Condensed indole derivative or its pharmaceutically acceptable salt, pharmaceutical composition active antagonist 5-ht*004 - receptor

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds, active antagonist of 5-HT4the receptor. The inventive condensed indole derivative of the formula I

,

where X Is O, A is -(CH2)3, R1, R2, R3, R4is hydrogen, Y is NH, Z represents a group of the formula

< / BR>
where R5represents hydrogen, C1-12alkyl, phenyl(C1-C6) alkyl, or R5-(CH2)Z- R10where Z = 2 or 3, and R10selected from phenoxy and SO2NR11R12where R11and R12is hydrogen or C1-6alkyl, or its pharmaceutically acceptable salt, and a pharmaceutical composition active antagonist of 5-HT4receptor containing an effective amount of the compounds of formula (I). 2 S. and 2 C.p. f-crystals, 2 tab.

The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals.

In European application [1] describes indole derivatives having activity antagonist of 5 - HT3the receptor.

In European journal of Pharmacology, 146 1988,187 - 188 and Naunyn Yong, - like receptor 5 - HT4and ICS 205 - 930, which is also an antagonist of the receptor 5-HT3that acts as an antagonist at this receptor.

In the international application [2] described the use of receptor antagonists of 5-HT4for the treatment of cardiac arrhythmias and paralysis.

In European patent application N A-501322 (Glaxo Group limited) describes indole derivatives having activity receptor antagonist 5-HT4.

Now open the new class of different structures of the compounds,which are indologie derivatives, 1,2-disubstituted, alkylene, with azacyclonol, condensed azabicyclic or aminoacylase component of these compounds have activity receptor antagonist 5-HT4.

Thus, in accordance with the present invention the compound obtained of the formula (I) or acceptable for pharmaceutical purposes of its salt:

< / BR>
where X IS O, S, SO, SO2CH2CH or NR,

where R is hydrogen or C1-6alkyl;

A - the purpose of saturated or unsaturated polymethylene with 2 to 4 carbon atoms;

R1and R2is hydrogen or C1-6alkyl;

R3is hydrogen, halo, C1-6alkyl, amino, nitro or1-6alkoxy;

R
< / BR>
where n1- 1, 2, 3 or 4; n2is 0, 1, 2, 3 or 4; n3- 2, 3, 4 or 5;

q is 0, 1, 2 or 3; p is 0, 1 or 2; m = 0, 1, or 2;

R5is hydrogen, C1-12alkyl, aralkyl or R5= (CH2)z-10where Z is equal to 2 and 3;

R10selected from cyano, hydroxyl, C1-6alkoxy, phenoxy, C(O)C1-6of alkyl, COC6H5, - CONR11R12, NR11COR12, SO2NR11R12or NR11SO2R12where R11and R12is hydrogen or C1-6alkyl; and

R6, R7and R8- independently hydrogen or C1-6alkyl; and R9is hydrogen or C1-10alkyl;

or the compound of formula (I), in which CO - Y bond substituted heterocyclic bioisosteres connection; with the activity of the receptor 5 - HT4.

Examples alilovic or alkalmazasa groups include C1C2C3C4C5C6C7C8C9C10C11or C12branched, normal chain or cyclic alkyl as a group C1-4alkalemia groups include methyl, ethyl, n - and ISO - propyl, n -, ISO-, sec - tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, Cyclops is by one or more substituents, selected from halo, C1-6the alkyl and C1-6alkoxy.

Halo includes fluorine, chlorine, bromine and iodine.

Relevant bioisosterism connection for communication amide or ether complex containing Y in the formula (I) is a compound of formula (d):

< / BR>
where the circle marked points represents one or two double bonds in any position five-membered ring;

H, J, and 1 are independent oxygen, sulfur,nitrogen or carbon provided that at least one of H, J and 1 is other than carbon;

U - nitrogen or carbon.

In European patent application N A - 328200 (Merck sharp & Dohm Ltd.) given examples (d) for X, Y and Z, for example, oxadiazole component. X often represents a 0.

Values for A include - CH2- (CH2)rCH2where r is 0, 1 or 2; - CH2- CH = CH -; - C(CH3) = CH - or when x = CH or N, A - can be - (CH2)2- CH = or - CH = CH - CH =.

In the examples that will be presented, described other examples A.

R1and R2often hydrogen or R1and R2- gem - dimethyl. The r value is often equal to 1;

R3- preferably hydrogen;

R4- preferably hydrogen or galielo equal to 2, 3 or 4.

R9and R10- preferably both - alkyl, especially one of R9and R10is (C4or more) alkyl.

Particular values for z, which are of particular interest, are the following:

< / BR>
< / BR>
The invention also relates to new compounds of the formula (I) with the side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). According to another aspect, piperidino ring in (i), (ii) or (iii) may be pyrrolidinium or azetidinol, and/or N-substituent in (i) or (ii) may be substituted C3or mainly alkyl or possibly substituted by benzyl.

According to another aspect, the N - substituent in the formula (i) or formula (ii) may be substituted (CH2)nR4as shown in the formula (I) and in the specific examples presented in the application EP - A - 501322.

Pharmaceutically acceptable salts of compounds of formula (I) include salts of acids from the reaction of accession with conventional acids such as hydrochloric, Hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, methansulfonate and Ketoglutarate and glycerophosphoric and cnie derivatives of compounds of formula (I), for example, compounds quaternion connection Rx- T, where Rx= C1-6alkyl, phenyl - C1-6alkyl or C5-7cycloalkyl, and T is a radical corresponding to an anion of the acid. Examples Rxinclude methyl, ethyl and n - and ISO - propyl; and benzyl and phenethyl. Relevant examples of T include halogen, such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internal salts, such as N-oxides.

The compounds of formula (I), their pharmaceutically acceptable salts (including Quaternary derivatives and N-oxides) can also form pharmaceutically acceptable solvate such as a hydrate, which include listed here the compound of formula (I) or its salt.

Also provided that component (CH2)n2 in the compounds of formula (I), where Z = (b) may take, or the configuration of the related condensed azabicycles component.

The compounds of formula (I) can be obtained by the usual connections Indology component Z. the Corresponding methods described in the patents great Britain NN A (Sandoz limited), A and in patents EP-A-36269 (scourge of group p. l. c.), 429984 (Nishin Four Fiber is about input/modification (CH2)rO - containing ring, or R3/R4can be done before or after connection.

Aza(bi)cyclic intermediate chemical compounds with side chain are known compounds, but they can be obtained in accordance with methods described in PCT/GB 92/01519 and /01612 (Smithklein scourge p.l.c.).

Compounds in accordance with the present invention are antagonists of the receptor 5-HT4therefore, they can be used for the treatment of prophylaxis of gastrointestinal disorders, cardiovascular diseases and disorders of the Central nervous system (CNS).

These compounds are of potential interest for the treatment of such diseases as syndrome IBS (bowel disease), in particular diarrhea disorders of the digestive tract, that is, these compounds block the ability of the receptor 5-HT to induce the intestines into action through the activation of neurons. Syndrome disorders of the bowel (IBS) in animals this can be verified by reducing the amount of feces. These compounds can also be used to treat a disease, such as incontinence, which is often associated with the syndrome IBS.

They can also prominately alimentary canal, and as an antiemetic. In particular, they may find potential application for the relief of symptoms of gastritis in the gastric-intestinal diseases and dispersion. Antiemetic activity determined in known animal models for vomiting caused by cytotoxic substance or radiation.

Also believe that specific antagonists of the receptor 5-HT4that prevent the occurrence of atrial fibrillation and other arrhythmias associated with 5-HT, will reduce the possibility of paralysis (A. J. Kaumann 1990, Nauman-Smedberg with Apr. Pharmacology, 342, 619 - 622. The appropriate method of animal testing).

I believe that 5-HT, derived from blood platelets (thrombocytes), causing the arrhythmia, which leads to atrial arrhythmias, and cardiac abnormalities associated with symptomatic occlusion of the blood vessels of the brain and systemically embolism. Blockage of the blood vessels of the brain is the cause of coronary disease, and heart is the most known source of material for the blocking of the blood vessels. Of particular interest is the frequency of occurrence of embolism, the STS, probably influenced ammonium horn brain (Dupuis and others, 1988, Mol. Pharmacol. , 34, 880 - 887). The activity can be demonstrated in standard animal models by testing for social interaction and through the labyrinth test-X.

Those who suffer from migraine often have the situation of anxiety and emotional stress, which precede the headache (see Sachs, 1985, Migraine, Pan Books, London). Also found that within 48 h of migraine levels of cyclic AMR significantly increased in the cerebrospinal fluid (Welch and others, 1976, Headache, 16, 160 - 167). Believe that migraine, including the phase preceding the beginning of the attack, and a corresponding increase in levels of cyclic AMR, associated with the excitation of receptors 5-HT4therefore, the appointment of a receptor antagonist 5-HT4can bring potential benefits in removing the migraine attack.

Also proposed pharmaceutical composition in accordance with the invention containing a compound of the formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

These compositions are obtained by mixing the components and usually they intended the diamonds in the form of tablets, capsules, liquid preparations for oral administration, powders, granules, pellets, powders, aerosol spray through the nose, suppositories, solutions or suspensions for injection. Also provides for the input of the medication under the tongue or through injection into the skin. Formulations intended for reception through the mouth, preferred because they are more convenient to use.

Tablets and capsules for admission through the mouth, usually in the form of a unit dose, and they contain conventional inert excipients, such as binders, fillers, diluents, substances for tabletting, lubricants, dispersing agents, dyes, fragrances and moisturizers. The tablets can be applied by known coating methods, for example, against irritation of the intestines.

Appropriate fillers for use include cellulose, mannitol, lactose and other similar substances. Appropriate dispersing agents include starch, polyvinylpolypyrrolidone and such starch derivatives such as starch glycolate, sodium. Appropriate lubricants include, for example, magnesium stearate.

Appropriate pharmaceutically acceptable moisturizers include lauric sulfonate sodium. Emulsi, syrups or elixirs or in the form of a dry product for mixing with water or other suitable media to its application. Such liquid preparations may contain conventional additives, for example, suspendresume agents, for example sorbitol, syrup, methylcellulose, gelatin, acetylcellulose, carboxymethylcellulose, Gelo aluminum stearate or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan-monooleate or Arabian gum; non-aqueous vehicles (which may include edible oils), for example, almond oil, rectified coconut oil, oily esters such as esters of glycerine, propylene glycol or ethyl alcohol; anticoagulatory, for example, methyl or propyl p - oxybenzoic or sorbic acid, and, if required, you can add regular fragrances or dyes.

Liquid preparations for adoption through the mouth are usually present in the form of water for oily suspensions, solutions, emulsions, syrups or elixirs or in the form of a dry product for mixing with water or an appropriate medium before applying it. Such liquid compositions may contain conventional additives, for example suspendresume agents, emulsifiers, asiausa substances.

Compositions for use through the mouth can be obtained by ordinary methods of blending, filling or tableting. You can apply the subsequent mixing to distribute the active substance in these compositions using a large number of fillers. Such operations, of course, known in the art.

For parenteral application are prepared in the form of a single dose of a liquid containing the compound in accordance with the present invention and a sterile solvent. The connection depending on the solvent and the concentration can be suspended or dissolved. Solutions for parenteral application is usually prepared by dissolving the compounds in a solvent, and to fill in the appropriate vial or ampoule and sealing it sterilized through a filter. Mainly in the solvent also dissolve pharmaceutical drugs that enhance the effect of another drug, such as funds for local anesthesia, anticoagulatory and buffer agents. For enhanced stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Suspension for parenteral use is prepared by sushestvam exposure to the action of ethylene oxide to the suspension in sterile media. Mainly to facilitate uniform distribution of the compounds in accordance with the invention, the composition add a surfactant or humidifier.

Also in accordance with the invention, a method for treatment of irritable bowel syndrome (IBS), diseases of the stomach and esophagus, dispersion, heart arrhythmia and paralysis, anxiety and/or migraine in mammals, for example humans, and the method is in the use of effective amounts of compounds of formula (I) or pharmaceutically acceptable salts thereof. In particular, the method consists in the treatment of irritable bowel syndrome (IBS), cardiac arrhythmia and paralysis.

The amount effective to treat the above disorders, depends on the relative efficacy of the compounds in accordance with the invention, the nature and complexity of the disease, and weight of the mammal. However, a single dose for an adult weighing 70 kg will usually contain 0.05 to 1000 mg, for example 0.5 to 500 mg of the compounds in accordance with the invention. A single dose can be taken once or several times a day, for example 2, 3 or 4 times a day, usually 1 to 3 times a day, i.e. in the range of 0.0001 to 50 mg/kg/day, Obie.

The invention also concerns the compounds of formula (I) or pharmaceutically acceptable salts thereof for use as an active therapeutic substance, in particular for use as a receptor antagonist 5-HT4for the treatment of the above disorders.

The invention concerns the use of compounds of formula (I) in the preparation of medicaments for use as a receptor antagonist 5-HT4for the treatment of diseases described.

The examples illustrate the preparation of compounds of formula (I) (PL. 1). The subsequent descriptions illustrate the production of intermediate compounds.

Example 1. (1-p-butyl-4-piperidyl)methyl-3,4-dihydro - 2H-[1,3] oxazino[3,2-a]indole-10-carboxylate (E1).

a) a Suspension of indole-3-carboxylic acid (500 mg, of 0.003 mol) in dichloromethane (50 ml) was treated with oxalylamino (0,635 g of 0.005 mol) and two drops of dimethylformamide. The mixture was stirred at room temperature for 1.5 h, then was removed under vacuum of the solvent, leaving the acid chloride.

A solution of 1-butyl-4-piperidinemethanol, D6, (513 mg, of 0.003 mol) in dry THF (10 ml) under nitrogen atmosphere was cooled in an ice bath. One drop was added n-utility (1,88 ml of 1.6 M solution in hexane, 0, in dry THF (20 ml) and the solution was added drop by drop into a solution of lithium alcoholate at 0oC.

The reaction mixture was allowed to warmed to room temperature and was stirred for 3 hours the Solvent was removed under vacuum and the residue is divided between chloroform and water. The chloroform was separated, washed several times with water, dried and concentrated, obtaining (1-butyl-4-piperidyl) methyl-1H-indole-3-carboxylate as a pale brown resin.

