RU2530881C1 - DERIVATIVES OF 1,2,3,4-TETRAHYDROPYRIDO[4,3-b]INDOLE-CONTAINING PHENOTHIAZINES AS INHIBITORS OF CHOLINESTERASES AND BLOCKERS OF SEROTONIN RECEPTORS 5-HT6, METHODS OF OBTAINING THEIR CHLOROHYDRATES AND BASED ON THEM PHARMACEUTICAL PREPARATION - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,2,3,4-tetrahydropyrido[4,3-b]indole-containing phenothiazines of general formula 1

as inhibitors of cholinestrerases and blockers of serotonin receptors 5-HT₆, a pharmaceutical preparation on their base, in particular for treatment of neurodegenerative diseases. In general formula 1, 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=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: increased efficiency of the application of compounds.

6 cl, 1 dwg, 1 tbl, 38 ex

Description

The invention relates to a number of new phenothiazine derivatives modified with gamma-carboline fragments, methods for their preparation, pharmaceutical compositions containing them and their use in medicine. In particular, it relates to compounds and compositions that demonstrate the ability to inhibit cholinesterase and block the 6th subtype of serotonin receptors, 5-HT ₆ , which is especially useful for the treatment of a number of diseases of the central nervous system.

In the development of cognitive dysfunctions - the main symptom of Alzheimer's disease (AD) and dementia of other origin - an important role is played by a deficiency of central acetylcholine, which is a rational basis for the use of acetylcholinesterase inhibitors (AChE, EC 3.1.1.7) for the treatment of AD. The use of AChE inhibitors that increase the concentration of the neurotransmitter acetylcholine leads to moderate improvements in the cognitive function of patients suffering from AD. These compounds, however, cause unwanted side effects such as nausea and vomiting [Martinez A, Castro A. Novel cholinesterase inhibitors as future effective drugs for thetreatment of Alzheimer's disease. Expert Opin. Investig. Drugs, 2006, 15, 1-12].

Selective butyrylcholinesterase (BChE) inhibitors, as shown by recent studies, increase the level of acetylcholine in the brain and improve cognitive function in rodents, without having the classic side effects of ACE inhibitors [Greig NH, Utsuki T, Ingram DK, Wang Y, Pepeu G, Scali C, Yu QS, Mamczarz J, Holloway HW, Giordano T, Chen D, Furukawa K, Sambamurti K, Brossi A, Lahiri DK. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc. Natl. Acad. Sci. USA, 2005, 102 (47), 17213-17218].

One of the best known phenothiazine derivatives is Methylene Blue, which has a wide spectrum of biological activity [Schirmer RH, Adler H, Pickhardt M, Mandelkow E. "Lest we forget you-methylene blue ...". Neurobiol. Aging. 2011, 32 (12), 2325. e7-16], including high inhibitory activity against AChE and BChE [Pfaffendorf M, Bruning TA, Batnik HD, vanZwieten PA. The interaction between methylene blue and the cholinergic system. Br. J. Pharmacol, 1997, 122 (1), 95-98], being a reversible inhibitor of both enzymes [Kucukkilinc T., Ozer I. Multi-site inhibition of human plasma cholinesterase by cationic phenoxazine and phenothiazine dyes. Arch. Biochem. Biophys., 2007, 461, 294-298]. It is believed that inhibition of cholinesterases with Methylene Blue may be one of the mechanisms for improving cognitive function in rats [Deiana S., Harrington C.R., Wischik S.M., Riedel G., Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology (Berl), 2009, 202, 53-65].

However, modern approaches to the treatment of neurodegenerative diseases require the use of drugs with a wider spectrum of action.

One of the most promising approaches in the treatment of Alzheimer's disease and other neurodegenerative diseases is based on the use of compounds active against serotonin 5-HT ₆ receptors [Holenz J., Pauwels PJ, Diaz JL, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT ₆ receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006, 11, 283-299]. These mammalian receptors are located exclusively in the central nervous system (CNS), and mainly in the areas of the brain responsible for learning and memory [Ge'rard C, Martres M. - R., Lefe'vre K., Miquel M. - C, Verge 'D., Lanfumey L., Doucet E., Hamon M., El Mestilcawy S. Immunolocalization of serotonin 5-HT ₆ receptor-like material in the rat central nervous system. Brain Research. 1997, 746, 207-219]. 5-HT6 receptor antagonists have been studied in various learning and memory models, where they enhanced the cognitive functions of experimental animals [KG Liu, AJ Robichaud. 5-HT ₆ Antagonists as Potential Treatment for Cognitive Dysfunction. Drug Development Research. 2009, 70, 145-168].

The obtained data on the important role of serotonin receptors in the central nervous system and the development of various neuropsychiatric diseases intensified the search and synthesis of high-affinity selective ligands (“molecular tools”), and then clinical candidates. Currently, a significant number of serotonin 5-HT receptor ligands are at different stages of clinical trials as potential substances for the treatment of various diseases of the central nervous system [http://integrity.prous.com].

Derivatives of gamma-carbolines, which exhibit pharmacological activity in various CNS lesions, including the blocking mechanism of the 6th subtype of serotonin receptors, are one of the known classes of serotonin receptor blockers. [Ivashchenko A.V., Mitkin O.D., Kadieva M.G., Tkachenko S.E. Synthesis and physiological activity of 2,3,4,5-Tetrahydro-1H-pyrido [4,3-6] indoles. Advances in Chemistry, 2010, 79 (4), 325-347; Ivachtchenko AV, Mitkin OD, Tkachenko SE, Okun IM, Kysil VM. 8-Sulfonyl-substituted tetrahydro-l1H-pyrido [4,3-b] indoles as 5-HT ₆ receptor antagonists. Eur. J. Med. Chem. 2010, 45 (2), 782-789].

However, there is no indication that these compounds have inhibitory activity against cholinesterases.

For the cholinesterase inhibitors described above - phenothiazine derivatives - the property to block the 6th subtype of serotonin receptors is unknown.

