a Method of obtaining 4-(2-Methyl-1,2,3,4-tetrahydro-pyrido[43-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (III).

As starting substances took 1 mmol of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 120-140°C for 20 h DMSO was removed in vacuum of 3 mm Hg, from about the TATKO the product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 83%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeN); 2.68 (s, 6H, CH2); 3.49 (s, 2H, CH2); 4.17 (ush. s, 2H, CH2); 6.67-6.95 (m, 8H, CHAr); 7.00-7.16 (m, 4H, CHAr).

Example 10: the Method of obtaining 4-(2-Methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (III).

As starting substances took 1 mmol of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of MeONa in 1.5 ml of DMSO. Was heated under stirring at 120-140°C for 11 hours DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. Yellow solid, yield: 80%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeN); 2.68 (s, 6H, CH2); 3.49 (s, 2H, CH2); 4.17 (ush. s, 2H, CH2); 6.67-6.95 (m, 8H, CHAr); 7.00-7.16 (m, 4H, CHAr).

Example 11: a Method of obtaining 4-(2-Methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (III).

As starting substances took 1 mmol of 2-methyl-2,3,4,5-tetrahydro what-1H-pyrido[4,3-b]indole, 1 mmol of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of tert.-BuOK in 1.5 ml DMF. Was heated under stirring at 120-130°C for 6 hours, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. Yellow solid, yield: 81%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeN); 2.68 (s, 6H, CH2); 3.49 (s, 2H, CH2); 4.17 (ush. s, 2H, CH2); 6.67-6.95 (m, 8H, CHAr); 7.00-7.16 (m, 4H, CHAr).

Example 12: a Method of obtaining 4-(2-Methyl-1.2.3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (III).

As starting substances took 1 mmol of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 100 mg of KOH in 1.5 ml DMSO was heated under stirring at 130-140°C for 10 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 79%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeN); 2.68 (s, 6H, CH2); 3.49 (s, 2H, CH2); 4.17 (ush. s, 2H, CH); 6.67-6.95 (m, 8, CHAr); 7.00-7.16 (m, 4H, CHAr).

Example 13: a Method of obtaining 4-(2-Ethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (IV).

As starting substances took 1 mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 120-140°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 88%. An NMR spectrum1H (CDCl3) δ ppm: 1.12 (t, 3H, J=6.7, Me); 2.49 (K, 2H, J=6.7, MeCH2); 2.65 (m, 6H, CH2); 3.46 (s, 2H, CH2); 4.09 (ush. s, 2H, CH2); 6.62-6.82 (m, 8H, CHAr); 6.90-7.05 (m, 4H, CHAr).

Example 14: the Method of obtaining 4-(2-Ethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (IV).

As starting substances took 1 Mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmole of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of MeONa in 1.5 ml DMF. Was heated under stirring at 140-150°C for 6 hours, the DMF was removed in vacuum of 3 mm Hg, the residue product extrage is ovali methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 83%. An NMR spectrum1H (CDCl3) δ ppm: 1.12 (t, 3H, J=6.7, Me); 2.49 (K, 2H, J=6.7, MeCH2); 2.65 (m, 6H, CH2); 3.46 (s, 2H, CH2); 4.09 (ush. s, 2H, CH2); 6.62-6.82 (m, 8H, CHAr); 6.90-7.05 (m, 4H, CHAr).

Example 15: the Method of obtaining 4-(2-Ethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (IV).

As starting substances took 1 mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of tert.-BuOK in 1.5 ml of DMSO. Was heated under stirring at 120-130°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 81%. An NMR spectrum1H (CDCl3) δ ppm: 1.12 (t, 3H, J=6.7, Me); 2.49 (K, 2H, J=6.7, MeCH2); 2.65 (m, 6H, CH2); 3.46 (s, 2H, CH2); 4.09 (ush. s, 2H, CH2); 6.62-6.82 (m, 8H, CHAr); 6.90-7.05 (m, 4H, CHAr).

Example 16: a Method of obtaining 4-(2-Ethyl-1,2,3,4-tetrahydro-pyrido[4.3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (IV).

As starting substances took 1 mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 100 mg of KOH in 1.5 ml DMF. Was heated under stirring at 130-140°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 77%. An NMR spectrum1H (CDCl3) δ ppm: 1.12 (t, 3H, J=6.7, Me); 2.49 (K, 2H, J=6.7, MeCH2); 2.65 (m, 6H, CH2); 3.46 (s, 2H, CH2); 4.09 (ush. s, 2H, CH2); 6.62-6.82 (m, 8H, CHAr); 6.90-7.05 (m, 4H, CHAr).

Example 17: a Method of obtaining 4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-it (V).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 120-130°C for 12 h of DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The product made is the focus of a yellow solid, yield: 85%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 6N, CHAr); 7.36-7.47 (m, 3H, CHAr).

Example 18: a Method of obtaining 4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-it (V).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of MeONa in 1.5 ml of DMSO. Was heated under stirring at 120-130°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 83%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 6H, CHAr); 7.36-7.47 (m, 3H, CHAr).

Example 19: a Method of obtaining 4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-it (V).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-]indole, 1 mmol of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of tert.-BuOK in 1.5 ml DMF. Was heated under stirring at 120-140°C for 8 h DMSO (or DMF) was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 84%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 6H, CHAr); 7.36-7.47 (m, 3H, CHAr).

Example 20: the Method of obtaining 4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-it (V).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 100 mg of KOH in 1.5 ml DMF. Was heated under stirring at 140-150°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield:80%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 6H, CHAr); 7.36-7.47 (m, 3H, CHAr).

Example 21: a Method of obtaining 4-(8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-it (VI).

As starting substances took 1 mmol of 8-methyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 120-130°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 84%. An NMR spectrum1H (CDCl3) δ ppm: 1.21 (t, 3H, J=7.1, MeCH2); 2.42 (s, 3H, MeC); 2.65 (K, 2H, J=6.7, MeCH2); 2.80 (m, 6H, CH2); 3.65 (s, 2H, CH2); 4.32 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.4, CH2); 7.00 (d, 1H, J=8.4, CHAr); 7.08-7.28 (m, 7H, CHAr); 7.33-7.44 (m, 2H, CHAr).