1HNMR (250 MHz) CDCl3< / BR>
: 9,90 (brs, 1H), 8,10 - 8,18 (m, 1H), 7,78 (d, 1H), 7,37 - 7,46 (m, 1H), 1,16 - 7,28 (m, 2H), 4,19 (d, 2H), 3,05 - 3,15 (brd, 2H), 2.40 a - 2,49 (m, 2H), of 0.90 (t, 3H), 1,20 - to 2.18 (m, 11H).

b). A suspension of N-chlorosuccinimide (57 mg, 0.48 mmol) in chloroform (2 ml) was treated with solution (1-pbutyl-4-piperidyl) methylindol-3-carboxylate (100 mg, 0.32 mmol) in chloroform (2 ml) and the mixture was stirred at room temperature for 2 h Pale yellow solution was treated with 3-bromo-1-propanol (of 0.03 ml, 0.32 mmol), was stirred at room temperature for 16 h; then by 10%-aqueous solution of Na2CO3increased basicity and was extracted with chloroform. The extract was dried and concentrated leaving a yellow resin which was dissolved in acetone (6 ml), treated with anhydrous potassium carbonate (130 mg, of 0.94 mmol) and stirred at room temperature for 18 hours the Mixture of processing the Aviv brown oil, which was subjected to chromatography, first on silica gel, with elution was performed with chloroform/methanol (97:3), then on basic alumina with elution by ethyl acetate, having a colorless oil. He was led from simple ether/pentane to obtain the compound (E1) as a white solid (11 mg) with a melting point 117 - 119oC.

1HNMR (CDCl3)

: of 7.97 (d, 1H), 7,10 - 7,30 (m, 3H), 4,55 (t, 2H), 420 (d, 2H), 4,11 (t, 2H), 2,90 - 3,03 (m, 2H), 2,25 - to 2.40 (m, 4H), 1,75 - 2,00 (m, 5H), 1,22 - of 1.55 (m, 6H), of 0.91 (t, 3H)

MS (EI) M+370.

Example 2. eq-finalisation-2-ylmethyl-3,4-dihydro-2H- [1,3]oxazino[3,2-a] indole-10-carboxylate (E2).

a) eq-2-oxymethylene (N. J. Leonard and others, as well.Organic chemistry, 1957, 22, 1445) was subjected to reaction with indole-3-carboxylic acid chloride using the method described in example 1, to obtain eq-finalisation-2-yl-methyl-1-H-indole-3-carboxylate with a melting point 154-157oC.

1HNMR (CDCl3)

: 9,40 (b.r.s, 1H), 8,10 - to 8.20 (m, 1H), 7,87 (d, 1H), 7,35 - 7,45 (m, 1H), 7,20 - 7,30 (m, 2H), 4,20 (d, 2H), 2,80 - of 2.97 (m, 2H), 1,43 - of 2.20 (m, 11H), 1,10 - 1,40 (m, 3H).

b) eq-finalisation-2-yl-methyl 1H-indole-3-carboxylate was treated first N-chlorosuccinimide (1.5 equivalents) for 2 hours, then 3-bromo-1-propanolamine in example 1B. The crude product was purified, it was applied the same chromatography conditions as in example 1B, to obtain compound as a colourless oil (51%). It turned into a hydrochloric salt, and was led from acetone at a temperature of melting point 164 - 167oC.

1HNMR (HCl salt) (d6DMSO)

: 10,35 (b.r.s., 1H), a 7.85 (d, 1H), 7,32 (d, 1H), 7,07 - 7,20 (m, 2H), 4,54 (t, 2H), 4,13 (t, 2H), of 4.05 (d, 2H), 3.25 to of 3.43 (m, 2H), 2,74 is 3.15 (m, 3H), 2,20 - of 2.33 (m, 2H), 2.00 in to 2.15 (m, 1H), 1,35 - of 1.95 (m, 10H).

Example 3. N-[1-pbutyl-4-piperidyl)methyl] -3,4-dihydro-2H- [1,3]oxazino[3,2-a]indole-10 carboxamid (E3).

Method 1. The mixed solution of N-chlorosuccinimide (57 mg, 0.48 mmol) in chloroform (3 ml) was treated with a solution of N-[(1-pbutyl - 4-piperidyl)methyl]indole-3-carboxamide, 1, (100 mg, 0.32 mmol) in chloroform (8 ml) and kept at room temperature for 2 h, then was treated with 3-bromo-1-propanol (of 0.03 ml, 0.32 mmol). After stirring for 16 h was added 3-bromo-1-propanol (of 0.03 ml, 0.32 mmol). The mixture was stirred at room temperature for 3 h, then treated with excess 10% solution of Na2CO3and was extracted with chloroform. The extract was dried (Na2SO4) and concentrated in vacuum, obtaining a yellow oil, which was dissolved in and is within 16 hours The mixture was concentrated under vacuum, the residue was treated with 10% solution of Na2CO3(10 ml) and was extracted with chloroform. The extract was dried (Na2SO4) and concentrated under vacuum, leaving a yellow oil, which was subjected to chromatography, first on silica gel with elution by chloroform/methanol (19:1), then on basic alumina with elution by ethyl acetate. The obtained colorless oil was led from simple ether, obtaining the compound (E3) as a white solid (20 mg, 17%) with a melting point of 110 - 113oC.

1HNMR(CDCl3)

: a 8.34 (d, 1H), 7,05 - 7,30 (m, 3H), 6,55 (t, 1H), 4.53-in (t, 2H), 4,10 (t, 2H), 3.33 and (t, 2H), 2,90 was 3.05 (m, 2H), 2,25 - of 2.45 (m, 4H), 1,90 was 2.25 (m, 2H), 1,20 - of 1.85 (m, 9H), to 0.92 (t, 3H)

M(Cl) MH+370.

Method 2. Stirred suspension of N-[(1-pbutyl-4 - piperidyl)methyl]indole-3-carboxamide (D1, 120 g, 0.38 mol) in chloroform (2 l) under nitrogen atmosphere at room temperature was treated with fresh distilled 3-bromo-1-propanol (69 ml, 0.77 mol), followed by parts) was added dry N-chlorosuccinimide (55 g, 0.42 mol) for 5 min Obtained yellow solution was stirred for 2.5 h, then was treated IMHCl in ether (15 ml, 0.015 mol). Formed of moderate ectoderm and the color of the reaction changed to orangery, dried (Na2SO4) and concentrated in vacuo, leaving a thick red oil. He was treated with acetone (1.5 l) and anhydrous potassium carbonate (130 g, 0.95 mol) and then stirred at room temperature for 18 hours the Reaction mixture was concentrated in vacuo, the residue was treated with water (1 l) and extracted with ethyl acetate. After 2 h at 8oC he was profiled and dried, obtaining of 51.7 g of compound (E3) as a solid. The mother liquor was extracted using IMHCl acid (800 ml), then the acidic extract was turned into the basis with the use of K2CO3and was extracted with chloroform (CH ml). The combined chloroform extracts were dried (Na2SO4), concentrated in vacuo, and the remainder was subjected to chromatography on silica gel with elution by chloroform/methanol (96: 4). Received a yellow oil which after grinding into a powder by a simple ether gave the addition of 21.3 g of the indicated compound (E3) as a white solid. Transformation into a hydrochloric salt and recrystallization from ethanol / 60 - 80 benzyl gave a solid substance with a melting point of 254 - 256oC.

Salt HCl-1HNMR (D2O)

: of 7.90 (d, 1H), 6,88 - 7,20 (m, 3H), 4,35 (br.t, 2H), 3,70 (br.t, 2H), 3,40 (br. d. , 2H), 3,20 (br.d., 2H), 2,9 (br.t $ -10-carboxylate (E4).

a). 1-piperidinemethanol was subjected to reaction with 1H-indole-3-hardcoremovie acid, using the method described in example 1a, to obtain 2-(1-piperidyl)ethyl 1H-indole-3-carboxylate.

1HNMR (CDCl3)

to 9.6 (br.s, 1H), 8,03 - to 8.12 (m, 1H) 7,43 (d, 1H), 7,30 - 7,40 (m, 1H), 7,13 - 7,25 (m, 2H), 4,48 (t, 2H), 2,82 (t, 2H), 2,82 (t, 2H), 2,50 - to 2.65 (m, 4H), 1,35 is 1.70 (m, 6H).

b). 2-(1-piperidyl)ethyl 1H-indole-3-carboxylate first treated with N-chlorosuccinimide (1.5 equivalents) for 2 h, then 3-bromo-1-propanol (3 equivalent) for 21 h, then anhydrous carbonate in acetone using the method described in the description 1b. The crude product was purified using the same conditions chromatography, as in the description 1b, to obtain the compound (E4) as a pale yellow oil (15%). It was turned in his oxalato salt and was led from acetone with a melting point of 174 - 177oC.

Free base:1HNMR (CDCl3)

: 8,02 (d, 1H), 7,07 - 7,30 (m, 3H), 4,40 - 4,55 (m, 4H), 4,08 (t, 2H), 2,78 (t, 2H), 2,45-to 2.65 (m, 4H), 2,25-of 2.38 (m, 2H), 1,54 - of 1.66 (m, 4H), 1,35 - 1, 50 (m, 2H).

MS (Cl) MH+329.

Example 5. N-[2-(1-piperidyl)ethyl] 3,4-dihydro - 2H-[1,3]oxazino[3,2-a] indole-10-carboxamide (E5).

N-[2-(1-piperidyl)ethyl] 1H-indole-3-carboxamide (D2) was treated first N-chlorosuccinimide example 3. The crude product was subjected to chromatography on silica gel with elution by chloroform/methanol (19: 1), having a pale yellow oil, which was led from simple ether, having specified the title compound (E5) as a white solid (29%) with a melting point 124-127oC.

1H NMR (CDCl3)

: with 8.33 (d, 1H), 7,06-7,28 (m, 3H), 7,02 (Br.t, H), 4,51 (t, 2H), 4,08 (t, 2H), 3,50-3,60 (m, 2H), 2,54 (t, 2H), 2,30-2,60 (m, 6H), 1,40-of 1.65 (m, 6H)

MS (Cl) MH+328.

Example 6. (1-pbutyl-4-piperidyl)methyl-2,3-dihydrooxazolo[3,2-a] indol-9-carboxylate (E6).

(1-pbutyl-piperidyl)methyl 1H-indole-3-carboxylate (E1a) was treated first with N-chlorosuccinimide (1,5-equivalents) for 4 h, then 2-bromo-ethanol (2 equivalent) for 18 h followed by treatment with anhydrous potassium carbonate in acetone (18 h) in the manner described in example 1b. The crude product was purified under the same conditions chromatography as in example 1b, having a colorless oil (26%), which was led from simple ester, having the specified product (E6) in the form of a white solid with a boiling point 128-130oC.

1HNMR (CDCl3)

: 7,95-8,03 (m, 1H), 7,07-7,27 (m, 3H), 5,18 at 5.27 (m, 2H), 4,24-to 4.33 (m, 2H), 4,19 (d, 2H), 2,92 totaling 3.04 (m, 2H), 2,27-of 2.38 (m, 2H), 1,75-2,05 (m, 5H), 1,25-of 1.66 (m, 6H), of 0.91 (t, 3H).

(1-p-butyl-4-piperidyl)methyl-1H-indole-3-carboxylate (E1a) was treated first with N-chlorosuccinimide (1.5 equivalents) for 2 h, then 3-bromo-2,2-dimethyl-1-propanol (2 equivalent) for 20 h and then anhydrous potassium carbonate in acetone (2 1/2 days) according to the method described in example 1b. The crude product was subjected to chromatography on silica gel with elution by chloroform/methanol (95:5) with the specified connection (E7) in the form of a solid white color (10%) with a melting point of 134-135oC.

1HNMR (CDCl3)

: 7,98 (d, 1H), 7,08-7,30 (m, 3H), 4,21 (d, 2H), 4,15 (S, 2H), of 3.77 (S, 2H), 2.95 and-of 3.07 (m, 2H), 2.95 and-of 3.07 (m, 2H), 2,32-to 2.42 (m, 2H), 1,80-2,10 (m, 5H), 1,26 is 1.60 (m, 6H), of 1.20 (S, 6H), of 0.93 (t, 3H).

MS (Cl) MH+399.

Example 8. (1-pbutyl-4-piperidyl)methyl-3,4-dihydro - 2H-[1,3] thiazino[3,2-a]indole-10-carboxylate (E8).

(1-pbutyl-4-piperidyl)methyl-1H-indole-3-carboxylate, E1a (314 ml, 0,0010 mol) was treated first with N-chlorocinnamate (180 mg, 0,0015 mol) for 2 h, then 3-chloro-1-propandiol (0,20 ml, 0,0020 mol) for 5 days according to the method described in example 1b. The resulting solution increased the basicity using a 10% solution of Na2CO3and was extracted with chloroform. The extract was dried (Na2SO4) and conc is orapharma/methanol (95: 5), receiving (1-pbutyl-4-piperidyl)methyl-2-(3-chloropropylene)- -1H-indole-3-carboxylate in the form of oil gray (220 mg). It was dissolved in acetone (50 ml), treated with anhydrous potassium carbonate (220 mg, 0,0015 mol) and sodium iodide (390 mg, 0,0026 mol) and was heated under phlegm (irrigation) within 8 hours the Mixture was concentrated under vacuum and the residue was treated with 10% solution of Na2CO3and then was extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated. The residue was subjected to chromatography on basic alumina with elution by ethyl acetate. The obtained colorless oil was led from simple ester, having the specified connection (E8) in the number of white solid (80 mg, 21%) with a melting point of 99-100oC.

1H NMR (CDCl3)

: 7,97-0,04 (m, 1H), 7,14-7,30 (m, 3H), 4,22 (d, 2H), 4,15 (t, 2H), 3,05 is 3.15 (m, 2H), 2,92-to 3.02 (m, 2H), 2,38-of 2.50 (m, 2H), 2,27-is 2.37 (m, 2H), 1,75-2,02 (m, 5H), 1,20-of 1.55 (m, 6H), of 0.91 (t, 3H)

MS (E1) M+386.

Example 9. (1-pbutyl-4-piperidyl)methyl - 2,3,4,5-tetrahydro[1,3]oxazepan[3,2-a]indole-11-carboxylate (E9).

(1-pbutyl-4-piperidyl)methyl 1H-indole-3-carboxylate (EIa) was treated first with N-chlorosuccinimide (1.5 equivalents) for 2 h, then 4-chloro-1-butanol (2 equivalent) for 1 who piperidyl)methyl 2-(4-chloroethoxy)-1H-indole-3-carboxylate as a yellow oil. Solution in acetone was treated with anhydrous potassium carbonate and sodium iodide and heated under irrigation for 30 m, then it was purified as in example 8, having the specified connection (E9) as a pale yellow oil (21%). It was turned in his oxalato salt and was led from acetone, having a white solid with a boiling point 161-164oC.