A promising modern approach for the treatment of complex, multifactorial diseases, including AD and other neurodegenerative disorders, is the creation of multi-target ligands that interact with several targets responsible for pathogenesis. The rational design strategy for multi-target drugs is based on linking two pharmacophores through a linker that are active against two different molecular targets. [Youdim M.V., Buccafusco JJ Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci. 2005, 26, 27-35; Zhang HY One-compound-multiple-targets strategy to combat Alzheimer's disease. FEBS Lett. 2005, 579, 5260-5264; Cappelli A., Gallelli A., Manini M, Anzini M., Mennuni L., Makovec F., Menziani MC, Alcaro S., Ortuso F., Vomero, S. Further studies on the interaction of the 5-hydroxytryptamine3 (5 -HT ₃ ) receptor with arylpiperazine ligands. Development of a new 5-HT ₃ receptor ligand showing potent acetylcholinesterase inhibitory properties. J. Med. Chem. 2005, 48, 3564-3575; Piazzi L., Rampa A., Bisi A., Gobbi S., Belluti F., Cavalli A., Bartolini M., Andrisano V., Valenti P., Recanatini M. 3- (4 - [[Benzyl (methyl) amino] methyl] phenyl) -6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer's disease therapy. J. Med. Chem. 2003, 46 (12), 2279-2282].

However, the selection of pairs is not predictable and depends on the structure of the new molecule as a whole. Preservation of the properties of both constituent parts in a new molecule depends both on the structure of each of the parts and on the structure of the linker.

The present invention solves the problem of creating a multi-drug preparation that combines the properties of cholinesterase inhibitors and 5-HT ₆ blockers, which allows to increase its effectiveness in the treatment of neurodegenerative diseases.

To solve this problem, derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines of the general formula 1 and their hydrochlorides as cholinesterase inhibitors and serotonin receptor blockers are proposed:

in which R ₁ = H, (C ₁ -C ₆ ) alkyl;

R ₂ , R ₃ , R ₄ , R ₅ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,

R ₆ , R ₇ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, NH ₂ , NHAlkyl, NAlkyl ₂ ;

A = CH ₂ CH ₂ , CH = CHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH [(C1-C6) alkyl] C (O), CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ ); CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O) N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ ), CH ₂ CH (OH) CH ₂ , CH ₂ CH (OH) CH ₂ NHCH ₂ CH ₂ , CH ₂ CH (OH) CH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ , CH ₂ CHFCH ₂ NHCH ₂ CH ₂ , CH ₂ CHFCH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ .

Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines may be compounds of the general formula 1.1

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ have the meanings defined above for formula 1;

X = CH ₂ CH ₂ , CH = CHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH [(C1-C6) alkyl] C (O), CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ ); CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O) N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ ).

Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines can also be compounds of general formula 1.2

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ have the meanings defined above for formula 1:

Y = CH ₂ CH (OH) CH 2, CH ₂ CH (OH) CH ₂ NHCH ₂ CH ₂ ,

CH ₂ CH (OH) CH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ .

Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines can also be compounds of the general formula 1.3

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ have the meanings defined above for formula 1;

Z = CH ₂ CHFCH ₂ NHCH ₂ CH ₂ or CH ₂ CHFCH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ .

Another aspect of the invention is a method for producing hydrochlorides of compounds of formula 1.1, formula 1.2, formula 1.3.

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

Another aspect of the invention is a pharmacological agent as cholinesterase inhibitors and serotonin receptor blockers in the treatment of neurodegenerative diseases, containing an active principle and a pharmaceutically acceptable carrier, characterized in that it contains an effective amount of a compound of formula 1 as an active principle.

The term "pharmacological agent" means the use of any dosage form containing a compound of formula 1, which could find prophylactic or therapeutic use in medicine as cholinesterase inhibitors and serotonin receptor blockers in the treatment of neurodegenerative diseases.

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

To obtain a pharmacological agent, one or more compounds of the formula 1 are mixed as an active ingredient with a pharmaceutically acceptable carrier known in medicine according to pharmaceutical methods. Depending on the dosage form of the drug, various carriers may be used.

The technical effect of the proposed group of compounds is the creation of a multi-target drug that combines the properties of cholinesterase inhibitors (IC ₅₀ = 10 ^-6 -10 ^-7 M) and 5-HT ₆ receptor blockers (IC ₅₀ = 10 ^-7 -10 ^-8 M), which allows to increase the effectiveness of the treatment of neurodegenerative diseases.

The structurally individual class of multifunctional drugs based on the original binary structures developed by the authors combines the pharmacophore groups of phenothiazine and gamma-carbolines and combines the properties of cholinesterase inhibitors and blockers of the 6th subtype of serotonin receptors due to both the structure of each part and the structure of the linker, which makes them promising for the development of drugs with a wider spectrum of action.

As the examples show, these compounds demonstrate high selectivity for BChE compared to AChE and have the ability to block the 6th subtype of serotonin receptors.

Thus, these compounds have several advantages over known cholinesterase inhibitors. On the one hand, they predominantly inhibit BChE, i.e. should not cause side effects characteristic of AChE inhibitors, on the other hand, the improvement of cognitive functions when using these compounds should be achieved by two mechanisms - by inhibiting cholinesterase and blockade of the 6th subtype of serotonin receptors, which should lead to an increase in the therapeutic effect.

In addition, it was found that modification with the phenothiazine fragment enhances the weak anticholinesterase activity inherent in gamma-carboline derivatives. The resulting new binary compounds are effective and selective reversible inhibitors of BChE, inhibiting the enzyme of a mixed type.

Multitarget drugs that combine the properties of cholinesterase inhibitors and 5-HT ₆ receptor blockers are not known in the prior art, which informs the invention of meeting the criteria of “novelty” and “inventive step”.

Table 1 presents the results of the evaluation of the biological activity of phenothiazine derivatives of gamma-carbolines as ACE and BChE warm-blooded inhibitors and 5-HT ₆ serotonin receptor blockers.