Example 22: a Method of obtaining 4-(8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-it

As starting substances took 1 mmol of 8-methyl-2-the Teal-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of MeONa in 1.5 ml of DMSO. Was heated under stirring at 130-140°C for 8 h DMSO (or DMF) was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 81%. An NMR spectrum1H (CDCl3) δ ppm: 1.21 (t, 3H, J=7.1, Mesn2); 2.42 (s, 3H, MeC); 2.65 (K, 2H, J=6.7, MeCH2); 2.80 (m, 6H, CH2); 3.65 (s, 2H, CH2); 4.32 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.4, CHAr); 7.00 (d, 1H, J=8.4, CHAr); 7.08-7.28 (m, 7H, CHAr); 7.33-7.44 (m, 2H, CHAr).

Example 23: a Method of obtaining 4-(8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (IV).

As starting substances took 1 mmol of 8-methyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of tert.-BuOK in 1.5 ml DMF. Was heated under stirring at 120-130°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The product performance is possessing a yellow solid, yield: 86%. An NMR spectrum1H (CDCl3) δ ppm: 1.21 (t, 3H, J=7.1, MeCH2); 2.42 (s, 3H, MeC); 2.65 (K, 2H, J=6.7, MeCH2); 2.80 (m, 6H, CH2); 3.65 (s, 2H, CH2); 4.32 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.4, CHAr); 7.00 (d, 1H, J=8.4, CHAr); 7.08-7.28 (m, 7H, CHAr); 7.33-7.44 (m, 2H, CHAr).

Example 24: the Method of obtaining 4-(8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-it (VI).

As starting substances took 1 mmol of 8-methyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 100 mg of KOH in 1.5 ml DMF. Was heated under stirring at 130-140°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 82%. An NMR spectrum1H (CDCl3) δ ppm: 1.21 (t, 3H, J=7.1, MeCH2); 2.42 (s, 3H, MeC); 2.65 (K, 2H, J=6.7, MeCH2); 2.80 (m, 6H, CH2); 3.65 (s, 2H, CH2); 4.32 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.4, CH2); 7.00 (d, 1H, J=8.4, CHAr); 7.08-7.28 (m, 7H, CHAr); 7.33-7.44 (m, 2H, CHAr).

Example 25: the Method of obtaining 4-(2-Methyl-8-fluoro-1,2,3-4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (VII).

the quality of the original substances took 1 mmol of 2-methyl-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 130-140°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform = 1/5. The resulting product is a yellow solid, yield: 78%. An NMR spectrum1H (CDCl3) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH2); 2.72 (m, 2H, CH2); 3.49 (s, 2H, CH2); 4.25 (ush. s, 2H, CH2); 6.79 (dt, 1H, J=9.0, 2.2, CHAr); 6.94-7.11 (m, 7H, CHAr); 7.23-7.30 (m, 2H, CHAr); 7.54 (d, 1H, J=2.2, CHAr).

Example 26: the Method of obtaining 4-(2-Methyl-8-Fluoro-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (VII).

As starting substances took 1 mmol of 2-methyl-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of MeONa in 1.5 ml DMF. Was heated under stirring at 130-140°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, you who od: 81%. An NMR spectrum1H (CDCl3) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH2); 2.72 (m, 2H, CH2); 3.49 (s, 2H, CH2); 4.25 (ush. s, 2H, CH2); 6.79 (dt, 1H, J=9.0, 2.2, CHAr); 6.94-7.11 (m, 7H, CHAr); 7.23-7.30 (m, 2H, CHAr); 7.54 (d, 1H, J=2.2, CHAr).

Example 27: the Method of obtaining 4-(2-Methyl-8-fluoro-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (VII).

As starting substances took 1 mmol of 2-methyl-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmole of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of tert.-BuOK 1.5 ml of DMSO. Was heated under stirring at 130-140°C for 8 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 82%. An NMR spectrum1H (CDCl3) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH2); 2.72 (m, 2H, CH2); 3.49 (s, 2H, CH2); 4.25 (ush. s, 2H, CH2); 6.79 (dt, 1H, J=9.0, 2.2, CHAr); 6.94-7.11 (m, 7H, CHAr); 7.23-7.30 (m, 2H, CHAr); 7.54 (d, 1H, J=2.2, CHAr).

Example 28: the Method of obtaining 4-(2-Methyl-8-fluoro-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (VII).

As starting substances took 1 mmol of 2-methyl-8-FPO is -2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmole of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 100 mg of KOH in 1.5 ml DMF. Was heated under stirring at 120-130°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 75%. An NMR spectrum1H (CDCl3) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH2); 2.72 (m, 2H, CH2); 3.49 (s, 2H, CH2); 4.25 (ush. s, 2H, CH2); 6.79 (dt, 1H, J=9.0, 2.2, CHAr); 6.94-7.11 (m, 7H, CHAr), 7.23-7.30 (m, 2H, CHAr); 7.54 (d, 1H, J=2.2, CHAr).

Example 29: the Method of obtaining 1-(3,7-Bis-dimethylamino-phenothiazines-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)propan-1-she (VIII).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 200 mg of CsF in 1.5 ml of DMSO. Was heated under stirring at 140-150°C for 6 hours DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid is emesto, yield: 83%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 4H, CHAr); 7.36-7.47 (m, 3H, CHAr).

Example 30: a Method of obtaining 1-(3,7-Bis-dimethylamino-phenothiazines-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)propan-1-she (VIII).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of MeONa in 1.5 ml of DMSO. Was heated under stirring at 130-140°C for 12 h of DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 81%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 4H, CHAr); 7.36-7.47 (m, 3H, CHAr).

Example 31: the Method of obtaining 1-(3,7-Bis-dimethylamino-phenothiazines-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)propan-1-she (VIII).

As the Ref is breaking the substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol of 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 300 mg of tert.-BuOK in 1.5 ml of DMSO. Was heated under stirring at 120-130°C for 10 h DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 83%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 4H, CHAr); 7.36-7.47 (m, 3H, CHAr).

Example 32: a Method of obtaining 1-(3,7-Bis-dimethylamino-phenothiazines-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)propan-1-she (VIII).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol 1-(3,7-bis-dimethylamino-phenothiazines-10-yl)propenone, as a catalyst took 100 mg of KOH in 1.5 ml DMF. Was heated under stirring at 130-140°C for 12 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow t ardoe substance, yield: 82%. An NMR spectrum1H (CDCl3) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH2); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH2); 4.34 (ush. s, 2H, CH2); 6.92 (d, 1H, J=8.3, CHAr); 7.02 (d, 1H, J=8.3, CHAr); 7.14-7.28 (m, 4H, CHAr); 7.36-7.47 (m, 3H, CHAr).