Xalteva Sol: -1HNMR (d6DMSO)

: a 7.85 (m, 1H), 7,45 - of 7.55 (m, 1H), 7,10 - 7,25 (m, 2H), 4,15 - 4,30(m, 4H), 4,10 (d, 2H), 3,35 is - 3.45 (m, 2H), 2,80 was 3.05 (m, 4H), 1,80 - 2,10 (m, 7H), 1,50 - 1,75 m, 4H), 1,20 - 1,40 (m, 2H), 0,89 (t, 3H)

MS (EI) M+384.

Example 10. (1-pbutyl-4-piperidyl) methyl-6,7,8,9-tetrahydropyrido [1,2-a] indole-1-carboxylate (E10).

A solution of 6,7,8,9-tetrahydropyrido [1,2-a] indole-1-carboxylic acid, D3, (400 mg, 0,00186 mol) in dichloromethane (20 ml) was treated with oxalylamino (0,20 ml, is 0.023 mol) and 2 drops of DMF (dimethylformamide) and stirred at room temperature for 2 h, then was concentrated in vacuum, obtaining the acid chloride in a solid orange color.

Solution (1-pbutyl-4-piperidyl)methanol (D6)(0.32 g, 0,0186 mol) in dry THF (tetrahydrofuran) (25 ml) and 5oC in nitrogen atmosphere was treated with 1.5 M methyllithium simple ether (1,24 ml, 0,00186 mol) and left DLCI 16 h at room temperature the mixture was treated with saturated solution of K2CO3(50 ml) and was extracted into ethyl acetate (CH ml), dried (Na2SO4) and concentrated in vacuum. The residue was subjected to chromatography on silica gel with elution by chloroform (95:5) with the specified connection (E10) as a yellow oil. It was turned into its hydrochloric salt to obtain a white solid with melting point 230-232oC.

HCl salt:1H NMR (d6DMSO)

: (br. s., 1H), 7,92-8,03 (m, 1H),7,43 - of 5.53 (m, 1H), 7,16 - 7,26 (m, 2H), 4.18 (d, 2H), 4,11 (t, 2H), 3.43 points of 3.56 (m, 2H), 3,23 (t, 2H), 2,82 was 3.05 (m, 4H), 1.85 to a 2.12 (m, 7H), 1,60 - 1,80 (m, 4H), 1,25 - 1,40 (m, 2H), of 0.90 (t, 3H)

MS (E1) M+368.

Example 11. (1-pbutyl-4-piperidyl) methyl-2,3-dihydro-1H-pyrrolo[1,2-a] indole-9-carboxylate (E11).

The specified connection (E11) was prepared from 2,3-dihydro-1H-pyrrolo[1,2-a] indole-9-carboxylic acid (D4), using the method of example 10, and he was isolated in the form of a solid pale orange (24%) with a melting point of 100-102oC.

1H NMR (CDCl3)

: 8,03-to 8.12 (m, 1H), 7,13 - 7,28 (m, 3H), 4,17 (d, 2H), 4,11 (t, 2H), 3,29 (t<2H), 2.95 and - is 3.08 (m, 2H), 2.57 m - 2,72 (m, 2H), 2,30 - to 2.41 (m, 2H), 1,92 - 2,07 (m, 2H), 1,73 - 1,90 (m, 3H), 1,40 - 1,60 (m, 4H), 1,22 - of 1.39 (m, 2H), to 0.92 (t, 3H)

MS (EI) M+354.

Example 12 (1-pbutyl-4-piperidyl)methyl-7,8,9,10-tetrahydro-6H-azepin[1,2-f]indol-11-carboy acid (D5) according to the method of example 10. The crude product was purified by chromatography on silica gel with elution by chloroform/ethanol (98 : 2), having a yellow oil, which was converted to its hydrochloric salt to obtain a solid (20%) with a melting point of 196 - 198oC.

1H NMR (d6DMSO) - HCl salt

: 10,52 (br.s, 1H), 7,93 - of 8.00 (m, 1H), 7,55 to 7.62 (m, 1H), 7,13 - 7,25 (m, 2H), 4,25 - and 4.40 (m, 2H), 4,17 (d, 2H), 3,35 - 3,55 (m, 4H), 2,80 - 3,10 (m, 4H), 1,55 - of 2.15 (m, 13H), 1,24 - of 1.40 (m, 2H), from 0.88 (t, 3H)

MS (Cl) MH+383.

Example 13. N-[(1-pbutyl-4-piperidyl)methyl] -2,3 - dihydro-1H-pyrrolo[1,2-a]indol-9-carboxamide (E13).

A solution of 2,3-dihydro-1H-pyrrolo[1,2-a] indole-9-carboxylic acid, D4, (180 mg, 0.89 mmol) in dichloromethane (20 ml) was treated with oxalylamino (0,096 ml, 1.1 mmol) and 2 drops of dimethylformamide (DMF) was stirred at room temperature for 1 h, then was concentrated in vacuum, obtaining the acid chloride as a yellow solid.

Solution (1-pbutyl-4-piperidyl) methylamine, d, (150 mg, 0.89 mmol) and triethylamine (0.15 ml, 1.1 mmol) in dichloromethane (20 ml) under nitrogen atmosphere was treated with a solution mentioned acid chloride in dichloromethane (5 ml) and stirred at room temperature for 3 hours the Solution was treated with 10% solution of Na2CO3
oC.

1H NMR (CDCl3)

: 7,75 - to 7.84 (m, 1H), 7,13 - 7,33 (m, 3H0, to 5.93 (br.t, NH), 4,10 (t, 2H) 3,38 (t<2H), and 3.31 (t, 2H), 2,90 - to 3.02 (m, 2H), 2,65 (quintet, 2H), 2,28 - of 2.36 (m, 2H), 12,60 is 2.10 (m, 6H), 1,22 - of 1.55 (m, 5H), of 0.90 (t, 3H)

MS (Cl) MH+354.

Example 14. N-[(1-pbutyl-4-piperidyl)methyl]-2,3-dihydrooxazolo[3,2-a]indole-9-carboxamide (E14).

N-[(1-pbutyl-4-piperidyl)methyl] indole-3-carboxamide (1) was treated first with N-chlorosuccinimide (1.5 equivalents) for 2 h, then 2-bromoethanol (2 equivalent) for 16 h and then potassium carbonate (3 equivalents) in acetone for 68 h according to the method of example 1B.

The crude product was purified by chromatography on silica gel with elution by chloroform/ethanol (19:1) to obtain the compound (E14) as a white solid followed by recrystallization from chloroform/ether (14%) with a melting point 156 - 158oC.

1H NMR (CDCl3)

: 8,19 (d, 1H), 7,00 - 7,30 (m, 3H), 6,00 (t, NT), 5,15 (t, 2H), 4,20 (t, 2H), 3,32 (t, 2H), 2,90 is 3.15 (m, 2H) 2,25 - to 2.42 (m, 2H), 1,20 - 2,05 (m, 1H), from 0.90 (t, 3H)

MS (Cl) MH+356.

Example 15. (1-benzyl-4-piperidyl) m is its acid chloride and then subjected to reaction with 1-benzyl-4-piperidinemethanol (d) according to the method, described in example 1A. The obtained orange oil was subjected to chromatography on silica gel with elution by chloroform/ethanol (9:1) education (1-benzyl-4-piperidyl) methyl-indole-3-carboxylate as a yellow oil (88%).

1H NMR (CDCl3)

: 9,24 (s, 1H), 8,12 - to 8.20 (m, 1H), 7,81 (d, 1H), 7,20 was 7.45 (m, 8H), 4,20 (d, 2H), 2,90 totaling 3.04 (m. 2H), 1,73 is 2.10 (m, 5H), 1,36 is 1.58 (m, 2H)

b) (1-benzyl-4-piperidyl) methyl-indole-3-carboxylate first treated with N-chlorosuccinimide (1.5 equivalents) for 2 h, then 3-bromo-1-propanol (2 equivalent) for 16 h and then anhydrous potassium carbonate in acetone using the method described in example 1B. The crude product was purified by chromatography of silica gel with elution by chloroform/ethanol (19: 1) to obtain the compound (E15 motorway) in the form of a solid substance, followed by recrystallization from chloroform/ether (47%) with a melting point 158-160oC.

1HNMR (CDCl3)

: 7,94-of 8.00 (m, 1H), 7,10-7,38(m, 8H), 4,48 - 4,56 (m, 2H), 4,19 (d, 2H), 4,19 (d, 2H), 4,05-4,12 (m, 2H), 3,50 (S, 2H), 2,28 are 2.98 (m, 2H), 2,28-2,39 (m, 2H), 1,75-of 2.08 (m, 5H), 1,35 - of 1.55 (m, 2H)

MS (Cl) MH+405.

Example 16. (1-p-butyl-4-piperidyl)methyl-3,4-dihydro-1-oxo - 2H-[1,3-a] thiazino[3,2-a] indole-10-carboxylate (U).

Solution (1-pthe 5 ml) was treated with periodate sodium (100 mg, 0.46 mmol) and stirred at room temperature for 24 h Then the solution was processed and saturated solution of K2CO3(10ml) and extracted using ethyl acetate (2 × 25 ml). The extract was dried (Na2SO4) and concentrated in vacuum, obtaining a yellow oil, which was subjected to chromatography on silica gel with elution with 5% methanol/chloroform. The obtained colorless oil was led from the ether, having the specified connection (e) as a white solid (27 mg, 32%) with a melting point of 130 - 135oC.

1H NMR (CDCl3)

: 8,24 (d, 1H), 7,30-to 7.50 (m, 3H), of 4.54 (dd, 1H), 4,22-to 4.38 (m, 2H), 4,05 (dt, 1H), 3,40 (dd, 1H), 3,21(dg, 1H), 2,86-is 3.08(m,3H), 2,30 at 2.45 (m, 3H), 1,80-2,10 (m, 4H), 1,20-1,40 (m, 2H), of 0.90 (t, 3H)

MS(Cl) MH+403.

Example 17. (1-pbutyl-4-piperidyl)methyl 6,7-dihydropyrido[1,2-a]indole-10-carboxylate (E17).

The specified connection received from 6,7-dihydropyrido[1,2-a] indole-10-carboxylic acid (d) according to the method described in Example 10, and was subjected to chromatography on silica gel with elution by ethyl acetate, receiving a yellow solid (18%) with a melting point 60-62oC (n-pentane).

1H NMR (CDCl3)

: 8,10 - 8,17 (m, 1H), 7,42 (dt, 1H), 7.18 in-7,33(m, 3H), of 6.25 to 6.35 (m, 1H), 4,22 (d, 2H), 4,15 (t, 2H),2,90 - 32-a]indole - 10-carboxylate (E18).

The specified connection received from pyrido[1,2-a]indole-10-carboxylic acid (D9) according to the method of example 10 and was subjected to chromatography on silica gel with elution ethyl acetate, receiving a yellow solid (10%) with a melting point 57-59oC (n-pentane)

1H NMR (CDCl3)

: 8,35 - of 8.50 (m, 3H), 7,88 (d, 1H), of 7.48 - 7,56 (m, 1H), 7,28 - 7,40 (m, 2H), 6,78 - 6,86 (m, 1H), 4,30 (d, 2H), 2.95 and was 3.05 (m, 2H), 2,30 - to 2.40 (m, 2H), 1.85 to 2.05 is (m, 5H), 1,43 is 1.60 (m, 4H) 1,25 - 1,40 (m, 2H), 0,92 (t, 3H)

MS(E1) M+364.

Example 19. N-[1-pbutyl-4-piperidyl)methyl]3,4-dihydro-2H-[1,3]thiazin [3,2-a] indole-10-carboxamide(E19).

The specified connection was obtained from N-[1-pbutyl - 4-piperidyl)methyl]indole-3-carboxamide (DV) according to the method of Example 8 as a white solid (7%) with a melting point 141-142oC.

1H NMR (CDCl3)

: of 7.70 (d, 1H), 7,13 - 7,30 (m, 3H), 6,0oC7 (t, 1H), 4,16 (t, 2H), 3,38 (t, 2H), is 3.08 (t, 2H), 2,90 - to 3.02 (m, 2H), 2,38 - of 2.50 (m, 2H), 2,25-of 2.36 (m, 2H), 1,60 - 2,00 (m, 5H), 1,23 - of 1.56 (m, 6H), of 0.91 (t, 3H)

MS(E1) M+385.

Example 20. N-[(1-benzyl-4-piperidyl]3,4-dihydro - 2H-[1,3]oxazin[3,2-a] indole-10 carboxamid (E20).

a). Indole-3-carboxylic acid was converted into the chloride solution of this acid and then subjected to reaction with (1-Benzyl-4-piperidyl) methylamine (D10) according to the method disclosed is VA (60%).

1H NMR (CDCl3).

: 9,90 (S, 1H), 7,85 - to 7.95 (m, 1H), to 7.64 (d, 1H), 7,15 - the 7.43 (m, 8H), 6,17 (n, 1H), 3,48 (S, 2H), 3,37 (t, 2H), 2,83 are 2.98 (m, 2H), 1,87 - of 2.08 (m, 2 H), 1,54 - to 1.82 (m, 3H), 1,23 of 1.50 (m, 2H).

b) a Stirred suspension of N-[1-benzyl-4-piperidyl)methyl]indole - 3-carboxamide (17.5 g, 0,050 mol) in chloroform (250 ml) was treated with 3-bromo-1-propanol (10.1 ml, 0.11 mol) and N-chlorosuccinimide (8.7 g, 0,065 mol) at room temperature and for 15 minutes got a clear solution.

After 1 h the reaction mixture darkened, changing its color from pale yellow to orange, and the temperature rose to 38oC. After a further 1 h the reaction mixture was treated with 10% solution of NAHCO3the chloroform layer was separated, dried (NA2SO4) and concentrated in vacuum, obtaining a yellow oil, which was subjected to chromatography on silica gel with elution with 3% methanol/chloroform. The intermediate compound 2-(3-bromopropane) indole was dissolved in acetone (400 ml), treated with anhydrous potassium carbonate (11 g, 0.80 mol) and stirred at room temperature for 2 hours the Reaction mixture was concentrated under vacuum and the residue was treated with water (200 ml) and was extracted with chloroform (2 × 250 ml). The combined extracts were dried (Na2SO4), concentrated under vakuumnoi connection (E20) in the form of a pale yellow oil (3.1 g, 15%). It was turned in his oxalato salt and was led from acetone, having a white solid with a melting point 169-170oC.