Figure 1 presents the double reverse coordinates of Lineuiver-Burke on the kinetics of inhibition of BChE by the compound of Example 9: in the absence of an inhibitor [I = 0] and in the presence of three increasing concentrations of the inhibitor: 5 × 10 ^-7 , 1 × 10 ^-6 and 2 × 10 ^-6 M, where [S] is the concentration of the substrate, V _i is the rate of hydrolysis of the substrate.

Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines of the general formula 1 having the claimed properties can be obtained by conjugation of the indole and phenothiazine components corresponding to the claimed composition and combined through the claimed molecular spacer. The synthetic methods for preparing compounds of formula 1 and their hydrochlorides are represented by four general groups, illustrated by examples.

The above examples confirm, but do not limit the invention.

Synthesis of compounds of formula 1.1 (general procedure)

The process is carried out by heating an equimolar mixture of gamma-carbolines 2 and acetylene-containing phenothiazines 3 (Scheme 1) or vinyl-containing phenothiazines 4 (Scheme 2) in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) in the presence of a catalyst selected from the series: sodium methylate (MeONa), tert potassium butylate (tert-BuOK), potassium hydroxide (KOH) and cesium fluoride (CsF) at a temperature of 120-160 ° C for 6-24 hours.

Scheme 1.

R ₁ = H, (C ₁ -C ₆ ) alkyl;

R ₂ , R ₃ , R ₄ , R ₅ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,

R ₆ , R ₇ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, NH ₂ , NHAlkyl, NAlkyl;

kat = MeONa, t-BuOK, KOH, CsF

Scheme 2.

R ₁ = H, (C ₁ -C ₆ ) alkyl;

R ₂ , R ₃ , R ₄ , R ₅ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,

R ₆ , R ₇ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, NH ₂ , NHAlkyl, NAlkyl ₂ ;

W = no, CH ₂ ; CH [(C ₁ -C ₆ ) alkyl] C (O); C (O) NHCH ₂ CH ₂ ); C (O) N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ ; CH [(C ₁ -C ₆ ) alkyl] C (O) N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ ),

X = CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O) CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ ); CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O) N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ ).

kat = MeONa, t-BuOK, KOH, CsF

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

As starting materials, 1 mmol of 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 were taken -2-ynyl-10H-phenothiazine-3,7-diamine. As a catalyst, 200 mg of CsF in 1.5 ml of DMSO was taken. Heated with stirring at 140-160 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 82%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.86 m (4H, CH ₂ ); 2.94 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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 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-phenothiazin-3,7-diamine (I).

As starting materials, 1 mmol of 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- were taken prop-2-ynyl-10H-phenothiazine-3,7-diamine, 300 mg of MeONa in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 130-140 ° C for 8 hours. Then, DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 78%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.86 m (4H, CH ₂ ); 2.94 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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: Method for the preparation of 10- [3- (2,8-Dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -allyl] -N, N, N, N -tetramethyl-10H-phenothiazin-3,7-diamine (I).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of N, N, N, N-tetramethyl-10-prop -2-ynyl-10H-phenothiazine-3,7-diamine, 300 mg of tert-BuOK in 1.5 ml of DMSO were taken as a catalyst. Heated with stirring at 120-130 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 80%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.86 m (4H, CH ₂ ); 2.94 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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 for the preparation of 10- [3- (2,8-Dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -allyl] -N, N, N, N -tetramethyl-10H-phenothiazin-3,7-Diamine (I).

As starting materials, 1 Mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol N, N, N, N-tetramethyl-10-prop -2-ynyl-10H-phenothiazine-3,7-diamine, 100 mg of KOH in 1.5 ml of DMF was taken as a catalyst, heated with stirring at 120-140 ° C for 8 h. DMF was removed in vacuum 3 mm Hg ., from the residue the product was extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. Yellow solid, yield: 79%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.48 and 2.53 both s (3H, Me); 2.65 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.86 m (4H, CH ₂ ); 2.94 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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: Method for the preparation of 10- [3- (2,8-Dimethyl-1,2,3-4-tetrahydropyrido [4,3-b] indol-5-yl) ethyl] -N, N, N, N -tetramethyl-10H-phenothiazin-3,7-diamine (II).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 10-allyl-N, N, N, N-tetramethyl were taken -10H-phenothiazin-3,7, -diamine, 200 mg of CsF in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 140-150 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 86%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH ₂ , J = 6.4 Hz); 2.60-2.86 m (6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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: Method for the preparation of 10- [3- (2,8-Dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) ethyl] N, N, N, N- tetramethyl-10H-phenothiazine-3,7-diamine (II).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 10-allyl-N, N, N, N-tetramethyl were taken -10H-phenothiazin-3,7, -diamine, 300 mg of MeONa in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 150-160 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 82%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH ₂ , J = 6.4 Hz); 2.60-2.86 m (6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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: Method for the preparation of 10- [3- (2,8-Dimethyl-1,2,3 <4-tetrahydropyrido [4,3-b] indol-5-yl) ethyl] -N, N, N, N -tetramethyl-10H-phenothiazin-3,7-diamine (II).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 10-allyl-N, N, N, N-tetramethyl were taken -10H-phenothiazin-3,7, -diamine, 300 mg tert-BuOK in 1.5 ml DMSO. Heated with stirring at 140-150 ° C for 18 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 85%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH ₂ , J = 6.4 Hz); 2.60-2.86 m (6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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: Method for the preparation of 10- [3- (2,8-Dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) ethyl] -N, N, N, N tetramethyl-10H-phenothiazin-3,7-diamine (II).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3b] indole, 1 mmol of 10-allyl-N, N, N, N-tetramethyl-10H were taken β-phenothiazine-3,7, -diamine, 100 mg of KOH in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 150-160 ° C for 12 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 78%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.54 both s (3H, Me); 2.63 t (2H, CH ₂ , J = 6.4 Hz); 2.60-2.86 m (6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 s (2H, CH ₂ ); 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: Method for the preparation of 4- (2-Methyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan-1- she (III).