The synthesis of compounds of General formula 1.2 (General method)

The process is carried out by heating equimole mixture of gamma-carbolines, which General formula 2 and epoxydodecane fenotiazinas General formula 5 (scheme 3) in dimethyl sulfoxide or dimethylformamide in the presence of a catalyst selected from the range: sodium methylate (MeONa), trebuchet potassium (tert.-BuOK), potassium hydroxide (KOH) and cesium fluoride (CsF) at a temperature of 100-140°C for 2-12 hours.

Scheme 3.

R1=H, (C1-C6)alkyl;

R2, R, R4, R5=H, F, O, Br, (C1-C6)alkyl, (C1-C6)alkoxy,

R6, R7=. H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2;

D=CH2; CH2NHCH2CH2; CH2N[(C1-C6)alkyl]CH2CH2

Y=CH2CH(OH)CH2CH2CH(OH)CH2NHCH2CH2CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2,

kat=MeONa, tert.-BuOK), KOH, CsF.

Example 33: a Method of obtaining 1-(3,7-Bis-diethylaminopentane-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-propan-2-it (X).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol N,N,N,N-tetramethyl-10-oxiranylmethyl-10H-phenothiazines-3,7-diamine as a catalyst took 200 mg CsF, mg in 1.5 ml of DMSO. Was heated under stirring at 100-120°C for 6 hours DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 88%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.52 both s (3H, Me); 2.64 t (2H, CH2, J=6.4 Hz); 2.70-2.85 m (4H, CH2); 2.95 (s, 12H, Me); 3.16 (DD, 1H, J=13.3, 6.2 Hz), 3.30 (DD, 1H, J=13.3, 6.2 Hz), 3.42 (m, 1H), 4.30-4.43 (m, 3H), 6.70-7.00 (m, 2H), 7.01-7.26 (m, 3H), 7.30 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=2.2 Hz).

Example 34: a Method of obtaining 1-(3,7-Bis-diethylaminopentane-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-propan-2-she (IX).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol N,N,N,N-tetramethyl-10-oxiranylmethyl-10H-phenothiazines-3,7-diamine as a catalyst took 200 mg of MeONa in 1.5 ml DMF. Was heated under stirring at 110-120°C for 8 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Chloride m is tilen was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 83%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.52 both s (3H, Me); 2.64 t (2H, CH2, J=6.4 Hz); 2.70-2.85 m (4H, CH2); 2.95 (s, 12H, Me); 3.16 (DD, 1H, J=13.3, 6.2 Hz), 3.30 (DD, 1H, J=13.3, 6.2 Hz), 3.42 (m, 1H), 4.30-4.43 (m, 3H), 6.70-7.00 (m, 2H), 7.01-7.26 (m, 3H), 7.30 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=2.2 Hz).

Example 35: a Method of obtaining 1-(3,7-Bis-diethylaminopentane-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-propan-2-she (IX).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol N,N,N,N-tetramethyl-10-oxiranylmethyl-10H-phenothiazines-3,7-diamine as a catalyst took 200 mg of tert.-BuOK 1.5 ml of DMSO. Was heated under stirring at 100-120°C for 12 h of DMSO was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 80%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.52 both s (3H, Me); 2.64 t (2H, CH2, J=6.4 Hz); 2.70-2.85 m (4H, CH2); 2.95 (s, 12H, Me); 3.16 (DD, 1H, J=13.3, 6.2 Hz), 3.30 (DD, 1H, J=13.3, 6.2 Hz), 3.42 (m, 1H), 4.30-4.43 (m, 3H), 6.70-7.00 (m, 2H), 7.01-7.26 (m, 3H), 7.30 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=2.2 Hz).

Example 36: a Method of obtaining 1-(3,7-Bis-diethylaminopentane-10-yl)-3-2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-propan-2-she (IX).

As starting substances took 1 mmol 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 1 mmol N,N,N,N-tetramethyl-10-oxiranylmethyl-10H-phenothiazines-3,7-diamine as catalyst was taken as the catalyst took 200 mg of KOH in 1.5 ml DMF. Was heated under stirring at 100-110°C for 2 h, the DMF was removed in vacuum of 3 mm Hg, the residue product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 76%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.52 both s (3H, Me); 2.64 t (2H, CH2, J=6.4 Hz); 2.70-2.85 m (4H, CH2); 2.95 (s, 12H, Me); 3.16 (DD, 1H, J=13.3, 6.2 Hz), 3.30 (DD, 1H, J=13.3, 6.2 Hz), 3.42 (m, 1H), 4.30-4.43 (m, 3H), 6.70-7.00 (m, 2H), 7.01-7.26 (m, 3H), 7.30 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=2.2 Hz)

The synthesis of compounds of formula 1.3 (General method)

The process is carried out by mixing equimolar amounts of hydroxyl-containing conjugates gamma-carbolines, which and fenotiazinas General formula 6 and diethylaminosulfur (Et2NSF3) (scheme 4) in dimethyl sulfoxide or dimethylformamide at temperatures (-78)-0°C for 1-3 hours:

Scheme 4.

R1=H, (C1-C6)alkyl;

R2, R3, R4, R5=H, F, Cl, Br, (C1-C6)alkyl, (C1-Csub> 6)alkoxy,

R6, R7=. H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2;

E=CH2; CH2NHCH2CH2; CH2N[(C1-C6)alkyl]CH2CH2.

Z=CH2CHFCH2NHCH2CH2CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

Example 37: a Method of obtaining 10-[3-(2,8-Dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-2-forproper]-N,N,N,N-tetramethyl-10H-phenothiazines-3,7-diamine (X).

As an initial matter took 1 mmol 1-(3,7-Bis-diethylaminopentane-10-yl)-3-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-propan-2-it in 3.0 ml of DMSO and 1 mmol of diethylaminosulfur. The reagents were mixed at a temperature (-78)°C. the Reaction mass was stirred for 3 hours, raising the temperature to 0°C, was poured into 10 ml of water, was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographically on silica gel (60 mesh), eluent methanol/chloroform =1/5. The resulting product is a yellow solid, yield: 63%. An NMR spectrum1H (CDCl3) δ ppm: 2.50 and 2.53 both s (3H, Me); 2.65 t (2H, CH2, J=6.4 Hz); 2.70-2.85 m (4H, CH2); 2.94 (s, 12H, Me); 3.16 (DD, 1H, J=13.3, 6.2 Hz), 3.30 (DD, 1H, J=13.3, 6.2 Hz), 3.42 (m, 1H), 3.90 (t, 1H, J=6.3 Hz), 4.40 (m, 1H), 5.10 (DM, 1H, JHF=48 Hz), 6.88 (1H, CHAr, J=8.8 Hz); 6.90 (DD, 2H, J=8.8, 2.2 Hz), 7.01-7.20 (m, 2H), 7.31 (d, 2H, J=8. Hz), 7.54 (d, 2H, J=2.2 Hz).