Free base:1H NMR (CDCl3)

: 8,32 (d, 1H), 7,05 - 7,38 (m, 8H), 6,53 (t, 1H), 4,50 (t, 2H), 4,08 (t, 2H), 4,08 (t, 2H), 3,48 (s, 2H), and 3.31 (t, 2H), 2,83 - of 2.97 (m, 2H), 2,27 - to 2.41 (m, 2H),1,54 e 2.06 (m, 5H), 1,25 - 1,45 (m, 2H).

Example 21. N-(4-piperidinylmethyl)of 3,4-dihydro-2H-[1,3]oxazin[3,2-a]indole - 10 carboxamid (E21).

Stirred suspension of N -[(1-benzyl-4-piperidyl)methyl]3,4-dihydro-2H-[1,3] oxazino[3,2-a] indole - 10-carboxamide-oxalato salt (E20, 2.25 g, 0,0046 mol) in ethanol (100 ml) and glacial acetic acid (4 ml) was hydrogenosomal over 10% Pd-C(0.8 g) at atmospheric pressure and a temperature of 45oC for 18 hours the Mixture was filtered, the filtrate was concentrated under vacuum. Most of the product was in the form of a solid, which was filtered. This material was dissolved in concentrated potassium carbonate solution (50 ml) and chloroform (50 ml) together with the residue from the filtrate. The mixture was filtered, the separated layer of chloroform and dried (Na2SO4), then concentrated in vacuum, given a specified compound as a white solid (1.52 g, 100%). He was led from chloroform/ 60 -80 gasoline, 2H), of 4.05 (t, 2H), 3,30 (t, 2H), 3,02 is 3.15 (m, 2H), 2,52 - 2,70 (m, 2H), and 2.27 - 2.40 a (m, 2H), 1,65 - 1,90 (m, 4H), 1,10 - 1,30 (m, 2H).

MS(EI) M+313.

Example 22. N-[(1-phexyl-4-piperidyl)methyl]3,4-dihydro - 2H-[1,3]oxazino[3,2-a]indole-10-carboxyl (E22).

A solution of N-(4-piperidinylmethyl)of 3,4-dihydro-2H-[1,3] oxazino[3,2-a] indole - 10-carboxamide (E21, 250 mg, 0.70 mmol) in acetone (12 ml) was treated with 1-bromhexina (of 0.14 ml, 1.0 mmol) and anhydrous potassium carbonate (280 mg, 2.0 mmol) and stirred at room temperature for 10 hours the Mixture was concentrated in vacuo, and the residue was treated with 10% solution of Na2CO3and was extracted with chloroform. The extract was dried (Na2SO4),concentrated in vacuo, and the residue was subjected to chromatography on silica gel with elution with 5% methanol/ chloroform, receiving a yellow oil. Missed it through a short plug of basic alumina with elution by ethyl acetate, obtaining the compound (E22) as a colourless oil (150 mg, 54%). It was turned into its hydrochloric salt and was led from acetone/ether, having a white solid with a melting point of 170 171oC.

Free base:1HNMR (CDCl3)

: (d, 2H), 7,02 - 7,30 (m, 3H), 6,53 (t, 1H), 4,48 (t, 2H), Android 4.04 (t, 2H), 3,32(t, 2H), 2,90 - 3,00 (m, 2H), 2,25 - of 2.38 (m, 4H), 1,8 3,4-dihydro - 2H-[1,3] oxazin[3,2-a] indole-10 carboxamid (E23). -(4-piperidinylmethyl) of 3,4-dihydro-2H-[1,3] oxazin [3,2-a] indole-10-carboxamide (E21) alkilirovanie cyclohexylethylamine way of example 22, with duration of response was 10 h at room temperature, then the reaction was conducted for 8 hours at a temperature of phlegmy. The specified connection (E23) was obtained as a white solid (31%), which was turned into its hydrochloric salt and was led from acetone/ether as a white solid with a melting point 209-210oC

HCl salt: -1HNMR (CD3OD)

: 8,03 - of 8.09 (m, 1H), 7,20 - 7,28 (m, 1H), 7,10 - 7,17 (m, 2H), 4,60 (t, 2H), 4,15 (t, 2H), 3,53 - the 3.65 (m, 2H), 3,36 (d, 2H), 2,85 was 3.05 (m, 4H), 2,30 is 2.43 (m, 2H), 1,50 - 2,07 (m, 11H), 1,18 - of 1.46 (m, 3H), 0.95 to - 1,13 (m, 2H).

MS (EI) M+409.

Example 24. N-[(1-ethyl-4-piperidyl)methyl] 3,4-dihydro - 2H-[1,3] oxazin[3,2-a]indole-10-carboxamide (E24).

N-(4-piperidinylmethyl)of 3,4-dihydro-2H[1,3] oxazin[3,2-a]indole - 10-urea (E21) alkilirovanie iodide ethanol according to the method of example 22. The specified connection is received in the form of a white solid (27%), which was turned into its hydrochloric salt and was led from acetone/ ethanol/ether, having a solid white color with a melting point 243-245oC.

Free is 1.55V - to 1.98 (m, 5H), 1,25 - 1,45 (m, 2H)

MS (E1) M+341.

Example 25. N-[(1-(2-methanesulfonylaminoethyl)- 4-piperidyl)methyl]3,4-dihydro-2H-[1,3]oxazin[3,2-a]indole - 10-carboxamide (E25).

The mixed solution of N-(4-piperidyl)of 3,4-dihydro - 2H-[1,3]oxazin[3,2-a] indole-10-carboxylamide (E21, 220 mg, 0.70 mmol) in acetonitrile (8 ml) was treated with diisopropylethylamine (of 0.24 ml, 1.4 mmol) and N-(2-bromacil) methanesulfonamide (D14, 160 mg, 0.77 mmol) and the mixture was heated under phlegm for 2.5 hours the Reaction mixture was concentrated in vacuo and the residue was subjected to chromatography on silica gel with elution with dichloromethane/methanol /0.88 / l solution of ammonia (200 : 10 : 1).

The obtained colorless oil was dissolved in chloroform (30 ml) and washed with water (2x20 ml), then dried (Na2SO4) and concentrated in vacuum. The remainder pass through a short plug of basic alumina with elution by ethyl acetate, given a specified compound as a colourless oil (34 mg, 11%). It was turned in his oxalato salt and was led from acetate, having a white solid with a melting point of 80 - 85oC.

Free base:1HNMR (CDCl3)

: 8,32 (d, 1H), 7,05 - 7,30 (m, 3H), 6,56 (t, 1H), 4.53-in (t, 2H), 4,08 (t, 2H), 3.33 and (t, 2H), 3,17 (t, 2H), 2.95 and (s, 3H), 2,78 of 2.92 (m oxazin-[3,2-a]indole-10-carboxamide (E26).

a)eq-finalisation-2-ylmethylamino (D12) was subjected to reaction with indole-3-carboxylic acid chloride using the method disclosed in example 1b, to obtain the compound N-(eq-finalisation-2-ylmethyl)indole-3-carboxamide in the form of a white solid (55%).

1HNMR (CD3OD)

: 8,06 - of 8.15 (m, 1H), 7,39 - 7,46 (m, 1H), 7,10 - 7,22 (m, 2H), 3.27 to (d, 2H), 2,80 - 2,95 (m, 2H), 2,04 - of 2.23 (m, 2H), 1,53 - to 1.98 (m, 8H), to 1.22 to 1.48 (m, 3H), 0,96 - 1,15 (m, 1H).

b). Stirred suspension of N-(eq-finalisation-2-ylmethyl)indole - 3-carboxamide (300 mg, of 0.94 mmol) in chloroform (16 ml) was treated with 3-bromo-1-propanol (0.17 ml, 1.9 mmol), then N-chlorosuccinimide (140 mg, 1.05 mmol) and obtained clear solution within 30 min After 2 h the mixture was treated with IH HCl/ether (3 drops), having painted it yellow, then after 1.5 h the mixture was treated with an excess of 10%th solution of NaHCO3the chloroform layer was separated, dried (Na2SO4) and concentrated in vacuum, obtaining a yellow oil. It was dissolved in acetone (20 ml), treated with anhydrous potassium carbonate (400 mg, 2.9 mmol) and stirred at room temperature for 24 h, then concentrated in vacuo. The residue was treated with 10% solution of Na2CO3and was extracted with chloroform. The extract was dried (Na2SO4) and concentrated, the remaining is aslo go through a short tube of basic alumina with elution by ethyl acetate, given a specified connection (E26) as a colourless oil (110 mg, 32%). It was turned into its hydrochloric salt and was led from methanol/ether as a white solid with a melting point 243-247oC.

Free base: -1H NMR (CDCl3).

: 8,30 (d, 1H), 6,98 - 7,25 (m, 3H), 6,51 (t, 1H), 4,45 (t, 2H), 3.96 points (t, 2H), 3,20 - 3,37 (m, 2H), 2,78 of 2.92 (m, 2H), measuring 2.20 to 2.35 (m, 2H), 1,94 with 2.14 (m, 2H), 0,98 - of 1.85 (m, 12H)

MS (Cl) MH+368.

Example 27. (I-pbutyl-4-piperidyl)methyl 8-fluoro-3,4 - dihydro-2H-[1,3] oxazin[3,2-a]indole-10-carboxylate (E27).

a) 5-Florinda-3-carboxylic acid chloride was subjected to reaction with (I-pbutyl-4-piperidyl)methanol (D6), using the method of Example 1a, having (I-pbutyl-4-piperidyl)methyl 5-Florinda-3-carboxylate in the form of an orange oil (30%), then subjected to chromatography on silica gel with the manifestation of a 10% ethanol/chloroform.

1H NMR (CDCl3)

: 9,95 (br.s, 1H), 7,82 (s, 1H), 7,78 (dd, 1H), 7,33 (dd, 1H), 7,00 (dt, 1H), 4,22 (d, 2H), 3.00 and is 3.15 (m, 2H), 2,33 - 2,47 (m, 2H), 1,95 - 2,10 (m, 2H), 1,75 - of 1.93 (m, 3H), 1,22 - of 1.65 (m, 6H), to 0.92 (t, 3H).

b) (I-pbutyl-4-piperidine)methyl-5-Florinda-3-carboxylate was subjected to reaction with chlorosuccinimide and 3-bromo-1-propanol, then with potassium carbonate in acetone, using the method of example what cloroformo.

The specified connection (E27) was obtained as a pale yellow oil (8%), which was turned into his oxalato salt and got a solid substance with a melting point 118-119oC.

Free base: -1H NMR (CDCl3).

: to 7.64 (dd, 1H),? 7.04 baby mortality (dd, 1H), 6.87 in (dt, 1H), 4,55 (t, 2H), 4,20 (d, 2H), 4,10 (t, 2H), 2,96 - 3,10 (m, 2H), 2,28 - 2,47 (m, 2H), 1.77 in with 2.14 (m, 5H), 1,25 - of 1.65 (m, 6H), to 0.92 (t, 3H)

MS (Cl) MH+389.

Example 28. N-[I-pbutyl-4-piperidyl)methyl] 8-fluoro-3,4 - dihydro-2H-[1,3] oxazin[3,2-a]indole-10-carboxamide (E28).

a)5-Florinda-3-carboxylic acid chloride was subjected to reaction with (I-pbutyl-4-piperidyl)methylamine (D1a) according to the method, opened in the Description 1b, having the compound N-[I-pbutyl-4 - piperidyl)methyl]5-Florinda-3-carboxamide in the form of a white solid (64%).

1H NMR (CD3OD)

: a 7.92 (S, 7h), 7,78 (DD, 1h), 7,38 (dd, 1H), 6,95 (dt, 1H), 3,28 (d, 2H), 2,93 - of 3.07 (m, 2H), 2,30 - to 2.42 (m, 2H), 1.60 - to to 1.87 (m, 3H), 1,22 - to 1.60 (m, 6H), were 0.94 (t, 3H).

b) N-[(I-pbutyl-4-piperidyl)methyl]-5-Florinda-3 - carboxamide was subjected to reaction with 3-bromo-1-propane and N-chlorosuccinimide, then with potassium carbonate in acetone, using the method of example 26b, got a yellow oil, which was subjected to chromatography on silica gel with the manifestation of 20% ethanol/holdem is th salt, received in the form of a solid substance with a melting point 90oC.

Free base: -1H NMR (CDCl3)

: 7,98 (dd, 1H), 6,98 (dd, 1H), 6,83 (dt, 1H), 6,56 (t, 1H), 4,56 (t, 2H), 4,08 (t, 2H), 3.33 and (t, 2H), 3,05 - 3,20 (m, 2H), 2,30 - of 2.58 (m, 4H), 2,10 - of 2.26 (m, 2H), 1,25 - 1,90 (m, 9H), to 0.92 (t, 3H)

MS (Cl) MH+388.

Example 29. (I-pbutyl-4-piperidyl)methyl-1-methyl-1,2,3,4 - tetrahydropyrimido[1,2-a]indole-10-carboxylate (E29).

Solution (I-nbutyl-4-piperidyl)methanol (D6, 1.7 g, 0,010 mol) in dry THF (20 ml) in nitrogen atmosphere at a temperature of 10oC was treated with 1,5 M methyllithium in ether (2.7 ml of 0.004 mol) and was stirred for 15 min, then was added a solution of methyl 1-methyl-1,2,3,4-tetrahydropyrimido [1,2-a]indole-10-carboxylate (D11, 0.5 g, 0.002 mol) in THF (5 ml) and the reaction mixture was heated under reflux for 24 hours the Mixture allowed to cool and then it was treated with 10% solution of Na2CO3(50 ml) and was extracted with ethyl acetate (2x40 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo, and the residue was subjected to chromatography on silica gel with elution with 2% methanol/chloroform, has received the specified connection (E29) as a colourless oil (0,58 g, 74%). The connection turned in his oxalato salt and RH">

Free base: - 1HMNR (CDCl3).

: a 7.92 (d, 1H), 7,00 - 7,20 (m, 3H), 4,17 (d, 2H), 3,95 (t, 2H), 3,37 (t, 2H), or 3.28 (s, 3H), 2,92 - 3,03 (m, 2H), 2,28 - of 2.38 (m, 2H), 2,12 - of 2.24 (m, 2H), 1,80 - 2,03 (m, 5H), 1,23 - of 1.57 (m, 6H), to 0.92 (t, 3H)

MS (E1) M+383.

Example 30. (I-pbutyl-4-piperidyl)methyl-3-methylthiazole[3,2 - a]indole-9-carboxylate (E30).

The specified connection (E30) was obtained from 3-methylthiazole [3,2-a]indole-9-carboxylic acid (d13) in accordance with the method of example 10. The crude product was purified by chromatography on silica gel with elution by chloroform/methanol (95:5), then pass through a short plug of basic alumina with elution with ether, having a pale yellow oil (35%). It was turned in his oxalato salt and was led from methanol, having a white solid with a melting point 224 - 226oC.