As starting materials, 1 mmol of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine-10- il) propenone, 200 mg of CsF in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 120-140 ° C for 20 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 83%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeN); 2.68 (s, 6H, CH ₂ ); 3.49 (s, 2H, CH ₂ ); 4.17 (br s, 2H, CH ₂ ); 6.67-6.95 (m, 8H, CH _Ar ); 7.00-7.16 (m, 4H, CH _Ar ).

Example 10: Method for the preparation of 4- (2-Methyl-1,2,3,4-tetrahydro-pyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan-1- she (III).

As starting materials, 1 mmol of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine-10- il) propenone, 300 mg MeONa in 1.5 ml DMSO were taken as a catalyst. Heated with stirring at 120-140 ° C for 11 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. Yellow solid, yield: 80%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeN); 2.68 (s, 6H, CH ₂ ); 3.49 (s, 2H, CH ₂ ); 4.17 (broad s, 2H, CH ₂ ); 6.67-6.95 (m, 8H, CH _Ar ); 7.00-7.16 (m, 4H, CH _Ar ).

Example 11: Method for the preparation of 4- (2-Methyl-1,2,3,4-tetrahydro-pyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan-1- she (III).

As starting materials, 1 mmol of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine-10- il) propenone, 300 mg of tert-BuOK in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 120-130 ° C for 6 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. Yellow solid, yield: 81%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeN); 2.68 (s, 6H, CH ₂ ); 3.49 (s, 2H, CH ₂ ); 4.17 (br s, 2H, CH ₂ ); 6.67-6.95 (m, 8H, CH _Ar ); 7.00-7.16 (m, 4H, CH _Ar ).

Example 12: Method for the preparation of 4- (2-Methyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) - (phenothiazin-10-yl) propan-1-one ( III).

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

Example 13: Method for the preparation of 4- (2-Ethyl-1,2,3,4-tetrahydro-pyrido [4,3-b] 1indol-5-yl) -1- (phenothiazin-10-yl) propan-1- she (iv).

As starting materials, 1 mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine-10- il) propenone, 200 mg of CsF in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 120-140 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 88%. ¹ H NMR Spectrum (CDCl ₃ ) 5, ppm: 1.12 (t, 3H, J = 6.7, Me); 2.49 (q, 2H, J = 6.7, MeCH ₂ ); 2.65 (m, 6H, CH ₂ ); 3.46 (s, 2H, CH ₂ ); 4.09 (br s, 2H, CH ₂ ); 6.62-6.82 (m, 8H, CH _Ar ); 6.90-7.05 (m, 4H, CH _Ar ).

Example 14: Method for the preparation of 4- (2-Ethyl-1,2,3,4-tetrahydro-pyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan-1- she (iv).

As starting materials, 1 mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine-10- il) propenone, 300 mg of MeONa in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 140-150 ° C for 6 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 83%. ¹ H NMR Spectrum (CDCl ₃ ) 8, ppm: 1.12 (t, 3H, J = 6.7, Me); 2.49 (q, 2H, J = 6.7, MeCH ₂ ); 2.65 (m, 6H, CH ₂ ); 3.46 (s, 2H, CH ₂ ); 4.09 (br s, 2H, CH ₂ ); 6.62-6.82 (m, 8H, CH _Ar ); 6.90-7.05 (m, 4H, CH _Ar ).

Example 15: Method for the preparation of 4- (2-Ethyl-1,2,3,4-tetrahydro-pyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan-1- she (iv).

As starting materials, 1 mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine-10- il) propenone, 300 mg of tert-BuOK in 1.5 ml of DMSO were taken as a catalyst. Heated with stirring at 120-130 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 81%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 1.12 (t, 3H, J = 6.7, Me); 2.49 (q, 2H, J = 6.7, MeCH ₂ ): 2.65 (m, 6H, CH ₂ ); 3.46 (s, 2H, CH ₂ ); 4.09 (br s, 2H, CH ₂ ); 6.62-6.82 (m, 8H, CH _Ar ); 6.90-7.05 (m, 4H, CH _Ar ).

Example 16: Method for the preparation of 4- (2-Ethyl-1,2,3,4-tetrahydro-pyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan-1- she (iv).

As starting materials, 1 mmol of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine-10- il) propenone, 100 mg of KOH in 1.5 ml of DMF was taken as a catalyst. Heated with stirring at 130-140 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 77%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 1.12 (t, 3H, J = 6.7, Me); 2.49 (q, 2H, J = 6.7, MeCH ₂ ); 2.65 (m, 6H, CH ₂ ); 3.46 (s, 2H, CH ₂ ); 4.09 (br s, 2H, CH ₂ ); 6.62-6.82 (m, 8H, CH _Ar ); 6.90-7.05 (m, 4H, CH _Ar ).

Example 17: Method for the preparation of 4- (2,8-Dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (V).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 200 mg of CsF in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 120-130 ° C for 12 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 85%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CH _Ar ); 7.14-7.28 (m, 6H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

Example 18: Method for the preparation of 4- (2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (V).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 300 mg MeONa in 1.5 ml DMSO were taken as a catalyst. Heated with stirring at 120-130 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 83%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CH _Ar ); 7.14-7.28 (m, 6H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

Example 19: Method for the preparation of 4- (2,8-Dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (V).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 300 mg of tert-BuOK in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 120-140 ° C for 8 hours. DMSO (or DMF) was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 84%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CH _Ar ); 7.14-7.28 (m, 6H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

Example 20: Method for the preparation of 4- (2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (V).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 100 mg of KOH in 1.5 ml of DMF was taken as a catalyst. Heated with stirring at 140-150 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 80%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CH _Ar ); 7.14-7.28 (m, 6H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

Example 21: Method for the preparation of 4- (8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (VI).

As starting materials, 1 mmol of 8-methyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino phenothiazin-10-yl) propenone, 200 mg of CsF in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 120-130 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 84%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 1.21 (t, 3H, J = 7.1, MeCH ₂ ); 2.42 (s, 3H, MeC); 2.65 (q, 2H, J = 6.7, MeCH ₂ ; 2.80 (m, 6H, CH ₂ ); 3.65 (s, 2H, CH ₂ ); 4.32 (br s, 2H, CH ₂ ); 6.92 (d, 1H , J = 8.4, CH _Ar ); 7.00 (d, 1H, J = 8.4, CH _Ar ); 7.08-7.28 (m, 7H, CH _Ar ); 7.33-7.44 (m, 2H, CH _Ar ).