Synthesis of clorhidrato compounds of formulas 1.1, 1.2, 1.3 (General method).

The process is carried out by dissolving the compounds of formulas 1.1, 1.2, 1.3 10%solution of HCl in isopropanol at 50°C.

Example 38: the Method of obtaining the Hydrochloride of 4-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(phenothiazines-10-yl)propane-1-she (XI).

As an initial matter take 1 mmol of 4-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-phenothiazines-10-yl-propane-1-it, dissolve in 2 ml of 10%HCl solution in isopropanol at 50°C. is Cooled to 0°C, the precipitation is filtered off. The resulting product is a white solid, yield: 95%. An NMR spectrum1H (CDCl3) δ, ppm: 2.59 (s, 3H, Months); 2.65 (s, 3H, MeN); 2.73-2.97 (m, 4H, CH2); 3.03-3.16 (m, 2H, CH2); 3.44-3.65 (m, 2H, CH2); 4.33 (ush. s, 2H, CH2); 6.96-7.15 (m, 2H, CHAr); 7.19-7.32 (m, 5H, CHAr); 7.38-7.49 (m, 4H, CHAr); 10.90 (s, 1H).

Another aspect of the invention is a pharmacological tool to reduce the uncontrolled aggregation of proteins in the nervous system in the treatment of neurodegenerative diseases, containing the active principle and a pharmaceutically acceptable carrier, the novelty of which consists in the fact that, as active principle an effective amount of the compounds of formula 1.

The term "pharmacological with adsto" means the use of any pharmaceutical form, containing the compound of formula 1, which could find a prophylactic or therapeutic use in medicine as a means for reducing uncontrolled aggregation of proteins in the nervous system

The term "effective amount", as used in this application involves the use of a number of compounds of formula 1, which in combination with its parameters of activity and toxicity, as well as on the basis of knowledge of a specialist should be effective in the form of the drug.

To obtain a pharmacological means of one or more compounds of formula 1 are mixed as an active ingredient with a pharmaceutically acceptable carrier known in medicine, according to accepted pharmaceutical methods. Depending on the dosage form of the drug carrier can be of different types.

The technical effect of the present invention is to provide new compounds, in which the combined gamma carolynowoe the phenothiazine nucleus and the core for receiving the means for reducing uncontrolled aggregation of proteins in the nervous system that increases the efficiency of treatment of neurodegenerative diseases.

Table 1 presents the results of 5 independent experiments, in which was studied the effect of the inventive substances for the maintenance of large T5 inclusions after transfectional culture SH-SY5Y.

Table 2 presents the effect of chronic injection of the inventive compounds on the number of amyloid inclusions in the anterior horn of the thoracic spinal cord at gamma synuclein transgenic mice at the symptomatic stage of proteinopathy.

Note: * - level of significance (p-level)in comparison with group of compound II,

x- arithmetic mean; m - average error.

Figure 1 shows representative pictures histopathological deposits on cross sections through the cervical spinal cord of mice Thy1mgSN; And where - Amyloid deposits, painted Congo red, B - Neurons containing clusters hyperphosphorylated protein tau. Histopathological fat arrow.

Figure 2 presents images of histological sections of the spinal cord 12-month control Thy1mγSN mice (a) and Thy1mγSN mice receiving compound I from 3 months of age (). Scale =100 ám.

Figure 3 presents the neurons with inclusions hyperphosphorylated protein tau in the control and experimental groups of mice tauP301S. * - p<0.05, the criterion of Mann-Whitney.

Figure 4 presents a quantitative analysis hyperphosphorylated protein tau in the spinal cord of mice tauP301Staking the connection (squares), compound II (Treugolnik) and control group (diamond) of different ages (3-6 months). Normalization to GAPDH. * - p<0.05, the criterion of Mann-Whitney.

Figure 5 presents the effect of the studied compounds on amyloid load in the cortex of 12-month-old mice of 5xFAD receiving drugs from the age of 3 months, compared with the control group, not receiving the drug (the cerebral cortex).

Figure 6 presents the inclusion of amyloid type in the cerebral cortex of 5xFAD mice at the age of 12 months who received (II) and not treated (control) compound II.

Figure 7 presents the effect of compound I on the severity of astrogliosis (marker GFAP) in line Thy1mgSN (the drug from the age of 3 months to 9 months).

On Fig presents the influence of substances II on the severity of astrogliosis (marker GFAP) in the spinal cord of P301S mice in the control group (a) and after receiving the receipt of the compound (II) with an age of 1 months to 5 months (B) according to the immunohistochemistry.

Figure 9 presents data on the effect of the drug II on the severity of astrogliosis (marker GFAP) in the spinal cord of mice P301S taking the drug II from the age of 1 months to 5 months (B), compared with the control necroshine mice (A) according to Western blot turns.

Figure 10 shows the test results of the assessment of balance and coordination on the rotating rod animal is x in different age periods. Square - a control group of transgenic animals; Diamond is an experienced group of transgenic animals treated with compound I; the Triangle is an experienced group of transgenic animals treated with compound II. The graph presents the average retention time on the rod in the group for each period of measurement.

Figure 11 shows the test results on the "reverse grid" animal lines tauP301Sreceiving compound I (diamond), II (triangle) and control animals (squares) in different age periods.

The influence of the studied substances on the formation of TDP43-reactive inclusions in undifferentiated cell culture SH-SY5Y

It was investigated the effect of the compounds I obtained in examples 1-4, II, obtained in examples 5-8, III, obtained in examples 9-12, IV, obtained in examples 13-16, V, obtained in examples 17-20, XI obtained in example 38, number, morphology and kinetics of the formation of deposits formed T5 pathogenic form of TDP43 protein in transfected SH-SY5Y cells. Cells were seeded on the processed polylysine glass with a diameter of 10 mm, placed in 24-hole culture plates. Plasmid DNA encoding a T5 form, was introduced in undifferentiated cells SH-SY5Y method of transient transfection. 3 hours after transfection to cultured cells were added to culture medium containing issled the controlled substances to a final concentration of 10 μg/ml; in the control samples were added to the medium without the drugs. After 16 hours of cell culture were fixed and counted the number of fluorescent inclusions, the size of which was not less than five micrometers. Considered include the entire area of the glass, for each drug took the average value of the three glasses. In each experiment 100% accepted number of inclusions in the control cultures, which were incubated after transfection without adding drugs. The number of inclusions in the samples cultured with the addition of these compounds, expressed as a percentage of the control.