Free base: - 1H MNR (CDCl3)

: 8,18 (d, 1H), to 7.77 (d, 1H), 7,14 - 7,42 (m, 2H), 6,40 (s, 1H), 4,25 (d, 2H), 2,92 - is 3.08 (m, 2H), by 2.73 (s, 3H), 2,28 - 222,40 (m, 2H), 1,75 - 2,05 (m, 5H), 1,20 - of 1.62 (m, 6H), to 0.92 (t, 3H)

MS (Cl) MH+385.

Example 31. (I-pbutyl-4-piperidyl)methyl-2,3-dihydrothiazolo [3,2-a]indole-9-carboxylate (E31).

The specified connection received from 2,3-dihydrothiazolo[2,3-a]indole - 9-carboxylic acid (D) according to canola/chloroform, after receiving a yellow oil. Missed it through the tube from the primary alumina with elution by ethyl acetate, given a specified compound as a pale yellow oil (31%), which was turned into his oxalato salt and was led from acetone, having a white solid with a melting point of 212 - 215oC.

Free base: -1H MNR (CDCl3)

: 7,98 (d, 1H), 7,09 - 7,26 (m, 3H), 4,29 (t, 2H), 4,20 (d, 2H), 3,80 (t, 2H), 2,94 - of 3.06 (m, 2H), 2,30 - to 2.40 (m, 2H), 1,73 e 2.06 (m, 5H), 1,24 - to 1.60 (m, 6H), to 0.92 (t, 3H).

Example 32. (I-pbutyl-4-piperidyl)materiasl[3,2-a]indole - 9-carboxylate E32).

The specified connection (E32) received from the thiazole[3,2-a]indole-9 - carboxylic acid (D16), using the method of example 10.The crude product was purified by chromatography on silica gel with elution with 3% methanol/chloroform, having pale purple solid (70%). It was turned in his oxalato salt and recrystallization from methanol, having a pale blue solid with a melting point of 217 218oC.

Free base:1HNMR (CDCl3)

: 8,18 (d, 1H), 7,79 (d, 1H), 7,65 (d, 1H), 7,33 - the 7.43 (m, 1H), 7,20 - 7,30 (m, 1H), 6,91 (d, 1H), 4,27 (d, 2H), 2.95 and - of 3.07 (m, 2H), 2,30 - to 2.40 (m, 2H), 1,79 - of 2.08 (m, 5H), 1,40 - of 1.62 (m, 4H), 1,33 (sextet, 2H), to 0.92 (t, 3H).

Example 33. (1oC.

Xalteva Sol: -1H NMR (d6DMSO).

: to 8.45 (d, 1H), 8,35 (d, 1H), to 7.59 (t, 1H), 7,41 (t, 1H), 6,97 (s, 1H), 4,90 (brs, 2H). 4,27 (d, 2H), 3,38 - of 3.60 (m, 2H), 3,14 (s, 3H), 3.27 to totaling 3.04 (m, 4H), 2,61 (s, 3H), 2,01 - of 2.27 (m, 3H), 1,55 - of 1.84 (m, 4H), to 1.37 (sextet, 2H), of 0.97 (t, 3H).

Example 34. N-[(1-pbutyl-4-piperidyl)methyl]2,3 - dihydrothiazolo[2,3-a]indol-9-carboxamide.

The specified connection (E34) received from 2:3-dihydrothiazolo [3,2-a]indole-9-carboxylic acid (D15) through this acid chloride using the method of example 13. The crude product was purified by chromatography, receiving a yellow solid (63%). It was turned in his oxalato salt and recrystallization from acetone, having a solid substance with a melting point of 203 204oC.

Xalteva Sol: -1H NMR (d6DMSO)

: 7,83 - a 7.92 (m, 1H), 7,33 was 7.45 (m, 2H), 7,08 - to 7.18 (m, 1H), 4,35 (t, 2H), 3,84 (t, 2H), 3,35 - to 3.50 (m, 2H), 3,18 - 3,30 (m, 2H), 2,75 0 3,05 (m, 4H), 1,75 - of 1.95 (m, 3H), 1,40 = 1,70 (m, 4H), of 1.30 (sextet, 2H), from 0.88 (t, 3H).

Example 35. N-[(1-pbutyl-4-piperidyl)Mamonovo acid (D16) through this acid chloride, using the method of example 13. The crude product was purified by chromatography on silica gel with elution with 5% methanol/chloroform, having a solid Magenta (73%). It was turned in his oxalato salt and recrystallization from acetone, receiving a purple solid with a melting point of 205 - 207oC.

Xalteva Sol: -1HNMR (d6DMSO)

: 8,49 (d, 1H), 8,14 (d, 1H), with 8.05 (d, 1H), 7,54 (t, 1H), 7,20 - 7,40 (m, 3H), 3,38 - to 3.50 (m, 2H), 3,24 - to 3.35 (m, 2H), 2,75 was 3.05 (m, 4H), 1,80 - 2,00 (m, 3H), 1,40 - 1,70 (m, 4H), of 1.30 (sextet, 2H), from 0.88 (t, 3H).

Example 36. (1-pbutyl-4-piperidyl)methyl,2,3,4,-tetrahydropyrimido [1,2-a] indole-10-carboxyl (E36).

The specified connection (E36) was obtained from methyl 1,2,3,4-tetrahydropyrimido[1,2-a] indole-10-carboxylate (D21) according to the method of example 29, and the time spent in the phlegm was 140 hours the Crude product was purified by chromatography on silica gel with elution first with ethyl acetate, then 10% methanol/ethyl acetate, receiving a yellow solid. His presence through the tube from the basic aluminum oxide, and the elution was performed with ethyl acetate, given a specified compound as a solid (23%), which was turned into his oxalato salt and crystallizes the tion:1H NMR (CDCl3)

: 7,71 (brd, 1H), 6,98 - to 7.18 (m, 3H), 7,0 (brs, 1H), 4,17 (d, 2H), 3,98 (t, 2H), 3.46 in is 3.57 (m, 2H), 2,92 - of 3.06 (m, 2H), 2,30 - to 2.40 (m, 2H), 2,22 (quintet, 2H), 1,75 - of 2.09 (m, 5H), 1,23 - to 1.60 (m, 6H), to 0.92 (t, 3H).

Example 37. eq-hemolysin-2 ylmethyl 2,3-dihydrooxazolo[3,2-a]indole - 9-carboxylate (E37).

Mixed suspension eq - chinolin-2-ylmethyl 1H-indole-3-carboxylate (E2a, 280 mg of 0.94 mmol) in chloroform (10 ml) was treated with 2-bromoethanol (0,13 ml), then N-chlorosuccinimide (135 mg, 1.0 mmol) and maintained for 2 hours at room temperature. Then the mixture was treated with 1M HCl in simple ether (0.05 ml, 005 mmol) and after 2 h the resulting yellow solution increased the basicity by adding a 10% aqueous solution of Na2CO3(10 ml) and was extracted with chloroform (2 x 15 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuum, obtaining an orange oil. It was dissolved in acetone (20 ml), treated with anhydrous potassium carbonate (410 mg, 3.0 mmol) and stirred at room temperature for 22 h,then concentrate in vacuo, and the residue was treated with 10% solution of Na2CO3(20 ml) and was extracted with ethyl acetate (2 x 20 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo, and the residue was subjected to chromatography on silonovoy alumina with elution by ethyl acetate, given a specified connection (E37), which was led in the form of a white solid from ethyl acetate/ether with a melting point 153 - 155oC.

1H NMR (CDCl3)

: to 7.95 (d, 1H), 7,00 - 7,25 (m, 3H), 5,14 (t, 2H), 4,10 (t, 2H), 4,15 (d, 2H), 2,73 are 2.98 (m, 2H), 1,02 - to 2.18 (m, 14H).

Example 38. N-[(1-pbutyl-4-piperidyl)methyl]2,3,4.5-tetrahydro[1,3]oxazepan[3,2-a]indol - 11-carboxamide (E38).

a) a Stirred suspension of N-[1-pbutyl-4-piperidyl)methyl]indole-3-carboxamide (D1b, 1.0 g, 0,0032 mol) in chloroform (25 ml) was treated with 4-chlorobutanol (0,69 ml, 0,0064 mol), then N-chlorosuccinimide (470 mg, 0,0035 mol) and within 5 minutes got a yellow solution. After an additional 40 min, it was noted that the solution darkened to orange. The mixture was maintained at room temperature for 1 h, then was treated with a 10% solution of Na2CO3(30 ml) and was extracted with chloroform (2 x 30 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuum, obtaining an orange oil, which was subjected to chromatography on silica gel with elution with 5% methanol/chloroform, obtaining N-[(1-pbutyl-4-piperidyl)methyl] 2-(4-chloroethoxy)indole-3-carboxamide (0,67 g, 50%) as a yellow oil.

1H NMR (CDCl

b) a Solution of N-[(1-pbutyl-4-piperidyl)methyl]2-(4-chloroethoxy]indole-3-carboxamide (0,67 g, 0,0016 mol) in acetone (25 ml) was treated with anhydrous potassium carbonate (0.74 g, 0,0054 mol) and sodium iodide (1,34 g, 0,0089 mol) and was heated under reflux for 24 hours the Mixture was concentrated in vacuo, and the residue was treated with 10% solution of Na2CO3(25 ml) and was extracted with chloroform (2 x 30 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo, and the residue was subjected to chromatography on silica gel with elution with 5% methanol/chloroform. The obtained colorless oil pass through the tube from the primary alumina with elution by ethyl acetate, having the specified connection (E38) as a white solid (370 mg, 60%). It was turned in his oxalato salt and was led from acetone in the form of a white solid with a melting point 210-211oC.

Free base: -1HNMR (CDCl3)

: at 8.36-8,44 (m, IH), 7,17-7,25 (m, 3H), 6,94 (t, IH), 4?30 (t, 2H), 4,11-4,20 (m, 2H), 3,35 (t, 2H), 2,90-3,00 (m, 2H), of 2.25 to 2.35 (m, 2H), 2,18 (quintet, 2H), 1,55-2,02 (m, 7H), 1,23-of 1.55 (m, 6H), to 0.92 (t, 3H).

Example 39. (I-pbutyl-4-piperidyl)methyl pyrimid[1,2-a]indole-10-carboxylate (E39).

The specified connection get the>C n-pentane, and the residue was subjected to chromatography on silica gel with elution with 5% methanol/chloroform, having an orange oil.

1HNMR (CDCl3)

: 8,68-8,78 (m, 2H), to 8.45 (d, IH), 7,87 (d, IH), to 7.59 (t, IH), 6,77-6,89 (m, IH), 4,37 (dd, 2H), 2,90-of 3.12 (m, 2H), 2,25-2,48 (m, 2H), 1,75 and 2.13 (m, 5H), 1,19 is 1.70 (m, 6H), to 0.92 (t, 3H).

Also prepared the following compounds:

eq-finalisation-2-ylmethyl 2,3-dihydrothiazolo[3,2-a] indole-9-carboxylate (E40).

The compound 2,3-dihydrothiazolo[3,2-a]indole-9-carboxylic acid was converted to its acid chloride and subjected to reaction with eq-2-hydromeliorative, using a method similar to the method described in example 10.

Free base: -1HNMR (CDCl3)

: of 8.00 (d, IH), 7,15-7,30 (m, 3H), 4,34 (t, 2H), 4,10-of 4.25 (m, 2H), a 3.87 (t, 2H), 2,80-3,00 (m, 2H), 1,05-of 2.20 (m, 14H).

eq-finalisation-2-ylmethyl 2,3-dihydrothiazolo[3,2-a] indole - 9-carboxamide (E).

The compound 2,3-dihydrothiazolo [3,2-a]indole-9-carboxylic acid was converted to its acid chloride and subjected to reaction with eq-finalisation-2-ylmethylamino (d13), applying the same way, opened in the description of the Ib.

eq-finalisation-2-ylmethyl[thiazole[3,2-a]indole-9-carboxylate (E).

The thiazole[3,2-a] indole-9-carboxylic acid was converted into the chloride of his kislota, having these compounds as white solids with temperature 129-131oC (plain air).

1HNMR (CDCl3)

: 8,16 (d, IH), of 7.75 (d, IH), to 7.61 (d, IH), 7,33-7,42 (m, IH), 7,19-7,30 (m, IH). 6.87 in (d, IH), 4,15-4,32 (m, 2H), 2,80-300 (m, 2H), 1,40-to 2.18 (m, IH), 1,08-of 1.40 (m, 3H).

eq-finalisation-2-ylmethyl the thiazole[3,2-a]indole-9-carboxamide (E43).

Connection thiazole [3,2-a]indole-9-carboxylic acid was converted to its acid chloride and subjected to reaction with eq-finalisation-2-ylmethylamino, applying the same way, opened in the description of the Ib.

eq-finalisation-2-ylmethyl 3,4-dihydro - 2H-[1,3]thiazino[3,2-a]indole-10-carboxylic (E).

3,4-dihydro-2H-[1,3] thiazin[3,2-a]indole-1-carboxylic acid was obtained from dioxindole, applying the same way, opened in description 15. It was turned into its acid chloride and subjected to eq-2-oxymethylene, using a method similar to the method described in example 10. Got oxalato salt with a melting point 130-132oC.

Free base: -1HNMR (CDCl3).

: of 7.96-of 8.04 (m, IH), 7,13-7,30 (m, 3H), 4,05-4,30 (m, 4H), 2,90-3,20 (m, 4H), 2,35 is 2.51 (m, 2H), 1,20 of-2.32 (m, 14H).

(I-pbutyl-4-piperidyl)methyl pyrimid[1,2-a]indole-10-carboxamide (e).

a) Applying to the who then hydrogenosomal 10% PD/C in ethanol, having pyrimid [1,2-a]indole-1-carboxylic acid.

b) Connection of pyrimid [1,2-a]indole-10-carboxylic acid was converted to its acid chloride and subjected to reaction (I-pbutyl-4-piperidyl)methylamine, using the method disclosed in the description of the Ib. (I-pbutyl-4-piperidyl) methyl 1,2,3,4-tetrahydropyrimido[1,2-a]indole-10-carboxamide (E).

a) 2-Clorinda-3-carboxylic acid (L. Marchetti and A. Andreani, Ann Chim. (Rome), 1973, 63, 681) turned into its acid chloride and subjected to reaction with N-(I-pbutyl-4-piperidyl)methyl-amine (SUBJECT), using the method of Description Ib, received N-1[(I-pbutyl-4-piperidyl)methyl]2-Clorinda-3-carboxamide.

b) N-[(I-butyl-4-piperidyl)methyl] 2-chlorinol-3-carboxamid was subjected to reaction with 3-chloropropylamine, applying the same way, opened in the description of 18.