Example 22: Method for the preparation of 4- (8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-she

As starting materials, 1 mmol of 8-methyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino phenothiazin-10-yl) propenone, 300 mg MeONa in 1.5 ml DMSO were taken as a catalyst. Heated with stirring at 130-140 ° C for 8 hours. DMSO (or DMF) was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 81%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 1.21 (t, 3H, J = 7.1, MeCH ₂ ); 2.42 (s, 3H, MeC); 2.65 (q, 2H, J = 6.7, MeCH ₂ ); 2.80 (m, 6H, CH ₂ ); 3.65 (s, 2H, CH ₂ ); 4.32 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.4, CH _Ar ); 7.00 (d, 1H, J = 8.4, CH _Ar ); 7.08-7.28 (m, 7H, CH _Ar ); 7.33-7.44 (m, 2H, CH _Ar ).

Example 23: Method for the preparation of 4- (8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (VI).

As starting materials, 1 mmol of 8-methyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino phenothiazin-10-yl) propenone, 300 mg of tert-BuOK in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 120-130 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 86%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 1.21 (t, 3H, J = 7.1, MeCH ₂ ); 2.42 (s, 3H, MeC); 2.65 (q, 2H, J = 6.7, MeCH ₂ ); 2.80 (m, 6H, CH ₂ ); 3.65 (s, 2H, CH ₂ ); 4.32 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.4, CH _Ar ); 7.00 (d, 1H, J = 8.4, CH _Ar ); 7.08-7.28 (m, 7H, CH _Ar ); 7.33-7.44 (m, 2H, CH _Ar ).

Example 24: Method for the preparation of 4- (8-Methyl-2-ethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (VI).

As starting materials, 1 mmol of 8-methyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino phenothiazin-10-yl) propenone, 100 mg of KOH in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 130-140 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 82%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 1.21 (t, 3H, J = 7.1, MeCH ₂ ); 2.42 (s, 3H, MeC); 2.65 (q, 2H, J = 6.7, MeCH ₂ ); 2.80 (m, 6H, CH ₂ ); 3.65 (s, 2H, CH ₂ ); 4.32 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.4, CH _Ar ); 7.00 (d, 1H, J = 8.4, CH _Ar ); 7.08-7.28 (m, 7H, CH _Ar ); 7.33-7.44 (m, 2H, CH _Ar ).

Example 25: Method for the preparation of 4- (2-Methyl-8-fluoro-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-one (VII).

As starting materials, 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- phenothiazin-10-yl) propenone, 200 mg of CsF in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 130-140 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 78%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH ₂ ); 2.72 (m, 2H, CH ₂ ); 3.49 (s, 2H, CH ₂ ); 4.25 (br s, 2H, CH ₂ ); 6.79 (dt, 1H, J = 9.0, 2.2, CH _Ar ); 6.94-7.11 (m, 7H, CH _Ar ); 7.23-7.30 (m, 2H, CH _Ar ); 7.54 (d, 1H, J = 2.2, CH _Ar ).

Example 26: Method for the preparation of 4- (2-Methyl-8-fluoro-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan- 1-she

As starting materials, 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- phenothiazin-10-yl) propenone, 300 mg of MeONa in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 130-140 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 81%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH ₂ ); 2.72 (m, 2H, CH ₂ ); 3.49 (s, 2H, CH ₂ ); 4.25 (br s, 2H, CH ₂ ); 6.79 (dt, 1H, J = 9.0, 2.2, CH _Ar ); 6.94-7.11 (m, 7H, CH _Ar ); 7.23-7.30 (m, 2H, CH _Ar ); 7.54 (d, 1H, J = 2.2, CH _Ar ).

Example 27: Method for the preparation of 4- (2-Methyl-8-fluoro-1,2,3,4 tetrahydropyrido [4,3-b] indol-5-yl) -1- (Phenothiazin-10-yl) propan-1 -one (VII).

As starting materials, 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-dimethylamines phenothiazine- 10-yl) propenone, 300 mg of tert-BuOK 1.5 ml of DMSO were taken as a catalyst. Heated with stirring at 130-140 ° C for 8 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated, the residue was chromatographed on silica gel (60 mesh), eluene methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 82%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH ₂ ); 2.72 (m, 2H, CH ₂ ); 3.49 (s, 2H, CH ₂ ); 4.25 (br s, 2H, CH ₂ ); 6.79 (dt, 1H, J = 9.0, 2.2, CH _Ar ); 6.94-7.11 (m, 7H, CH _Ar ); 7.23-7.30 (m, 2H, CH _Ar ); 7.54 (d, 1H, J = 2.2, CH _Ar ).

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

As starting materials, 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- phenothiazin-10-yl) propenone, 100 mg of KOH in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 120-130 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 75%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.44 (s, 3H, MeN); 2.65 (m, 4H, CH ₂ ); 2.72 (m, 2H, CH ₂ ); 3.49 (s, 2H, CH ₂ ); 4.25 (br s, 2H, CH ₂ ); 6.79 (dt, 1H, J = 9.0, 2.2, CH _Ar ); 6.94-7.11 (m, 7H, CH _Ar ); 7.23-7.30 (m, 2H, CH _Ar ); 7.54 (d, 1H, J = 2.2, CH _Ar ).

