Substituted tetrahydro-, or hexahydroazepin // indoles or pharmaceutically acceptable salt additive, and methods for their production

 

(57) Abstract:

Usage: medicine for the treatment of various memory disorders characterized by decreased cholinergic function. The inventive products: substituted tetrahedral hexahydrocannabinol (b) indoles f-ly I, where R1hydrogen, lower alkylaminocarbonyl, benzyloxycarbonyl, R2is hydrogen, lower alkyl, cycloalkyl, phenylselenenyl lower alkyl, quinil, formyl, benzyloxycarbonyl, R3is hydrogen, lower alkyl, R4is hydrogen, hydroxy, lower alkylaminocarbonyl, - - - denotes the absence of a relationship or single bond. Reagent I. the joint f-crystals 2, which is subjected to recovery. Reaction conditions: recovery is carried out using Raney alloy in sodium hydroxide solution. 2 S. and 4 C.p. f-crystals, 4 PL.

The invention relates to compounds of the formula:

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in which n is 2, 3, 4 or 5; X represents hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl or nitro group; R1represents hydrogen, lower alkyl, lower alkenyl, lower quinil, amino-lower alkyl, lower alkyl-eminently alkyl, di-lower alkylamino lower alkyl, cycloalkyl, cycloalkyl lower alkyl,th alkylenes group, and Y denotes hydrogen, lower alkyl, aryl or aryl lower alkyl; R2represents hydrogen, lower alkyl, formyl, lower alkylsulphonyl, benzyloxycarbonyl or lower alkylaminocarbonyl; or alternative group

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in General represents a

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R3represents hydrogen, lower alkyl, aryl lower alkyl, lower alkylsulphonyl or lower alkoxycarbonyl;

R4represents hydrogen, -HE,

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or , where R7represents lower alkyl, lower alkenyl, lower quinil, cycloalkyl, cycloalkyl lower alkyl, aryl, aryl lower alkyl, aristically, and R6represents hydrogen, lower alkyl, aryl or aryl lower alkyl; or alternatively the group as a whole, is a

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and R7represents lower alkyl, aryl or aryl lower alkyl; such compounds are useful for alleviating various memory dysfunction characterized by a cholinergic deficit such as Alzheimer's disease. The compounds of formula I of the invention also inhibit the monoamine oxidase and/or act on the Central2-adrenergic receptors and, therefore, can be used as antidepressants.

is t the above values, which are useful as direct predecessors of the target compounds of the present invention.

In the scope of the invention also includes compounds of formula III in which R8represents hydroxy, amino lower alkoxy, lower alkyl, cycloalkyl, cycloalkenyl, aryl lower alkyl, aristically, lower alkylcarboxylic or lower aminocarboxylate, which are useful for alleviating various memory dysfunction characterized by a cholinergic deficit such as Alzheimer's disease. Compound III of this invention also inhibit monoamine oxidase and/or act as antagonists at the pre2-adrenergic receptor and therefore are useful as antidepressants.

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Unless specified or indicated otherwise, the following definitions apply to the entire text of the description and the attached claims.

The term lower alkyl means alkyl group normal or isotrate containing 1-6 carbon atoms. The examples of the mentioned lower alkyl can serve as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec. -butyl, tert.-butyl and pentyl and hexyl normal or razvetvlenno"ptx2">

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

The term aryl means a phenyl group substituted by 0,1 or 2 substituents, each independently from each other represents a lower alkyl, lower alkoxy, halogen, trifluoromethyl, hydroxy or nitro group.

Everywhere in the text of the description and the attached claims chemical formula or name covers all stereo and tautomeric isomers in the case where such isomers exist.

Compounds of the present invention is produced by use of one or more stages of synthesis described below.

In the text descriptions of the stages of synthesis of the symbols n, X, Y, and R1R8have the respective meanings given above unless specified or indicated otherwise.

Stage A.

The compounds of formula IV in which R9represents hydrogen or-och3, is subjected to cyclization with obtaining the compounds of formula V. This reaction is usually carried out in aqueous sulfuric acid at a temperature of 25-150oC.

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Stage Century.

Produce a reaction between the compound V and sulfate compound of the formula (R10O)2SO2in which R10region, obtaining the compounds of formula VI. According to another method, carried out the reaction between the compound V and a halide compound of the formula R10-l, where R10has the above values, using the traditional method known in this field, to obtain the compounds of formula VI.

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Stage With.

Conduct the reaction between the compound V and di lower alkylaminocarbonyl formula R11-O-CO-O-CO-O-R11where R11represents a lower alkyl group, in the presence of a suitable catalyst, preferably 4-dimethylaminopyridine, obtaining the compounds of formula VII

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Stage D.