Example 40. Obtaining N-[(1-(3-phenoxypropan)-4-piperidinyl)methyl]3, 4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide. (Connection A).

a) a Solution of isonipecotamide (30.1 g, 0.23 mol) and benzylbromide (27.9 ml, 0.23 mol) in ethanol (250 ml) is treated with stirring with anhydrous potassium carbonate (64,9 g, 0.47 mol) and refluxed for 3 hours, the Mixture is left to cool, then filtered and film dried (Na2SO4) and concentrated in vacuo, receives a yellow solid (41,0 g). This solid is thoroughly mixed with phosphorous pentoxide (38,3 g, 0.27 mol) and the mixture was kept at 180oC in nitrogen atmosphere for 2.5 h under mild stirring. The reaction mixture is allowed to cool, then treated with water (300 ml). After dissolution of the solid mass of the solution is alkalinized by adding solid K2CO3and extracted with ethyl acetate (2 x 250 ml). The combined extracts are dried (Na2SO4) and concentrated in vacuo, get a brown oil (35.5 g). The oil is dissolved in dry ether (250 ml) and added dropwise over 30 min at 0oC in nitrogen atmosphere to a stirred suspension of lithium aluminum hydride (10.1 g, 0.26 mol) in ether (150 ml). After complete addition, the mixture allowed to warm to room temperature and stirred for 1.5 hours the Mixture was re-cooled to 0oC and carefully treated with water (10 ml), 10% NaOH solution (15 ml) and again water (25 ml). The mixture is filtered through diatomaceous earth and the filtrate was concentrated in vacuo, get a brown oil which is distilled in vacuum, after distillation (1-benzyl-4-piperidinyl)methylamine as a colorless oil (27.8 g, 67%), so CI is (m, 2H), 1,60-1,75 m, 2H), 1,10-1,40 (m, 5H).

b) To a solution of indole-3-carboxylic acid (15 g, 0,093 mol) in dichloromethane (250 ml) under stirring in nitrogen atmosphere add oxalicacid (8,7 ml, 0.10 mol) and dry dimethylformamide (6 drops). After 2 h the solvent is evaporated under reduced pressure. The remaining acid chloride (0,093 mol) dissolved in dichloromethane (100 ml) and added dropwise to a stirred solution of N-(1-benzyl-4-piperidinyl)methylamine (D1, 16,4 g, 0,093 mol) and triethylamine (15,5 ml, 0.11 mol) in dichloromethane (150 ml) and 5oC. After stirring at room temperature overnight, the reaction mixture was washed with 10% Na2CO3and the organic phase is dried (Na2SO4). The solvent is evaporated under reduced pressure and the remaining solid is recrystallized from ethyl acetate, to obtain N-[(1-benzyl-4-piperidinyl)methyl]indole-3-carboxamide in the form of a white solid (17.5 g, 60%).

Range PMR (CDCl3, M. D.) to 9.90 (s, 1H), 7,85-to 7.95 (m, 1H), to 7.64 (d, 1H), 7,15-the 7.43 (m, 8H), 6,17 (t, 1H), 3,84 (s, 2H), 3,37 (t, 2H), 2,83 are 2.98 (m, 2H), 1,87-of 2.08 (m, 2H), 1,54-to 1.82 (m, 3H), 1,23 of 1.50 (m, 2H).

C) a Suspension of N-[(1-benzyl-4-piperidinyl)methyl] indole-3 - carboxamide (17.5 g, 0,050 mole) in chloroform (250 ml) is treated under stirring and at room temp the solution. After 1 h the reaction mixture changes color from light yellow to orange, and the temperature rises to 38oC. After 1 h the reaction mixture was treated with 10% solution of Na2CO3the chloroform layer is separated, dried (Na2SO4) and concentrated in vacuo, receives a yellow oil, which chromatographic on silica gel, eluent of 3% methanol/chloroform. The intermediate 2-(3-bromopropane)indole is dissolved in acetone (400 ml), treated with anhydrous potassium carbonate (11 g, 0.08 mol) and stirred at room temperature for 20 hours the Reaction mixture was concentrated in vacuo and the residue is treated with water (200 ml) and extracted with chloroform (2 x 250 ml). The combined extracts are dried (Na2SO4), concentrated in vacuo and the residue chromatographic on silica gel, eluent 5% methanol/chloroform, to obtain N-[(1-benzyl-4-piperidinyl)-methyl] -3,4-dihydro-2H-[1,3] oxazino[3,2-a]indole-10-carboxamide in the form of light yellow (3.1 g, 15%). This compound is transferred to the salt of oxalic acid and crystallized from acetone in the form of a white solid substance, so pl. 169-170oC.

Range PMR (free base) (CDCl3, M. D.) 8,32 (d, 1H), 7,05-7,38 (m, 8H), 6,53 (t, 1H), 4,50 (t, 2H), 4,08 (t, 2H), 3,48 (s, 2H), and 3.31 (t, 2H), 2,83-of 2.97 (m, 2H), 2,27-to 2.41 (m, 2H), 1,54-to 2.06 (m, 5H), 1,25-1,45 m is samida (2.25 g, 0,0046 mol) in ethanol (100 ml) and glacial acetic acid (4 ml) under stirring hydronaut over 10% Pd-C (0.8 g) at atmospheric pressure and 45oC for 18 hours the Mixture is filtered and the filtrate concentrated in vacuo. Most of the product is in solid condition, it sucked. This product along with the remaining filtrate is shaken with concentrated potassium carbonate solution (50 ml) and chloroform (50 ml). The mixture is filtered, the chloroform layer separated and dried (Na2SO4), then concentrated in vacuo, to obtain N-(4-piperidinylmethyl)-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10 - carboxamide (E21) as a white solid (1.52 g, 100%). It is recrystallized from a mixture of chloroform/60-80 petrol, so pl. 139-141oC.

Range PMR (free base) (CDCl3, M. D.): 8,32 (d, 1H), 7.03 is-7,30 (m, 3H), 6,53 (t, 1H), 4,48 (t, 2H), of 4.05 (t, 2H), 3,30 (t, 2H),02-3,15 (m, 2H), 2,52-2,70 (m, 2H), and 2.27-2.40 a (m, 2H), 1,65-1,90 (m, 4H), 1,10-1,30 (m, 2H).

d) a Solution of N-(4-piperidinylmethyl)-3,4-dihydro-2H-[1,3]oxazino [3,2-a] indole-10-carboxamide (E21) (250 mg, 0.80 mmol) and triethylamine (0.25 ml, 1.8 mmol) in a mixture of acetonitrile (15 ml) and N,N-dimethylformamide (10 ml) with stirring, treated with 3-phenoxypropylamine (0,13 ml, 0.88 mmol) and the solution refluxed for 48 hours the DOI (20 ml). The organic solution is dried (MgSO4), concentrated in vacuo and the residue purified by rapid chromatography on silica gel, eluent 0-20% methanol/ethyl acetate, after trituration with ether to obtain N-[(1-phenoxypropan)-4-piperidinyl)methyl] 3,4-dihydro-2H-[1,3] oxazino [3,2-a]indole-10-carboxamide (E47, 44 mg) as a pale pink solid, so pl. 120-126oC.

Range PMR (CDCl3, M. D.) 8,30 (d, 1H), 7,0-7,37 (m, 5H), of 6.96 (t, 1H), to 6.88 (d, 2H), only 6.64 (t, 1H), 4,57 (t, 2H), 4,13 (t, 2H), 4,30 (t, 2H), 3,22-of 3.43 (m, 4H), 2,78-3,00 (m, 2H), 2,13-to 2.57 (m, 6H), 1,59-2,03 (m, 5H).

Description.

Description 1.Intermediate compounds of examples 3, 13, 14, 19 and 28.

a) N-(I-nbutyl-4-piperidyl)methylamine).

The mixed solution isonipecotamide (70 g, 0.55 mol) and 1-bromobutane (58,8 ml, 0.55 mol) in ethanol (700 ml) was treated with anhydrous potassium carbonate (152 g, 1.10 mol) and was heated under reflux for 3 hours the Mixture was allowed to cool, then was filtered, and the filtrate was concentrated under vacuum. The residual oil was dissolved in chloroform (400 ml) and washed with water (1 x 300 mg), then dried (Na2SO4) and concentrated under vacuum, obtaining a yellow oil (77,5 g). This oil is thoroughly mixed with phosphoric anhydride (75 g) and the mixture was heated at 160-180o2
CO3and then it was extracted with ethyl acetate (2 x 400 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuum, obtaining a brown oil (78 g). It was dissolved in dry ether (400 ml) and for 30 min was added drop by drop in the mixed suspension in alumoweld lithium (25 g, 0.66 mol) in ether (200 ml) at 0oC in nitrogen atmosphere. After completion of the additive mixture was allowed to warm to room temperature and was stirred for 18 hours It was again cooled to 0oC and carefully treated with water (25 ml), 10% NaOH solution (25 ml) and again water (75 ml). The mixture was filtered through infusorial the earth and the filtrate was concentrated in vacuum, obtaining a brown oil, which was subjected to distillation under vacuum, given a specified compound as a colourless oil (66 g, 71%) with a boiling point of 96 - 99oC under a pressure of 3 mm RT. Art.

1H MNR (CDCl3)

: 2,90-to 3.02 (m, 2H), 2,58 (d, 2H), 2,25-of 2.38 (m, 2H), 1,65-2,00 (m, 4H), 1,08 is 1.58 (m, 9H), to 0.92 (t, 3H).

b) N-[(I-nbutyl-4-piperidyl)methyl]indole-3-carboxamide.

In the mixed solution of indole-3-carboxylic acid (1 g) in dichloromethane (20 ml) at 0oC under the and evaporated under reduced pressure. Part of the residual acid chloride (420 mg) was dissolved in dichloromethane (12 ml) and added drop by drop into a solution of N-(I-pbutyl-4-piperidyl/methylamine (400 mg) in dichloromethane (12 ml) followed by treatment with triethylamine (0,36 ml). After stirring at ambient temperature overnight. The reaction mixture was washed with saturated NaHCO3and the organic phase was dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was recrystallization of ethyl acetate, after receiving the specified connection (1) (467 mg, 64%).

1HMNR (CDCl3) 250 MHz

: 9,29 (Brs, 1H), 8,05 to 7.9 (m, 1H), 7,81 (d, 1H), 7,55 to 7.4 (m, 1H), 7,39 to 7.2 (m, 2H), 6,28 (brs, 1H), 3,39 (t, 2H), 3,0 (brd, 2H), 2,45 was 2.25 (m, 2H), 2,1-1,1 (m, 11H), and 0.9 (t, 3H).

Description 2. The intermediate connection example 5. N-[2-(1-piperidinyl)ethyl]1H-indole-3-carboxamide.

1-piperidine ethylamine was subjected to reaction with 1H-indole-3-carboxylic acid chloride using the method disclosed in the description 1, when it has received the specified connection (D2) in the form of a solid substance.

1H MNR (CDCl3)

: 9,90 (brs, 1H), 7,97 - 8,07 (m, 1H), 7,97-8,07 (m, 1H), 7,78 (d, 1H), was 7.36 - to 7.50 (m, 1H), 7,15-7,30 (m, 2H), 7,13-13 (br.t, NH), 3,55-3,68 (m, 2H), 2,60 (t, 2H), 2,80 - to 2.55 (m, 4H), of 1.40-1.73 (m, 6H).

Description 3.The intermediate connection example 10.

was nezirovi 10% Pd /C catalyst (1 g) at room temperature and pressure for 18 hours The reaction mixture was filtered through infusorial earth and concentrated in vacuum, given a specified compound as a clear oil, which solidified upon exposure (10.8 g, 93%).

1H NMR (CDCl3)

: 7,05 - to 7.15 (m, 2H), 66,68 - 6,8 (m, 2H), 4,13 (q, 2H), 4,05 (br.s, 2H), 3,55 (s, 2H), 1,25 (t, 3H).

b)Ethyl 2-(5-chlorpheniramine)phenylacetate.

A solution of ethyl-2-aminophenylacetate (the ceiling of 5.60 g of 0.013 mol) and diisopropylethylamine (7,08 ml 0,042 mol) in dry tetrahydrofuran (THF) (75 ml) was treated with acid chloride 5 - haralanova acid (4,00 ml 0,031 mol) and left to stir for 1 h the Reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate (200 ml) and washed acid 1M HCl (100 ml), dried (Na2SO4) and concentrated in vacuum, obtaining a solid substance. It washed n-pentane/ether (1:1) and dried, after receiving the connection specified in the form of a light solid (8.1 g,91%).

1HNMR (CDCl3)

: 8,90 (br.s, 1H), 7,88 (d, 1H), 7,05-7,37 (m, 3H), 4,17 (q, 2H), 3,60 (s, 2H), 3.45 points-of 3.65 (m, 2H), 2,35 is 2.55 (m, 2H), 1,68-to 1.98 (m, 4H), of 1.28 (t, 3H).

c)Ethyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxylate.

A solution of ethyl 2-(5-chlorpheniramine)phenylacetate (8,10 g, or 0.027 mol) in dry THF (50 ml) was added to the stirred suspend the hydrated purple solution was treated with water (10 ml) and concentrated in vacuum. The residue was which with etiracetam (200 ml) and a saturated solution of ammonium chloride (150 ml), then separated organic layer (Na2SO4) and concentrated in vacuum, obtaining an orange oil. He was subjected to chromatography on silica gel with elution ether, given a specified compound as a yellow solid (1.25 g, 20%).

1H MNR (CDCl3)

: 8,07 - 8,17 (m, 1H), 7,13 - 7,30 (m, 3H), of 4.38 (q, 2H), 4.00 points (t, 2H), 3,30 (t, 2H), 1,82-2,12 (m, 4H), USD 1.43 (t, 3H).

d) 6,7,8,9-tetrahydropyrido [1,2-a] indole-10-carboxylic acid.

A solution of ethyl 6,7,8,9-tetrahydro-1H-pyrid[1,2-a] indole-10 - carboxylate (1.20 g, 0,0047 mol) in ethanol (50 ml) and 10% NaOH solution (50 ml) was heated under phlegm for 4 hours Then the reaction was acidified by acid 1MHCl (50 ml). The organic layer was separated and was extracted with a 10% solution of Na2CO3(120 ml), then aqueous solution was again acidified acid 5M HCl and was extracted in ethyl acetate (2 x 75 ml).The organic extracts were combined,dried (NaSO4) and concentrated in vacuum, given a specified compound (D3) as a white solid (400 mg, 40%).