Table 1 presents the results of 5 independent experiments, in which was studied the influence of the studied substances on the content of major T5 inclusions after transfection cell culture SH-SY5Y. The data obtained show that the compounds I and II can inhibit the aggregation of mutant forms T5 TDP43 protein, while the number of cells containing aggregates, reduced almost twice. The study of compounds III-V and XI showed that they are less likely possess this ability. From the presented data shows that the inventive compounds to deprive the uncontrolled agregati proteins in cell culture SH-SY5Y, and the most effective compounds I, II.

The study of the amount of amyloid deposits in model LM is now.

It has been demonstrated repeatedly that the number of amyloid deposits in the nervous tissue of patients with neurodegenerative diseases correlates with the degree of progression of neurological symptoms (Braak et al., 2006). In particular, this dependence was detected for senile plaques in Alzheimer's disease and Taurus levy in Parkinson's disease.

Studies on mice Thy1mgSN

Staining of amyloid aggregates in the spinal cord in animal lines Thy1mgSN were amyloid-specific dye Congo red, and the lines P301S - antibodies against Tau protein.

It was found that the progression of neurological symptoms (age points 3, 6 and 9 months for the line Thy1mgSN; 2, 4, and 6 months for the line P301S) there is a gradual increase in the number of units is the accumulation of amyloid deposits in the nervous system (spinal cord). The maximum number of pathological protein structures observed at the last time points and then (at the terminal stages) was not significantly increased. Representative pictures histopathological deposits in the nervous tissue of animals are presented in figure 1.

Histochemical study of sections of the spinal cord of dvenadcatiletnih animals line Thy1mgSN who received the investigational compound within nine months, showed a significant decrease in numbers is painted Congo red amyloid deposits (group, receiving compound I - 19,02±1,72; the group receiving compound II - 22,60±1,10) compared with animals of the same age who did not receive the drug (38,06±4,35) (table 2, Figure 2).

Thus the data obtained svedetelstvuyut that compounds I, II prevent the accumulation of pathological aggregates (amyloid deposits) in the nervous system of animal models line Thy1mgSN.

Studies on mice tauP301S

To estimate the number of neurons containing hyperphosphorylated forms of tau protein, was used for immunohistochemical analysis of cross sections of thoracic spinal cord of mice tauP301Susing antibody anti-tau AT. Analysis of samples of nervous tissue using Western blot turns with these antibodies showed that in the process of development of mariodelreal animals line tauP301Sthere has been a progressive increase in the number of neurons containing hyperphosphorilated Tau-protein. In the study of the action of the compounds I and II on the number of such neurons was identified trend towards reducing the number UT-positive neurons in the groups of animals treated with investigational drugs, compared with the control group. In groups of 6-month-old animals, these differences were statistically significant (Figure 3).

Study of the level of phosphorylation of the Tau protein

The analysis of the level of phospho what helirovanie Tau protein was carried out using quantitative Western blotting. It was shown that the total number hyperphosphorylated Tau-protein in the spinal cord of mice tauP301Swho the compounds decreases. At the time point of 6 months, these differences were statistically significant (Figure 4).

Research on the 5xFAD mice

Due to the fact that the deposits of beta-amyloid (senile plaques are extracellular, in contrast to intracellular neurofibrillary protein in the case of line with tapatia P301S, and very numerous animals line 5xFAD at the terminal stages of the disease, to assess the effect of the studied compounds was evaluated total area (in percentage)occupied by sediments. The definition of amyloid load was performed in the cerebral cortex of the human brain structure, characterized by the most severe amyloid pathology. It was found substantial and statistically significant decline in the area occupied by amyloid deposits in the cerebral cortex (Figure 5). 32% and 27% for compounds I and II, respectively.

A representative micrograph of the relevant sections of the brain of animals treated with compound II, and control groups is shown in Fig.6 (amyloid deposits visualized using a fluorescent dye Congo red).

The data obtained in this series of experiments show that the claimed compounds can reduce the number and/or act on the stability of aggregates, thereby slowing the progression of disease caused by aggregation of the corresponding protein.

The study of the specific neuroinflammatory reactions in model animals

It was investigated the effect of the studied compounds I and II in relation to the inflammatory response in the nervous system at an advanced stage of proteinopathy (6 months in line Thy1mgSN and 5 months in line P301S). According to the data obtained in the study of spinal cord of mice treated with compounds I, II within 6 months, there is a substantial weakening of the reaction of astrogliosis, resulting in a General decrease in GFAP-immunoreactivity and the number of activated astrocytes (Fig.7).

This effect was also confirmed in line P301S, in animals there was a decrease in the number of activated astrocytes after 4 months of receipt of the drug. On Fig shows representative pictures of the spinal cord of animals not treated with the drug and treated with compound II from the age of 1 month to 5 months.

Found immunohistochemical study of the effect was also confirmed using Western blot turns: the content of GFAP (two isoforms, 55 and 45 kDa) was significantly reduced in treated with the compounds of mice compared with the transgenic is Isami (tauP301S) of the same age and was similar to that found in wild-type mice (Figure 9).

Thus, the data obtained in the study of specific neuroinflammatory reactions in two lines of transgenic animals show that the claimed compounds have neuroprotective properties in animal modeling of proteinopathy.

Behavioral testing of animals

Test assess balance and coordination on the rotating rod

Using instrumental methods are able to identify violations of locomotor function in model mice at an early pre-symptomatic stage of the disease, starting from two months of age. So, when testing a 2-month-old mice of P301S on the rotating rod in the acceleration mode of rotation, we found that transgenic animals were not able to stay on the rod throughout the testing period, which amounted to 300 seconds, and fell before the completion of the test. At the same time, the control wild-type animals at this age, loosely held on the rotating rod for 300 seconds.

Further data were obtained on the effect of compounds I and II on the indices of motor function in line P301S (Figure 10). Testing was conducted on a monthly basis, between the third and sixth month of life. It has been shown that these substances improve the ability of experimental animals to remain on the rotating rod.