Example 29: Method for the preparation of 1- (3,7-Bis-dimethylamino-phenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole- 5-yl) propan-1-one (VIII).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 200 mg of CsF in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 140-150 ° C for 6 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 83%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CH _Ar ); 7.14-7.28 (m, 4H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

Example 30: Method for the preparation of 1- (3,7-Bis-dimethylamino-phenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole- 5-yl) propan-1-one (VIII).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 300 mg MeONa in 1.5 ml DMSO were taken as a catalyst. Heated with stirring at 130-140 ° C for 12 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 81%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CH _Ar ); 7.14-7.28 (m, 4H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

Example 31: Method for the preparation of 1- (3,7-Bis-dimethylamino-phenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole- 5-yl) propan-1-one (VIII).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 300 mg of tert-BuOK in 1.5 ml of DMSO were taken as a catalyst. Heated with stirring at 120-130 ° C for 10 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 83%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CH ^Ar ); 7.14-7.28 (m, 4H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

Example 32: Method for the preparation of 1- (3,7-Bis-dimethylamino-phenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3b] indole-5- il) propan-1-one (VIII).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of 1- (3,7-bis-dimethylamino-phenothiazine- 10-yl) propenone, 100 mg of KOH in 1.5 ml of DMF was taken as a catalyst. Heated with stirring at 130-140 ° C for 12 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 82%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.43 (s, 3H, MeC); 2.54 (s, 3H, MeN); 2.79 (m, 6H, CH ₂ ); 2.96 (s, 12H, Me); 3.64 (s, 2H, CH ₂ ); 4.34 (br s, 2H, CH ₂ ); 6.92 (d, 1H, J = 8.3, CH _Ar ); 7.02 (d, 1H, J = 8.3, CHAr); 7.14-7.28 (m, 4H, CH _Ar ); 7.36-7.47 (m, 3H, CH _Ar ).

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

The process is carried out by heating an equimolar mixture of gamma-carbolines of the general formula 2 and epoxy-containing phenothiazines of the general formula 5 (Scheme 3) in dimethyl sulfoxide or dimethylformamide in the presence of a catalyst selected from the series: sodium methylate (MeONa), potassium tert-butylate (tert-BuOK), hydroxide potassium (KOH) and cesium fluoride (CsF) at a temperature of 100-140 ° C for 2-12 hours.

Scheme 3

R ¹ = H, (C ₁ -C ₆ ) alkyl;

R ₂ , R ₃ , R ₄ , R ₅ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,

R ₆ , R ₇ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, NH ₂ , NHAlkyl, NAlkyl ₂ ;

D = CH ₂ ; CH ₂ NHCH ₂ CH ₂ ; CH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂

Y = CH ₂ CH (OH) CH ₂ , CH ₂ CH (OH) CH ₂ NHCH ₂ CH ₂ ,

CH ₂ CH (OH) CH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ ,

kat = MeONa, t-BuOK, KOH, CsF.

Example 33: Method for the preparation of 1- (3,7-Bis-dimethylaminophenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole-5- il) -propan-2-one (IX).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of N, N, N, N-tetramethyl-10-oxiranylmethyl were taken -10H-phenothiazin-3,7, -diamine, 200 mg of CsF, mg in 1.5 ml of DMSO was taken as a catalyst. Heated with stirring at 100-120 ° C for 6 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 88%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.52 both s (3H, Me); 2.64 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.85 m (4H, CH ₂ ); 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: Method for the preparation of 1- (3,7-Bis-dimethylaminophenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole-5- il) -propan-2-one (IX).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of N, N, N, N-tetramethyl-10-oxiranylmethyl were taken -10H-phenothiazin-3,7, -diamine, 200 mg of MeONa in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 110-120 ° C for 8 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 83%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.52 both s (3H, Me); 2.64 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.85 m (4H, CH ₂ ); 2.95 (s, 12H, Me); 3.16 (dd, 1H, J = 13.3, 6.2 Hz), 3.30 (dd, 1H, 7 = 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: Method for the preparation of 1- (3,7-Bis-dimethylaminophenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole-5- il) -propan-2-one (IX).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of N, N, N, N-tetramethyl-10-oxiranylmethyl were taken -10H-phenothiazine-3,7, -diamine, 200 mg of tert-BuOK 1.5 ml of DMSO were taken as a catalyst. Heated with stirring at 100-120 ° C for 12 hours. DMSO was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 80%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.52 both with (3H, Me); 2.64 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.85 m (4H, CH ₂ ); 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: Method for the preparation of 1- (3,7-Bis-dimethylaminophenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole-5- il) -propan-2-one (IX).

As starting materials, 1 mmol of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole, 1 mmol of N, N, N, N-tetramethyl-10-oxiranylmethyl were taken -10H-phenothiazin-3,7, -diamine, 200 mg of KOH in 1.5 ml of DMF were taken as a catalyst. Heated with stirring at 100-110 ° C for 2 hours. DMF was removed in vacuo 3 mm Hg, the product was extracted from the residue with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 76%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.52 both with (3H, Me); 2.64 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.85 m (4H, CH ₂ ); 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)

Synthesis of compounds of formula 1.3 (general procedure)

The process is carried out by mixing equimolar amounts of hydroxyl-containing conjugates of gamma-carbolines and phenothiazines of the general formula 6 and diethylaminosulfotrifluoride (Et ₂ NSF ₃ ) (Scheme 4) in dimethyl sulfoxide or dimethylformamide at temperatures (-78) -0 ° C for 1-3 hours:

Scheme 4.

R ₁ = H, (C ₁ -C ₆ ) alkyl;

R ₂ , R ₃ , R ₄ , R ₅ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,

R ₆ , R ₇ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, NH ₂ , NHAlkyl, NAlkyl ₂ ;

E = CH ₂ ; CH ₂ NHCH ₂ CH ₂ ; CH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ .

Z = CH ₂ CHFCH ₂ NHCH ₂ CH ₂ , CH ₂ CHFCH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ .

Example 37: Method for the preparation of 10- [3- (2,8-Dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -2-fluoropropyl] -N, N, N , N-tetramethyl-10H-phenothiazin-3,7-diamine (X).