1H NMR (CDCl3)

: 8,23 (d, 1H), 7,20 - 7,35 (m, 3H), 4,10 (t, 2H), 3,40 (t, 2H), 2.00 in to 2.15 (m, 2H), 1.85 to 2,00 (m, 2H).

Description 4.the intermediate connection for p ethyl 2-aminophenylacetate, using the method of description 3b, and isolated as a solid (100%).

1H MNR (CDCl3)

: 8,90 (br.s., 1H), a 7.85 (d, 1H), 7,05 - 7,35 (m, 3H), 4,15 (q, 2H), 3,68 (t, 2H), and 3.6 (s, 2H), 2,96 (t, 2H), to 2.1 - 2.3 (m, 2H), 1.26 in (t, 3H).

b)Ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate.

The specified connection was obtained from ethyl 2-(4-chloroethylamino) phenylacetate according to the method of description 3c, and was isolated as an orange oil, which was led at the time (15%).

1H MNR (CDCl3)

: 8,05 - of 8.15 (m, 1H), 7,15 - 7,30 (m, 3H), 4,35 (q, 2H), 4,06 (t, 2H), or 3.28 (t, 2H), 2,55 - of 2.72 (m, 2H), 1,40 (t, 3H).

c)2,3-dihydro-1H-Parrilo[1,2-a]indole-9-carboxylic acid.

The specified connection (D4) was obtained from ethyl 2,3-dihydro-1H - pyrrolo[1,2-a] indole-9-carboxylate using the method of Description 3d, then he was isolated in the form of a white solid (42%).

1H MNR (d6DMSO)

: 11,85 (br.s, 1H), of 7.90 - 8,02 (m, 1H), 7,32 - 7,47 (,, 1H), 7,10 - 7,25 (m, 2H), 4,15 (t, 2H), 3,20 (t, 2H), 2,50 - 2,70 (m, 2H).

5.The intermediate connection example 12.

a)Ethyl 2-(6-chlorhexidine)phenylacetate.

The specified connection was obtained from ethyl 2-aminophenylacetate and 6-bromohexadecane according to the method of description 3V and insulated s 2H), 3,42 (t, 2H), of 2.45 (t, 2H), 1,45 - 2,00 (m, 6H), of 1.28 (t, 3H).

b)Ethyl 7,8,9,10-tetrahydro-6H-azepin [1,2-a]indole-11-carboxylate.

The specified connection was obtained from ethyl 2-(6-chlorhexidine)phenylacetate, using the method of description 3c, then it was purified by chromatography on silica gel with elution 60 - 80 gasoline/ether (9: 1), having a more solid (16%).

1H NMR (CDCl3)

: 8,07 - 8,19 (m, 1H), 7,15 - 7,35 (m, 3H), and 4.40 (q, 2H), 4,15 - of 4.25 (m, 2H), 3.45 points - of 3.60 (m, 2H), 1,67 - 2,00 (m, 6H), of 1.45 (t, 3H).

c)7,8,9,10-tetrahydro-6H-azepin[1,2-a]indole-11-carboxylic acid.

The specified connection (D5) was obtained from ethyl 7,8,9,10-tetrahydro-6H-azepin[1,2-a] indole-11-carboxylate via hydrolysis using sodium hydroxide according to the method of description of 3d. After 4 h of heating under reflux, the mixture was acidified by acid 5M HC obtained white solid was filtered and dried (82%).

1H NMR (d6DMSO)

: a 12.05 (s, 1H), 7.95 is - of 8.04 (m, 1H), of 7.48 - of 7.60 (m, 1H), 7,05 - 7,20 (m, 2H), 4,24 is 4.36 (m, 2H), 3,38 - of 3.53 (m, 2H), 1,54 - 1,90 (m, 6H).

Description 6.The intermediate connection for examples of 1.10, 27 and 29)

(1-pbutyl-4-piperidyl)methanol.

A mixture of utilisedictated (102 g of 0.65 mol) and 1-bromobutane (72 ml, 0.67 mol) in ethanol (1.2 l), and less is to cool and then it was filtered through infusorial the ground. The filtrate was concentrated in vacuum, obtaining a yellow oil, which was dissolved in ether (300 ml) and added drop by drop within 20 min in stirred suspension of lithium aluminum hydride (50 g, 1.3 mol) in ether at 0oC in nitrogen atmosphere. The mixture was stirred at room temperature for 18 h, then was cooled to 0oC and treated with water (50 ml), 10% NaOH solution (50 ml) and water (150 ml). The mixture was filtered through infusoria of the earth, and the filtrate was concentrated under vacuum, obtaining a pale yellow oil, which was subjected to distillation and received the specified compound as a colourless oil (88,5 g, 80%) with a boiling point of 102 - 108oC under a pressure of 0.1 mm Hg.

1H NMR (CDCl3)

: 3,48 (d, 2H), 2,88 - 3,03 (m, 2H), 2,25 - of 2.38 (m, 2H), 2,10 (br.s, 1H), 1,66 - 2,00 (m, 4H),1,17 is 1.60 (m, 7H), of 0.90 (t, 3H).

Description 7.The intermediate connection for Example 15.

(1-benzyl-4-piperidyl)methanol.

Utilizedabated first alkilirovanie methyl-benzyl, and the product was subjected to distillation with lithium aluminum hydride according to the method of description 6, having the specified connection (d) as a colourless oil (100%).

1H NMR (CDCl3)

: 7,20 - to 7.35 (m, 5H), 3,52 (s, 2H), 3,48 (d, 2H), 2,86 - 3,00 (m, 2H), 1,20 - 2,05 (m, 8H).

Description 8. the L. K. Dalton, Australian journal of Chem", 1969, 22, 997) (1,0 g, 0,0044 mol) in methanol (40 ml) was treated with a solution of potassium hydroxide (3.0 g, 0,054 mol) in water (50 ml) and was heated under reflux for 3 hours the Solution is allowed to cool, then it was acidified by acid HCl and was extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated under vacuum, obtaining the specified connection (DV) as a yellow solid (600 mg, 64%).

1H NMR (CDCl3)

: 8,18 is 8.22 (m, 1H), 7,50 (d, 1H), 7,20 - 7,35 (m, 3H), 6,27 - 6,38 (m, 1H), 4,15 (t, 2H), 2,62 - 2,78 (m, 2H).

Description 9. The intermediate connection for example 18.

Pyrido[1,2-e]indole-10-carboxylic acid.

The specified connection (D9) received from methylpyridin[1,2-a]indole-10-carboxylate (So Tata and L. K. Dalton, Australian journal "Chem", 1969, 22, 997) in accordance with the method of the description of 8, got a light yellow solid (76%).

1H NMR (CDCl3+ CD3OD)

: 8,56 (d, 1H), 8.34 per - 8,46 (m, 2H), to 7.93 (d, 1H), 7,32 - EUR 7.57 (m, 3H), 6.87 in (t, 1H).

Description 10.The intermediate connection for example 20.

(1-benzyl-4-piperidyl)methylamine (D10).

First isonipecotamide alkilirovanie methyl-benzyl, then amide dehydrational pjatiokisi phosphorus, and the floor is TES compound as a colorless oil after distillation (67%) with a boiling point 106oC under a pressure of 0.25 mm H.

1H NMR (CDCl3)

: 7,20 - 7,37 (m, 5H), of 3.48 (s, 2H), 2,85 - 2,95 (m, 2H), by 2.55 (d, 2H), 1,37 is 2.00 (m, 2H), 1,60 - 1,75 m, 2H), 1,10 - 1,40 (m, 5H).

Description 11.The intermediate connection for example 29.

a)Methyl 2-Clorinda-3-carboxylate.

Mixed suspension methylindol-3-carboxylate (6.0 g, 0,034 mol) in chloroform (200 ml) was treated with N-chlorosuccinimide (5,04 g 0,033 mol), having at least 15 min a clear solution. After 2 h at room temperature, it was treated with 1M HCl/ether (34 ml, 0,034 mol) and allowed him to move for an additional 1 h, then was treated with excess 10% aqueous solution of Na2CO3, separated chloroform layer was dried (Na2SO4) and concentrated in vacuum. The residual yellow substance has recrystallization from chloroform /60 - 50 gasoline (petrol) with the specified connection (DIIa) in the form of a solid (3.4 g, 48%).

1H NMR (CDCl3/d6DMSO)

: 11,3 (br.s, 1H), 8,02 - to 8.12 (m, 1H), 7,30 - 7,40 (m, 1H), 7.18 in - 7,26 (m, 2H), 3,95 (s, 2H).

MS (E1) M+209 and 211

b) Methyl-1-methyl-1,2,3,4-tetrahydropyrimido[1,2-a]indole-10-carboxylate.

A solution of methyl 2-Clorinda-3-carboxylate (3.4 g, to 0.016 mol) in dry THF (70 ml) at 5oC in nitrogen atmosphere apperature within 30 minutes The resulting solution was treated with a solution of 3,3-dimethylaminopropylamine (0,020 mol in toluene (30 ml) and was heated under reflux for 48 h, then concentrated in vacuo, and the residue was treated with 10% solution of Na2CO3(50 ml) and was extracted with ethyl acetate (2 x 70 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuum, obtaining a yellow oil, which was subjected to chromatography on silica gel with elution with ether /60 - 80 petrol (1:1). The specified connection (D) was obtained in the form of solids (1,95 g, 50%).

1H NMR (CDCl3)

: a 7.92 (d, 1H), 6,97 - 7,19 (m, 3H), 3,92 (t, 2H), 3,88 (s, 3H), on 3.36 (t, 2H), 3.27 to (s, 3H), 2,10 - 2,22 (m,2H).

Description 12.The intermediate connection example 26).

eg-hinsides-2-ylmethylamino.

Stirred suspension of lithium aluminum hydride (400 mg, 0,010 mol) in THF (tetrahydrofuran) (20 ml) at room temperature under nitrogen atmosphere was treated with a solution of EC-2-cyanopyridine (I.e. Kopinga and other Yakugaku Zasshi, 1980, 100, 88) in THF (3 ml) and then the mixture was heated under reflux for 20 minutes the Mixture allowed to cool, then treated cautiously with water (0.4 ml), 10% NaOH solution and water (1.2 ml). The resulting mixture was filtered, and the filtrate concentration of the private oil (700 mg, 97%).

1HNMR (CDCl3)

: 2,80 of 2.92 (m, 2H), 2.57 m (d, 2H), 1,94 - 2,12 (m, 2H), 1,20 - 1,80 (m, 13H), from 0.88 to 1.05 (m, 1H).

Description 13.The intermediate connection for Example 30).

3 - methylthiazole [3,2-a] indole - 9 - carboxylic acid.

a) Mixed solution of 3-methylthiazole [3,2-a]indole (A. Kipriyanov Century and Chilia, Zh "Body. Chem". 2966, 2, 1474) (270 mg,0,0014 mol) in dimethylformamide (DMF) (3 ml) was cooled to 5oC under nitrogen and processed triperoxonane anhydride (0,23 ml, 0,0017 mol), then gave it to warm to room temperature for 3 hours the Solution was poured into water (25 ml) and the mixture was extracted with ethyl acetate (2 x 20 ml). The combined extracts were dried (Na2SO4and then were extracted in vacuum, obtaining 3-methyl-9-cryptanalytical[3,2-a] indole (370 mg, 90%) as a brown solid.

1HNMR (CDCl3)

: 8,10 (br.s, 1H), a 7.85 (d, 1H), 7,39 - 7,47 (m, 1H), 7,25 - 7,35 (m, 1H), 6,69 (S, 1H), and 2.83 (S, 3H).

b) 3-methyl-9-cryptanalytical[3,2-a] indole (370 mg, 0,0013 mol) was treated with 20% NaOH solution(15 ml) and ethanol (15 ml) and heated under reflux for 6 hours the Mixture was concentrated in vacuo to half its volume, the residue was acidified by acid 2M HCl and then was extracted with ethyl acetate (2 x 30 ml). United extras is avago solid (300 mg, 100%).

1HNMR (d6DMSO)

: 12,3 (v.br.s, IH), 7,93 - 8,08 (m, 2H), 7,16 - 7,40 (m, 2H), 6,95 (s, 1H), 2,59 (s, 3H).

Description 14.The intermediate connection for example 25).

N-(2 - bromacil)methanesulfonamide.

The stirred solution of 2-bromelain-bromhidrosis (5.10 g, of 0.025 mol) and triethylamine (6.9 g, 0,050 mol) in dichloromethane (200 ml) at a temperature of an ice bath was treated drop by drop with methanesulfonamide (1,96 ml of 0.025 mol). The mixture was allowed to warm to room temperature and was stirred for 16 h, then washed with water and acid 5 MHCl, dried (Na2SO4) and concentrated in vacuum, given a specified connection (d) as a colourless oil, which solidified upon exposure, giving a white solid (3.5 g, 69%).

1HNMR (CDCl3)

: to 4.92 (s, 1H), 3,62 - of 3.48 (m, 4H), 3,05 (s, 3H).

Description 15. The intermediate connection for example 31.

a) 2,3-dihydrothiazolo [3,2-a]indole.

The solution dioxindole (400 mg, 0,0027 mol) and 1,2-dibromethane (of 0.24 ml, 0,0027 mol) in dry THF (10 ml) was added to the stirred solution of potassium-t-butyl (760 mg, 0,0068 mol) in dry THF(tetrahydrofuran) (40 ml) at room temperature under nitrogen atmosphere. The mixture was stirred for 3 h, then treated with water (100 ml) and extreme, having an orange oil, which was subjected to chromatography on silica gel with elution with 10% ether/60-80 petrol. The specified connection is received in the form of a white solid (135 mg, 29%).

1HNMR (CDCl3)

: 7,42 - of 7.23 (m, 1H), 7,00 - 7,25 (m, 3H), of 6.20 (s, 1H), 4,23 (t, 2H), 3,79 (t, 2H).

C)2,3-dihydrothiazolo[3,2-a]indole-9-carboxylic acid.

2,3-dihydrothiazolo[3,2-a] indole was treated triperoxonane anhydride according to the method of description 13A, having a 9-cryptanalytical [3,2-a]indole in the form of a solid purple color (85%).

1HNMR (CDCl3)

: to 7.93 (br.s, 1H), 7,07 - 7,30 (3H), 4,30 (t, 2H), 3,85 (t, 2H).

The specified connection (15b) was obtained from 9-TRIFLUOROACETYL-2,3-dihydrothiazolo[3,2-a]indole, using the method of Description 13b, while receiving purple solid (95%) which was used without purification.