Test "reverse grid"

For instrumental evaluation of the locomotor dysfunction transgenic animals was also used test inverted grid. In normal wild-type animals can stay on the reversed grid for 60 seconds, keeping this ability even at the age of 2 years. However, dysfunction of the musculoskeletal system time on the grid can be significantly reduced up to the complete inability to even begin the test. We investigated P301S mice of different ages (from 3 to 6 months) had registered a progressive deterioration in the ability to stay on the grid, while at the age of 6 months homozygous transgenic animals were not actually able to stay on the inverted grid, whereas in the control group more than 80% of wild-type animals at the age of 18 months were able to stay on the inverted grid over the entire 60-second test.

Figure 11 shows the test results on the "reverse grid" animal lines tauP301Streated with the compounds, in comparison with the control. These data indicate that mice of this line is the ability to stay on the grid deteriorates with age. In the group of animals treated with experimental drugs, also there is a progression in motor dysfunction, however, the rate of progression is significantly lower.

Thus, Pref the experimental data indicate the ability of the inventive compounds to inhibit the progression of a neurodegenerative process in the nervous system of animal models, caused by the uncontrolled aggregation of pathogenic proteins.

Table 1
Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido-[4,3-b]indoles as a means for reducing uncontrolled aggregation of proteins in the nervous system, methods for their preparation, pharmacological tool based on them and the way to reduce uncontrolled aggregation of proteins in the nervous system.
SubstanceThe average of five experiments
I55%±0,06
II52%±0,10
III81%±0,13
IV75%±0,20
V89%±0,09
XI94%±0,43
Control100%

1. Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido[4,3-b]indoles of General formula 1 and their chlorhidrate as a means for reducing uncontrolled aggregation of proteins in the nervous system

in which R1=H, (C1-C6) alkyl;
R2, R3, R4, R5=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy,
R6, R7=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, NH2,
NHAlkyl, NAlkyl2;
A=CH2CH2CH=CHCH2CH2CH2CH2CH2CH[(C1-C6)alkyl]C(O)CH2CH2C(O)NHCH2CH2); CH2CH[(C1-C6) alkyl]C(O)N[(C1-C6) alkyl]CH2CH2), CH2CH=(OH)CH2CH2CH(OH)CH2NHCH2CH2,
CH2CH(OH)CH2N[(C1-C6) alkyl]CH2CH2CH2CHFCH2NHCH2CH2CH2CHFCH2N[(C1-C6) alkyl]CH2CH2.

2. Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido[4,3-b]indoles according to claim 1, which are compounds of General formula 1.1

in which R1, R2, R3, R4, R5, R6, R7have the meanings given above for formula 1;
X=CH2CH2CH=CHCH2CH2CH2CH2CH2CH[(C1-C6) alkyl]C(O)CH2CH2C(O)NHCH2CH2); CH2CH[(C1-C6) alkyl]C(O)N[(C1-C6)])alkyl]CH2CH2).

3. Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido[4,3-b]indoles according to claim 1, provide the Commissioner, the compounds of General formula 1.2

in which R1, R2, R3, R4, R5, R6, R7have the meanings given above for formula 1;
Y=CH2CH(OH)CH2CH2CH(OH)CH2NHCH2CH2,
CH2CH(OH)CH2N[(C1-C6) alkyl]CH2CH2.

4. Derivatives fenotiazinas 1,2,3,4-tetrahydropyrido[4,3-b]indoles according to claim 1, which are compounds of General formula 1.3

in which R1, R2, R3, R4, R5, R6, R7have the meanings given above for formula 1;
Z=CH2CHFCH2NHCH2CH2CH2or CH2CHFCH2N [(C1-C6) alkyl]CH2CH2,

5. Method of producing compounds of the formula 1.1, namely, that equinology a mixture of gamma-carbolines, which General formula 2

in which R1, R2, R3, R4, R5have the meanings given above for formula 1;
and acetylisoniazid fenotiazinas General formula 3

or vinylsamurais fenotiazinas General formula 4

in which R6, R7have the meanings given above for formula 1;
W=(CH2)nwhere n=0 or 1; C(O); CH[(C1-C6) alkyl]C(O);
C(O)NHCH2CH2); C(O)N[(C1-C6)and the Kil]CH 2CH2; CH[(C1-C6)
alkyl]C(O)N(C1-C6)alkyl]CH2CH2),
heated in dimethyl sulfoxide or dimethylformamide in the presence of a catalyst selected from the range: sodium methylate, tert-butyl potassium, potassium hydroxide or cesium fluoride at a temperature of 120-160°C for 6-24 hours.

6. The method of obtaining compounds of formula 1.2, namely, that equinology a mixture of gamma-carbolines, which General formula 2

in which R1, R2, R3, R4, R5have the meanings given above for formula 1;
and N-epoxydodecane fenotiazinas General formula 5

in which R6, R7have the meanings given above for formula 1;
D=CH2; CH2NHCH2CH2; CH2N[(C1-C6)alkyl]CH2CH2heated in dimethyl sulfoxide or dimethylformamide in the presence of a catalyst selected from the range: sodium methylate, tert-butyl potassium, potassium hydroxide or cesium fluoride at a temperature of 100-140°C for 2-12 hours.

7. The method of obtaining compounds 1.3, namely, that hydroxycobalamin conjugates gamma-carbolines, which and fenotiazinas General formula 6

in which R1, R2, R3, R4, R5, R6, R7matter, particularly the e above for formula 1;
E=CH2; CH2NHCH2CH2; CH2N[(C1-C6)alkyl]CH2CH2
foryouth equimolar number of diethylaminosulfur in dimethyl sulfoxide or dimethylformamide at temperatures (-78)-0°C for 1-3 hours.

8. Pharmacological tool to reduce the uncontrolled aggregation of proteins in the nervous system, containing the active principle and a pharmaceutically acceptable carrier, characterized in that the active agent contains an effective amount of the compounds of formula 1.

9. The way to reduce uncontrolled aggregation of proteins in the nervous system, which consists in the introduction to the patient a pharmaceutical containing an effective amount of the compounds of formula 1 in a dose of 0.01-1.5 mg/kg of body weight at least once a day during the period required to achieve a therapeutic effect.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel indolizine derivatives of formula , to their pharmaceutically acceptable salts or prodrugs, which represent C1-6alkyl ethers, where values U, R1, R2, R3 are given in item one of the formula.

EFFECT: compounds possess an inhibiting activity with respect to xanthine oxidase, which makes it possible to use them in a pharmaceutical composition for the prevention or treatment of a disease, selected from the group, consisting of hyperurecemia, gout nodule, gout arthritis with hyperurecemia of the renal disorder and urine concrements.