As the starting material, 1 mmol of 1- (3,7-Bis-dimethylaminophenothiazin-10-yl) -3- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indole- 5-yl) -propan-2-one in 3.0 ml DMSO and 1 mmol diethylaminosulfotrifluoride. The reagents were mixed at a temperature of (-78) ° C. The reaction mass was stirred for 3 hours, raising the temperature to 0 ° C, poured into 10 ml of water, extracted with methylene chloride. Methylene chloride was evaporated and the residue was chromatographed on silica gel (60 mesh), eluent methanol / chloroform = 1/5. The resulting product is a yellow solid, yield: 63%. ¹ H NMR spectrum (CDCl ₃ ) δ, ppm: 2.50 and 2.53 both s (3H, Me); 2.65 t (2H, CH ₂ , J = 6.4 Hz); 2.70-2.85 m (4H, CH ₂ ); 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, J _HF = 48 Hz), 6.88 d (1H, CH _Ar , 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 = 8.8 Hz), 7.54 (d, 2H, J = 2.2 Hz).

Synthesis of hydrochlorides of compounds of the formula 1.1, 1.2, 1.3 (general procedure).

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

Example 38: Method for the production of 4- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1- (phenothiazin-10-yl) propan-1 hydrochloride -one (XI).

As the starting material, take 1 mmol of 4- (2,8-dimethyl-1,2,3,4-tetrahydropyrido [4,3-b] indol-5-yl) -1-phenothiazin-10-yl-propan-1 -one, dissolved in 2 ml of a 10% solution of HCl in isopropanol at a temperature of 50 ° C. It is cooled to 0 ° C, and the precipitate formed is filtered off. The resulting product is a white solid, yield: 95%. ¹ H NMR Spectrum (CDCl ₃ ) δ, ppm: 2.59 (s, 3H, MeC); 2.65 (s, 3H, MeN); 2.73-2.97 (m, 4H, CH ₂ ); 3.03-3.16 (m, 2H, CH ₂ ); 3.44-3.65 (m, 2H, CH ₂ ); 4.33 (br s, 2H, CH ₂ ); 6.96-7.15 (m, 2H, CH _Ar ); 7.19-7.32 (m, 5H, CH _Ar ); 7.38-7.49 (m, 4H, CH _Ar ); 10.90 (s, 1H).

Biological Testing Procedure

Determination of the inhibitory activity of compounds of general formula 1 in relation to acetylcholinesterase and butyrylcholinesterase.

For kinetic studies, commercial preparations (Sigma, USA) of human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7) and horse serum butyrylcholinesterase (BChE, EC 3.1.1.8) were used.

Determination of enzyme activity

The activity of AChE and BChE was determined by the Ellman method (λ412 nm) using acetylthiocholine (1 mM) and butyrylthiocholine (1 mM) as a substrate, respectively; determination conditions: 0.1 M phosphate buffer pH 7.5, 25 ° C. Measurements were performed on a BioRad Benchmark Plus microplate spectrophotometer.

Determination of IC ₅₀ values for inhibition of AChE and BChE by test compounds.

To determine the IC ₅₀ inhibition of AChE and BChE (IC50-inhibitor concentration, which is required to reduce the enzyme activity by 50%), a sample of the corresponding enzyme was incubated with the test compound (DMSO concentration 2 vol%) for 10 minutes, then the residual enzyme activity was determined. The concentration range of the test compound was 2 × 10 ⁻¹² −2 −2 × 10 ⁻⁴ M. Each experiment was carried out in triplicate. Measurements were performed on a BioRad Benchmark Plus microplate spectrophotometer. The calculation of IC50 was performed using the Origin 6.1 program.

Determination of the mechanism of BChE inhibition by the studied compounds.

To elucidate the mechanism of BChE inhibition, we determined the dependence of the residual enzyme activity on the inhibitor concentration at various substrate concentrations. The data were analyzed in the double inverse coordinates of Lineuiver-Burke. The kinetic inhibition constants were calculated using the Origin 6.1 program.

The results of the evaluation of the anticholinesterase activity of some representatives of the compounds of general formula 1, presented in Table 1, indicate that the compounds very weakly inhibit AChE and in most cases exhibit high activity against BChE (IC ₅₀ = 10 ^-6 -10 ^-7 M).

Compounds inhibit BChE reversibly. Figure 1 shows the dependence of inhibitory activity of the compound of Example 9 on the substrate concentration obtained for 3 increasing concentrations of the inhibitor 5 × 10 ^-7 , 1 × 10 ^-6 and 2 × 10 ^-6 M. The dependences are presented in double inverse coordinates - coordinates Lineuivera Burke. The intersection of the direct dependences 1 / V = f (1 / S) obtained for different concentrations of the inhibitor in the upper left quadrant indicates a mixed type of inhibition.

Thus, as a result of studying the anticholinesterase activity of gamma-carboline derivatives modified with the phenothiazine fragment, it was found that modification with the phenothiazine fragment enhances the weak anticholinesterase activity inherent in gamma-carboline derivatives. The resulting new binary compounds are effective and selective reversible butyrylcholinesterase inhibitors that inhibit the enzyme in a mixed manner.

Determination of the binding of compounds of general formula 1 to the 5-HT ₆ serotonin receptor.

To screen substances for their potential ability to interact with the 5-HTb serotonin receptor, the radioligand binding method was used. For this, membrane preparations were prepared from rat brains by homogenizing them in a glass homogenizer, followed by separating plasma membranes from nuclei, mitochondria, and cell fragments by differential centrifugation.

A membrane preparation for radioligand analysis was prepared according to the method of [Boess F.G., Riemer C, Bos M., Bentley J., Bourson A., Sleight A.J. The 5-hydroxytryptamine6 receptor-selective radioligand [3H] Ro 63-0563 labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum. Mol. Pharmacol, 1998, 54, 577-583]. Before removing the striatum, rat brains were placed on ice. Then the striatums were removed and placed in a Potter homogenizer (Teflon-glass) in 10 volumes of 50 mM TrisHCl pH 7.4 buffer containing 0.32 M sucrose (buffer No. 1). The homogenate was diluted to 50 volumes with assay buffer No. 2 (50 mM TrisHCl, pH 7.4) and centrifuged for 10 min at 1000 g at 4 ° C. The supernatant was collected and centrifuged again for 30 minutes at 25,000 g. The precipitate was diluted in 50 volumes of 50 mM TrisHCl buffer, pH 7.4, and centrifuged for 15 min at 25000 g. The precipitate and its soft, unsteady layer were collected, diluted in 50 volumes of 50 mM TrisHCl buffer, pH 7.4, incubated for 15 min at 37 ° C and centrifuged for 15 min at 25000 × g. The resulting pellet was suspended in 50 mM Tris-HCl buffer, pH 7.4, and the suspension was again centrifuged for 15 min at 25000g. This washing procedure was carried out 2 more times. The final pellet was resuspended in 5 volumes of buffer No. 2 (50 mM TrisHCl, pH 7.4) and stored in liquid nitrogen.