Description 16.

a) Thiazole[3,2-a]indole.

The mixed solution dioxindole (3.8 g 0,025 mol) and bromoxynil anhydride - diethylacetal (3.9 ml, was 0.026 mol) in acetone (200 ml) was treated with anhydrous potassium carbonate (6.9 g, 0.50 mol) and the mixture was heated under reflux for 2 h and then for 12 h at room temperature, the mixture was concentrated in vacuume>2SO4), concentrated in vacuo, and the residue was subjected to chromatography on silica gel with elution 10%)canola/60-80 petrol, having a 2-(2,2-diethoxyacetate)indole (3.0 g, 44%) as a yellow oil.

1HNMR (CDCl3)

: of 9.30 (br.s, 1H) 7,52 (d, 1H), 7,28 (d, 1H),? 7.04 baby mortality - 7,20 (m, 2H), return of 6.58 (s, 1H), 4.72 in (t, 1H), 3,55 - of 3.85 (m, 4H), 3,05 (d, 2H), 1,31 (t, 6H).

A well stirred mixture of 2-(2,2-diethoxyacetate) indole (1.5 g, 0,0057 mole) in polyphosphoric acid 30 g) was heated to 130oC for 20 min, then cooled to room temperature and the mixture was diluted with water (300 ml). The resulting aqueous solution increased the basicity by the additive solid potassium carbonate and then it was extracted with ethyl acetate (2 x 120 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo, and the residue was subjected to chromatography on silica gel with elution with 10% ether/60 - 80 benzyl, given a specified compound as a white solid (0.56 g, 57%).

1HNMR (CDCl3)

: 7,60 - of 7.70 (m, 3H), 7,11 - 7,28 (m, 2H), 6,60 (d, 1H), 6,53 (S, 1H).

b)Thiazole[3,2-a]indole-9-carboxylic acid.

The thiazole[3,2-a] indole was treated triperoxonane anhydride, using the method of description 13A, received a 9-TRIFLUOROACETYL-thiazole[3,2(m, 1H), 7,30 - 7,37 (m, 1H), 7,18 (d, 1H).

The specified connection (16b) was obtained from 9-cryptanalytical[3,2-a] indole, using the method of Description 13B, and was isolated as a pale purple solid (84%).

1HNMR (CDCl3/d6DMSO)

: 7,98 - 8,08 (m, 2H), 7,73 (d, 1H), 7,10 - 7,31 (m, 2H), 7,00 (d, 1H).

Description 17.

Methyl 2,4-dimethylpyrimidin[1,2-a]indol-carboxylat.

The mixed solution of methyl 2-aminoindole-3-carboxylate (I. Forbes and others, Journal of Chem. Soc, Perkin 1, 1992, 275)(0.25 g, 0,0013 mol) in acid (5 ml) was treated with 2,4-pentanedione (0,13 g, 0,0013 mol) and a few crystals of 4-toluenesulfonic acid and heated under reflux for 2 hours the Mixture was concentrated in vacuo, and the residue was dissolved in chloroform (20 ml), washed with water (2 x 20 ml), dried (MgSO4) and concentrated in vacuum, given a specified compound as a brown solid (0.25 g, 75%).

: 8,58 (d, 1H), of 8.09 (d, 1H), 7,52 (dt, 1H), 7,34 (dt, 1H), 6,53 (s, 1H), 4,06 (s, 3H), 3,03 (s, 3H), 2,68 (s, 3H).

Description 18.

Methyl 1,2,3,4-tetrahydropyrimido[1,2-a]indole-10-carboxylate.

A solution of methyl 2-Haendel-3-carboxylate (Da, 1.5 g, to 0.007 mol) in THF (30 ml) under nitrogen atmosphere was treated vodorodom sodium (215 mg, 80% oil is aeroplain (0,0093 mol) in toluene (15 ml), thus was formed a white gelatinous precipitate. This mixture was diluted with more tetrahydrofuran (THF) (30 ml) and was heated under reflux for 18 h, then concentrated in vacuo, and the residue is sufficiently stirred with ethyl acetate (40 ml) and 10% solution of Na2CO3(30 ml). The organic layer was separated, dried (Na2SO4) and concentrated in vacuum, obtaining a solid substance. He was subjected to chromatography on silica gel with elution with ether/ 60 - 80 petrol (1:1) receiving unreacted starting material (600 mg) and a specified compound as a white solid (110 mg, 6%).

1HNMR (d6DMSO)

: 7,58 (d, 1H), 7,26 (br.s, 1H), 7,12 (d, 1H), 6,88 - 7,05 (m, 2H), 3,98 (t, 2H). to 3.73 (S, 3H), 3,38 - of 3.46 (m, 2H), 2,08 (quintet, 2H).

Description 19.

Methyl, pyrimido[1,2-a]indole-10-carboxylate.

The mixed solution of methyl-2-aminoindole-3-carboxylate (I. Forbes and others, Journal of Chem. Soc.", Perkin 1, 1992, 275) (0.5 g, 0,0026 mol) in xylene (10 ml) was treated with 1,1, 3,3-tetramethoxypropane (0,43 g, 0,0026 mol) and a few crystals of 4-toluenesulfonic acid and heated under reflux for 2.5 hours the Mixture was concentrated in vacuo, and the residue was dissolved in chloroform, 25 ml), washed with water (2x10 ml), dried (MgSO4and what on silica gel with elution by ethyl acetate, given a specified connection (DT) as an orange solid (0,23 g, 35%).

1HNMR (CDCl3)

: 8,68 - 8,78 (m, 2H), to 8.57 (d, 1H), 7,89 (d, 1H), to 7.59 (dt, 1H), 7,45 (dt, 1H), 6,80 - of 6.90 (m, 1H), 4,08 (S, 3H).

The activity of the receptor antagonist of 5 - HT4.

1) the large intestine of the Guinea pig.

Used Guinea pigs - males weighing 250-400, more separate from the center region of the colon samples were taken plexus of the intestinal longitudinal muscle length is approximately 3 see Them suspended under a load of 0.5 g in isolated tissue baths containing Krebs solution, which bubbled through a 5% CO2in O2and maintain at 37oC. In all experiments, the Krebs solution also contained methiothepin 10-7M and granisetron 10-6M for blocking effects on the receptors 5 - HT2and 5 - HT3.

After building a simple curve concentration-response to 5 - HT and applying the contact time 30 and the dispensing cycle of 15 min was chosen such concentration of 5 - HT to get the muscles around 40 - 70% of maximum (10-9M approximately). Then in the fabric alternately were administered every 15 min the concentration of 5 - HT and then, introduced about equally effective conc the different reactions of 5 - HT and DMPP was added to the bath solution increased concentrations estimated receptor 5 - HT4. Then determined the effects of this compound in the percentage of muscle contraction caused by 5 - HT or DMPP. From these data, determine the values of the pIC50expressed as - log concentration of the antagonist, which was reduced by 50% reduction of muscles. Consider that the connection, which reduces the response to 5 - HT, but not on DMPP, acts as a receptor antagonist 5 - HT4.

Compounds were effective at concentrations typically within about pIC50= 7 or more, and E1, E2, E4, E6, E8, E15, and E27 show particularly good activity, when Y is 0, and E3, E20, E23 and E28 demonstrate particularly good activity, when Y is NH.

2) Atrium Piglet.

Compounds were tested on spontaneous beating of the heart in piglets (Naunyn - Schmiede Berg's Arch. Pharmacol, 342, 619 - 622). The value of the pKB( - Log10KBfor compounds of example 3 was equal of 10.05.

3)the Esophagus in rats.

The mucous membrane of the muscle shirt esophagus in rats was investigated in accordance with the method described in the publication of the Baxter and others, Naunyn - Schmiedeberg''s Arch. Pharmacol, 343, 439 - 446 (1991).

the tension of the saturated oxygen (95% O2/ 5% CO2) Tyrodes solution at 37oC. All experiments were performed in preparations pretreated with pargyline (pargyline), (100 MK for 15 min, followed by washout and in the presence of cocaine (30 MK). The reaction relaxant 5 - HT get after first compressing the tissue of the esophagus carbocol (carbachol) (3 MK).

4)Mobility bags stomach in dogs caused by receptor 5 - HT.

The connection was tested with the exception of gastric motility bags, using the method tests in vivo, described in the article "Stimulate motility of the stomach in dogs by BRL 24924, a new agent for exceptions motility of the stomach". The Bermudez and other Magazine .1990 testing methods, 2 (4), 281-286.

Test in vivo activity, causing restlessness or anxiety.

A test to determine the relationship between the rats during their fellowship.

Rats (male, Sprague Dawleys, Charles River weighing 250 - 300 g) was placed groups of eight pieces in the room where they are incubated for 5 days. Then placed separately in a room located adjacent to the experimental room, for 4 days, until the day when you start the experiment. On the day of experiment, rats injected carrier, the test connection is inferred from 10 a.m. After 30 min they are placed in pairs with females with the same weight categories (individuals in the pair meet for the first time) in the box installed in a separate room, to study their reactions when communicating. The drawer is made of Perspex material white in color and has a size of 54 x 37 cm, and it is made with a transparent front wall of Perspex and it does not cover. The floor of the box is divided into 24 squares and the box is brightly lit (115 LK). In next 15 min on the video monitor with remote control saw that the animals appeared active behavior (making a pretty face, Obrucheva, crawling on top or bottom, walking one behind the other, biting, climbing and fighting). During the test also observe and summarize the number of squares crossed by each rat. After the completion of each test box carefully wipe.

Connection E3 increased the total number of observed interactions within the interval doses of 0.01 - 10 mg/kg p. O.

The example of the pharmaceutical composition (hard gelatin capsule).

Ingredient: Amount per 1 capsule, mg:

Connection example 3 - 1 , 5, 10 or 20

Hydroxypropyl - methylcellulose - 12

Glycolate sodium starch - 12

Magnesium stearate - 2,4

A (CH2)3;

R1and R2hydrogen;

R3hydrogen;

R4hydrogen;

Y NH;

The Z group of the General formula

< / BR>
where R5hydrogen, C1C12-alkyl, phenyl(C1C6)alkyl, or R5- (CH2)z-R10where Z is 2 or 3, R10- phenoxy or SO2NR11R12where R11and R12hydrogen or C1- C6-alkyl or its pharmaceutically acceptable salt.

2. Connection on p. 1, representing the hydrochloride of N-[(1-N. butyl-4 - piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide.

3. The pharmaceutical composition active antagonist of 5-HT4receptors containing the active ingredient and adjuvants, wherein as the active component contains an effective amount of the compounds under item 1.

4. Connection on p. 1 or 2 active antagonist of 5-HT4-receptor.

Priority signs:

12.03.92 when R5hydrogen, C1C10is alkyl or phenyl(C1-C6)alkyl;

25.09.92 when R5C11C12-alkyl;

29.12.92 Ave

 

Same patents:

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new cephalosporins, namely to derive 1-zetia-diazaphosphorines General formula 1:

(I)

where the wavy line represents a CIS - or TRANS-configuration; R1-C1-C4alkyl, if necessary, replaced by carboxypropyl;

R2-tetrazol-5-yl, if necessary, replaced by stands, methylthiourea or dihydroxyphenylethylamine, thiadiazole-2-yl, if necessary, replaced by stands, methylthio-, amino-, pyridylcarbonyl-, 3,4-diacetoxybiphenyl - carbonylmethyl - or 1-methylprednisolone - amino group of the purine-6-yl, 1,2,3-triazole-5-yl, 1,2,4-triazolyl, if necessary, replaced by stands and trifluoromethyl, thiazolo (5,4-C) pyridin-2-yl or 5,6-dioxo-1,2,4-triazinyl, replaced by chlorpropamide, cooa group COOH or R2-1 methylpyridine, sooa-radical soo-that may find application as antibacterial substances in medicine

The invention relates to new biologically active chemical compounds, specifically to derived dihydropyrimidine formula I

where R1- C1-C6-alkoxy or phenylaminopropyl,

R2- C1-C6-alkyl or phenyl,

R3is a hydrogen atom or a C1-C6-alkyl,

R4- C1-C6-alkyl or phenyl which may be substituted by one or more identical or different substituents from the group halogen, nitro, C1-C6-dialkylamino,1-C6-alkyl, C1-C6-alkoxy and hydroxy-group, or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

The invention relates to androidiani carboxanilides, compositions based on them and the way to deal with arteriotomy and can be used in agriculture

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions

The invention relates to methods of optical separation pornoencaricaturas compounds, which are important intermediate product in the synthesis of optically active derivative of pianolasociety, useful in the treatment of hypertension (hypertension) and asthma

The invention relates to pharmaceutically active bicyclic heterocyclic amines (XXX) and can be used as pharmaceuticals for the treatment of diseases and injuries

The invention relates to compounds corresponding to the following formula I:

< / BR>
where R1- represents a group of formula

< / BR>
where n = 1 or 2, R3represents hydroxyl, lower alkoxygroup, aryl (lower) alkoxygroup, amino group, lower alkylamino or di (lower alkyl) amino group, R4represents hydrogen, lower alkyl or aryl (lower) alkyl , R5represents hydrogen, lower alkyl, aryl (lower) alkyl or lower alkylsulphonyl, R6represents hydrogen or lower alkyl, provided that when R6is lower alkyl, then R6replaces one of the methylene hydrogen atoms, R2represents a group of formula

< / BR>
where X is hydrogen, halogen, lower alkyl or lower alkoxygroup,

R7represents lower alkyl or aryl (lower) alkyl,

R8represents hydrogen or lower alkyl,

R9represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl (lower) alkyl, formyl, lower alkyl carbonyl, aryl (lower alkyl) carbonyl Il is kilcarbery,

R11represents hydrogen, lower alkyl or aryl (lower) alkyl,

and such compounds are applicable for alleviating various memory disorders, characterized by a cholinergic deficit such as disease Alzheimer

The invention relates to the derivatives of triazolopyrimidine General formula (I), method of production thereof and to pharmaceutical compositions based on

The invention relates to a new tetrahydroimidazo [1,4] benzodiazepine, method of their production, intermediate products for their preparation and pharmaceutical compositions based on them

The invention relates to new derivatives of 2-amino-7-(CH2R2R3)-3H,5H-pyrrolo[3,2-d] pyrimidines having the properties of a selective inhibitor of T-lymphocytes, methods for their preparation and to a method of selective inhibition of proliferation of T-lymphocytes of a mammal and does not impact B-lymphocytes

The invention relates to androidiani carboxanilides, compositions based on them and the way to deal with arteriotomy and can be used in agriculture
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