18 cl, 17 tbl, 76 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts specified in a group consisting of phosphate salt, hydrochloride salt, sulphate salt, mesylate salt, maleate salt or malate salt. Also, the invention refers to a method for preparing the above salts, using them and a pharmaceutical composition on the basis of the above salts.

EFFECT: there are prepared new pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts effective in treating diabetes.

5 cl, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted pyrazino-quinolines of formula: , wherein the values R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, X and Y are presented in clause one of the patent claim, and to their pharmaceutically acceptable salts.

EFFECT: compounds can be used for treating cancer.

14 cl, 24 dwg, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 7-R-pyrido[1,2-a]benzimidazoles of the general formula where R=a) CF3, b) CN, c) COOH, d) C(O)NH2, e) COOCH3, f) COOC2H5, consisting in the following: reduction of chlorides of N-(2-nitro-4-R-phenyl)pyridinium is carried out in a mixture of alcohol and 4% hydrochloric acid, taken at a ratio 1:1, by means of electric current in a diaphragm cell in a galvanostatic mode at a temperature of 40-45°C on a lead cathode, with passing through an electrolytic cell 4 F charge for 0.5 h, with current intensity 0.6 A, as an anolyte used is 15% of sulphuric acid, and as an anode - platinum; target products are separated by filtration of a precipitated sediment after processing of a reaction mixture with ammonium hydroxide.

EFFECT: novel reagent-free method, making it possible to reduce synthesis cost and simplify the process of the target product separation, is elaborated.

7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing quinazoline derivatives of structural formula I:

,

where values of radicals R1-R6, R8, W, P are given in the claim. The method involves reacting an aldehyde of formula II:

with ethylene carbonate to form a compound of formula III:

and reacting a compound of formula III with a compound of formula IV:

to form a compound of formula I. The invention also relates to methods of producing derivatives of the compound of formula I of structural formulae VI and VIII.

EFFECT: said methods enable to obtain products with low content of impurities and high output.

23 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I)

wherein: A means a ring selected from phenyl group or heteroaryl group, Q means oxygen atom or a link -CH2-, X, Y and Z mean carbon atoms; R1 and R2, identical or different are selected from the following atoms and groups: hydrogen, halogen, -CF3, (C1-C6)alkyl, Alk, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -(CH2)m-SO2-(C1-C6)alkyl with m equal to 0, 1 or 2, benzyl, pyrazolyl, -CH2-triazolyl and -L-R12 wherein L represents a link or a bridge -CH2- and/or -CO- and/or -SO2-, and R12 means (C3-C8)cycloalkyl or group of formula ,

wherein: n=0 or 1, R13 means one-three groups, identical or different, selected from hydrogen atom and hydroxyl, (C1-C4)alkyl, oxo and phenyl, R14 means hydrogen atom or is selected from groups - NR18R19, -NR18-COOR19, -NR18-Alk-R20 and -R21, wherein R18, R19, R20, R21 and Alk have the values as specified below, R14' means -CO-(C1-C6)alkyl, R15 is selected from groups -Alk, -R20, -Alk-R20, -Alk-R21, -CO-Alk, -CO-R20, -CO-R21, -Alk-CO-NR18R19, (C3-C8)cycloalkyl and -CO-(C3-C8)cycloalkyl, wherein R18, R19, R20, R21 and Alk has the values as specified below, R16 means hydrogen atom or group Alk, wherein Alk has the values as specified below, R17 means group -Alk, -Alk-R20 or -Alk-R21, wherein Alk, R20 and R21 have the values as specified below, -CO-(C1-C6)alkyl, -CO-(C3-C8)cycloalkyl, R18 and R19, identical or different, mean hydrogen atom or (C1-C6)alkyl, R20 means phenyl or heteroaryl group (such as pyridinyl, pyrazolyl, pyrimidinyl or benzimidazolyl), which is optionally substituted by one (C1-C6)alkyl, R21 means heterocycloalkyl group optionally substituted by one or more halogen atoms or (C1-C6)alkyl, hydroxyl or (C1-C4)alkoxy groups, and Alk means (C1-C6)alkyl which is linear or branched and which is optionally substituted by one or two groups, identical or different, selected from hydroxyl, phenyl, (C1-C4)alkoxy and -NR18R19, wherein R18 and R19 have the values as specified above, R3 means linear (C1-C10)alkyl which is optionally substituted by one-three groups, identical or different, selected from halogen atoms and (C1-C4)alkoxy groups, R4 means hydrogen atom, R5 and R6 independently mean hydrogen atom or (C1-C5)alkyl, R7 and R8 independently mean hydrogen atom or (C1-C5)alkyl, R9 and R10 independently mean hydrogen atom, or R9 and R10 together form linear (C2-C3)alkylene chain, thereby forming 6-merous ring with nitrogen atom whereto attached with said alkylene chain optionally substituted by one-three groups selected from (C1-C4)alkyl, oxo, R11 means hydrogen atom or (C1-C8)alkyl which is optionally substituted by one-three groups selected from halogen atoms, hydroxyl, (C1-C6)alkoxy, -NR18R19, - or pyridinyl, wherein R18 and R19 have the values as specified above; wherein 'heterocyclic group' means saturated 5- or 6-member ring containing one or two heteroatoms selected from oxygen, nitrogen and sulphur atoms; 'heteroaryl group' means aromatic cyclic group containing 5-11 ring atoms selected from carbon, nitrogen and sulphur atoms with heteroaryl groups to be monocyclic or bicyclic, in this case at least one of two cyclic fragments are aromatic; in the form of a free base or an additive acid salt or base. Also, the invention refers to methods for preparing such compounds and to a based drug showing rennin inhibitory activity.

EFFECT: compounds can find application in medicine for preparing the drug for treating and preventing hypertension, cardiac damages, myocardial infraction, cardiac failure, cardiac and vascular hypertrophy, left ventricular dysfunction, restenosis, glaucoma, renal conditions, diabetic complications.

26 cl, 3 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: described is obtaining and pharmaceutical application of substituted derivatives of arylalkane acid of formula I , where ring A, ring B, R1, R2, R3, R4, R5, X, Alk1, Alk2, Ar1 and Ar2 are such as determined in said description. Said compounds, as selective agonists activating (RAPPs) receptors, activated by peroximal proliferator, in particular, RXRs/RAPPs-alfa, RXRs/RAPPs-gamma and RXRs/RAPPs-delta heterodimers, are applied in treatment and/or prevention of type 2 diabetes and connected with it metabolic syndrome, such as hypertension, obesity, insulin-resistence, hyperlipidemia, hyperglycemia, hyperolesterinemia, artheriaslerosis, coronary artery disease, and other cardio-vascular disorders, and possess improved profile of side effects, connected with common RAPPs-gamma agonists.