The binding of the studied compounds to the 5-HT ₆ receptor was determined in accordance with the procedure described in [Boess FG, Riemer C, Bos M., Bentley J., Bourson A., Sleight AJ The 5-hydroxytryptamine ₆ receptor-selective radioligand [3H ] Ro 63-0563 labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum. Mol. Pharmacol., 1998, 54, 577-583]. For this, membrane preparations were incubated with a 5-HT ₆ labeled ligand of ₆ receptors [ ³ H] SB258585 (2.0 nM) without and in the presence of the test compounds for 120 minutes at room temperature in an environment consisting of 50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 2 mM ascorbic acid, 0.001% BSA. Samples after incubation were filtered under vacuum on a G / F glass-microfiber filter (Millipor, USA), pre-soaked in 0.3% polyethyleneimine for 2 hours at 4 ° C. The filters were washed three times with cold 50 mM Tris-HCl buffer solution, and radioactivity was measured using a liquid scintillation beta analyzer (TriCarb, PerkinElmer, USA) with a counting efficiency of about 45%. Non-specific binding, which accounted for 30% of total binding, was determined by incubation of membrane preparations with a radioligand in the presence of 50 μl of 10 μM unlabeled ligand BGC 20-761.

The binding of the test compounds to the receptor was determined by their ability to displace the radioactive ligand and expressed as a percentage of displacement. The displacement percentage was determined by the following formula:

,

,

where TA is the total radioactivity in the presence of only a radioactive ligand, CA is radioactivity in the presence of a radioligand and test compound, and NA is radioactivity in the presence of a radioligand and serotonin (5 μM).

The test results of some representatives of the compounds of General formula 1, presented in Table 1, indicate the activity of these compounds in relation to 5-HT ₆ receptors.

Thus, the results of biological tests show that the compounds of general formula 1 inhibit cholinesterases, showing higher activity and selectivity for BChE compared to AChE, and are effective 5-HT ₆ ligands.

A further aspect of the invention is a pharmacological agent for improving cognitive function and memory, comprising an active principle and a pharmaceutically acceptable carrier, in which an effective amount of a compound of formula 1 is contained as an active principle.

The pharmacological agent according to the invention is prepared using techniques generally accepted in the art and includes a pharmacologically effective amount of an active agent representing a compound of formula 1 (“active principle”), typically from 1 to 20% by weight, or from 1 mg to 20 mg in a dosage form that is a tablet, granule, spheroid, bead, pill or capsule, in combination with one or more pharmaceutically acceptable adjuvants, such as diluents, binders, disintegrating agents Options, adsorbents, fragrances, flavoring agents. In accordance with known methods, pharmaceutical compositions may be in various liquid or solid forms. Examples of solid dosage forms include, for example, tablets, pills.

As can be seen from the above examples, the use of compounds of formula 1 of the present invention solves the problem of expanding and qualitatively improving the arsenal of drugs used in the treatment of neurodegenerative diseases that lead to the development of destructive processes in the central and peripheral nervous system, by combining the properties of cholinesterase inhibitors and effective ligands of the 6th subtype of serotonin receptors (5-HT ₆ ).

Claims (6)

1. Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines of the general formula 1 and their hydrochlorides as cholinesterase inhibitors and serotonin receptor blockers:

in which R ₁ = H, (C ₁ -C ₆ ) alkyl;
R ₂ , R ₃ , R ₄ , R ₅ = H, F, O, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy,
R ₆ , R ₇ = H, F, Cl, Br, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, NH ₂ ,
NHAlkyl, NAlkyl ₂ ;
A = CH ₂ CH ₂ , CH = CHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O), CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ ; CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O) N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ , CH ₂ CH (OH) CH ₂ , CH ₂ CH (OH) CH ₂ NHCH ₂ CH ₂ , CH ₂ CH (OH) CH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ , CH ₂ CHFCH ₂ NHCH ₂ CH ₂ , CH ₂ CHFCH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ . 2. Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines according to claim 1, which are compounds of the general formula 1.1

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ have the meanings defined above for formula 1;
X = CH ₂ CH ₂ , CH = CHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O), CH ₂ CH ₂ C (O) NHCH ₂ CH ₂ ) ; CH ₂ CH [(C ₁ -C ₆ ) alkyl] C (O) N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ ). 3. Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines according to claim 1, which are compounds of the general formula 1.2.

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ have the meanings defined above for formula 1;
Y = CH ₂ CH (OH) CH ₂ , CH ₂ CH (OH) CH ₂ NHCH ₂ CH ₂ , CH ₂ CH (OH) CH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ . 4. Derivatives of 1,2,3,4-tetrahydropyrido [4,3-b] indole-containing phenothiazines according to claim 1, which are compounds of the general formula 1.3.

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ have the meanings defined above for formula 1;
Z = CH ₂ CHFCH ₂ NHCH ₂ CH ₂ or
CH ₂ CHFCH ₂ N [(C ₁ -C ₆ ) alkyl] CH ₂ CH ₂ , 5. A method of producing hydrochlorides of any of the compounds of formulas 1.1, 1.2, 1.3, which consists in dissolving the corresponding compounds of formulas 1.1, 1.2, 1.3 in a 10% solution of HCl in isopropanol. 6. A pharmacological agent as cholinesterase inhibitors and serotonin receptor blockers in the treatment of neurodegenerative diseases, containing an active principle and a pharmaceutically acceptable carrier, characterized in that it contains an effective amount of a compound of formula 1 as an active principle.

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