EFFECT: obtaining compunds, which possess improved profile of side effects, connected with common RAPPs-gamma agonists.

22 cl, 38 ex, 2 tbl, 10 dwg

The invention relates to a method for producing 2-trifluoromethyl-10-[3-(1-methyl-piperazinil-4)-propyl)] -fenotiazina used to treat diseases of the Central nervous system
The invention relates to a method for producing 2-trifluoromethyl-10-(3-chlorpropyl)fenotiazina is a key product in the synthesis of psychopharmacological drugs

The invention relates to organic chemistry, namely the synthesis fenotiazina derivatives of the formula I

< / BR>
Known 2,3-dihydro-3-keto-1H-pyrido[3,2,1]phenothiazines [1] as antioxidants for lubricants

FIELD: medicine.

SUBSTANCE: what is presented is using magnesium salt of comenic acid as a preventive and therapeutic agent in an amount of 2 mg per 1 kg of body weight for 3 days orally on an empty stomach once a day.

EFFECT: there are shown antioxidant and neuroprotective activities of magnesium comenate, as well as its stimulant action on the growth processed of spinal ganglia exceeding that of the action of comenic acid.

7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new benzene sulphonamide compounds, wherein the compounds are specified in a group of the following compounds, including additive salts with pharmaceutically acceptable acid, additive salts with pharmaceutically acceptable base and enantiomers of these compounds: 1) 3-[(4-but-2-inyloxybenzenesulphonyl)-methylamino]-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-propionamide, 2) (S)-3-(4-but-2-inyloxybenzenesulphonylamino)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-propionamide, 3) (S)-3-(4-benzyloxybenzenesulphonylamino)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-propionamide, 4) (S)-3-[(4-benzyloxybenzenesulphonyl)-methylamino]-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-propionamide, 5) (S)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 6) (S)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)-benzenesulphonylamino]-propionamide, 7) (S)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-(4-propoxybenzenesulphonylamino)-propionamide, 8) (S)-3-[4-(3-cyanobenzyloxy)-benzenesulphonylamino]-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-propionamide, 9) (S)-3-[4-(4-cyanobenzyloxy)-benzenesulphonylamino]-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-propionamide, 10) benzyl-4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-entyl}-piperazine-1-carboxylate, 11) (S)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-phenylpiperidin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 12) (R)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 13) (S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-2-piperazin-1-ylpropionamide, 14) (S)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide hydrochloride, 15) tert-butyl-3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulphonylpiperazin-1-yl)-ethylsulphamoyl]-phenoxymethyl}-2-methylindole-1-carboxylate difluoroacetate, 16) (S)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 17) (S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 18) (S)-2-[4-(4-fluorobenzyl)-piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino-propionamide, 19) (S)-2-(4-ethulpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 20) (S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-2-[4-(4-trifluoromethylbenzyl)-piperazin-1-yl]-propionamide, 21) (S)-N-hydroxy-2-[4-(4-methylbenzyl)-piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 22) (S)-3-[4-(benzoisoxazol-3-ylmethoxy)-benzenesulphonylamino]-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-propionamide, 23) (S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 24) (S)-N-hydroxy-2-[4-(2-methylpropane-1-sulphonyl)-piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-propionamide, 25) (S)-N-hydroxy-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)-benzenesulphonylamino]-propionamide, 26) (S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)-benzenesulphonylamino]-2-[4-(propane-2-sulphonyl)-piperazin-1-yl]-propionamide, and 27) (S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)-benzenesulphonylamino]-propionamide. The invention also refers to pharmaceutical and cosmetic compositions on the basis of the above compounds possessing TNFα-converting enzyme (TACE) activity.

EFFECT: there are prepared new compounds and compositions on the basis thereof which can be used in medicine and veterinary science for treating rheumatoid arthritis, non-insulin dependent diabetes mellitus, Crohn's disease or inflammatory skin disease.

35 cl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

,

wherein: each of R1, R2, R4, R5, R6, R7, R8 R9, R10, R11, R12, R13, R14, R15 R16 and R17 is independently specified in a group consisting of deuterium or hydrogen; and R3 is independently specified in a group consisting of CD3 and CH3; provided R3 represents CH3, at least one of the groups R1, R2, R4, R5, R6, R7, R8 R9, R10, R11, R12, R13, R14, R15 R16 and R17 represents deuterium; and R18 represents hydrogen. The invention also refers to a drug on the basis of the above compound for treating a condition causing pain.

EFFECT: there are prepared new compounds inhibiting MMPs (metalloproteinases) which show the high activity, metabolic stability and/or lower toxicity in relation to the currently known MMP inhibitors for treating pain and other diseases, such as cancer.

16 cl, 2 dwg, 14 tbl, 136 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (VA-1), wherein WRW2 and WRW4 are independently specified in a hydrogen atom, -CN, -CF3, halogen, linear or branched (C1-C6)alkyl, a 3-12-merous cycloaliphatic group or phenyl, wherein WRW2 and WRW4 are independently and optionally substituted by up to three substitutes specified in -OR′, -CF3, -OCF3, -SR′, -S(O)R′, -SO2R′, halogen, -CN, -COOR′, -(CH2)OR′, -CH2CN, phenyl, phenoxy group, -N(R′)(R′), -NR′C(O)OR′, -NR′C(O)R′, -(CH2)N(R′)(R′); WRW5 is specified in a group consisting of a hydrogen atom, -CN, -CHF2, -N(R′)2, -NHC(O)R′, -NHC(O)OR′, -NHSO2R′, -OR′, -CH2OH, -CH2N(R′)2, -C(O)OR′, -SO2NHR′, -SO2N(R′)2 or -CH2NHC(O)OR′; X means a bond; Rx means the hydrogen atom; R′ is independently specified in the hydrogen atom, (C1-C8)aliphatic group, (C3-C8)cycloalkyl or phenyl. Also, the invention refers to a pharmaceutical composition possessing the properties of modulators of ATP-binding cartridge (ABC) transporters and containing the compound of formula , and to a method of treating or relieving a severity in a patient, wherein the above disease is specified in mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD) or dry eye disease.

EFFECT: compound of formula (VA-1) as the modulators of the ATP-binding cartridge (ABC) transporters.

24 cl, 14 tbl, 83 ex

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