Conduct the reaction between the compound V and acylchlorides formula R11-CO-CL, using a conventional method known in this field, to obtain the compounds of formula VIII.

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Stage E.

The compound of the formula IX obtained in stage B, is subjected to a cleavage reaction with obtaining the compounds of formula X. Usually at the end of this reaction, compound IX is reacted with a complex VVG3(tetrahydrofuran, and the resulting product hydrolyzing the usual way known from the literature.

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Stage F.

In special slowly conventional method, known in the literature, obtaining the compounds of formula XII (reaction Friedel -).

(XII)

Stage G.

The usual method known from the literature, conduct the reaction between the compound XII and nagkalat, preferably m-chlormadinone acid, to obtain the compounds of formula XIII (reaction Bayer-Villiger).

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Stage N.

Compound XIII hydrolyzing, preferably in the presence of such bases as sodium hydroxide to obtain the compounds of formula XIV.

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Stage I.

The compound of formula XV, in which R12represents hydrogen, methoxy or hydroxy which is received at one of the previous stages, is subjected to reaction with hydroxylamine hydrochloride using the traditional method, known from the literature, to obtain the compounds of formula XVI. Typically this reaction is carried out by suspension of compound XV in ethanol followed by addition of an aqueous sodium acetate solution and an aqueous solution of hydroxylamine hydrochloride, after which the suspension is stirred at a temperature of 25-150oC.

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Stage j

The standard way carried out the reaction between the compound XVI and the bromide Eminescu, obtaining the compounds of formula XVII.

(XVII)

Stage K.

The generally accepted method known from the literature, carried out the reaction between the compound XV and the primary amine of the formula

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where R14represents lower alkyl, lower alkenyl, lower quinil, cycloalkyl, cycloalkenyl, arlinski alkyl, aristically or aryl, to obtain the imine of formula XVIII.

This reaction is preferably carried out in the presence of isopropylate titanium (IV) in a suitable solvent such as acetonitrile. Typically this reaction is carried out at a temperature of 0-80oC. This method is more preferable than the method using TiCl4or the method in which the reaction is carried out in a sealed tube at an elevated temperature with molecular sieves used as photodamage tools.

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Stage L.

Compound XVI restore using Raney alloy and sodium hydroxide solution in accordance with the method described b Staskunas and T. van Asom (J. Chem. Soc. C, 531, 1966) to obtain the compounds of formula XIX.

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Stage M

Conduct the reaction between the compound XV and isopropylate titanium and a secondary amine of the formula where the group is cnyh descriptions R. J. Mattana with TCS. J.Org. Chem. 55 - 2552-4 (1990), with the compounds of formula XX.

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Stage n

The traditional method, known from the literature, compound XVIII was reduced by sodium borohydride, cyanoborohydride sodium or complex, borane/tetrahydrofuran to obtain the compounds of formula XXI.

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Stage Acting

Compound XIX was restored with the help of a complex of borane/tetrahydrofuran and triperoxonane acid to obtain the compounds of formula XXII.

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Stage R.

Carried out the reaction between the compound of formula XXIII, which was received at stage L or O, and a halide compound of the formula R15-l, in which R15represents lower alkyl, lower alkenyl, lower quinil, cycloalkenyl alkyl, arlinski alkyl,

obtaining the compounds of formula XXIV.

< / BR>
Stage q

Carried out the reaction between the compound of formula XXV in which R16represents hydrogen, lower alkyl, lower alkenyl, lower quinil, cycloalkyl, cycloalkenyl, arlinski alkyl or aristically, and formic acid in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 4-dimethylaminopyridine, or mixed anhydride obtained and the SS="ptx2">

The conventional method known from the literature, carried out the reaction between the compound XXV and acyl chloride of formula R17CO-CL, in which R17represents a lower alkyl group, to obtain compounds of formula XXVII.

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Stage S.

The generally accepted method known from the literature, carried out the reaction between the compound of formula XXV in which R12not a hydroxy group, and benzylchloride with obtaining the compounds of formula XXVIII.

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Stage I.

Carried out the reaction between the compound of formula XXV in which R12is not hydroxy and isocyanate of formula R17-N=C=O, in which R17represents lower alkyl, aryl or arimitsu alkyl group, to obtain compounds of formula XXIX. Typically this reaction is carried out in the presence of such a suitable catalyst, as 1,8-diazabicyclo[5.4.0]undec-7-ene

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Stage u

Carried out the reaction between the compound of formula XVI in which R12is not hydroxy and isocyanate in much the same way as in stage T, obtaining the compounds of formula XXX.

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Stage y

The conventional method known from the literature, conducted reactsAbout obtaining the compounds of formula XXXI.

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Stage W.

The conventional method known from the literature, carried out the reaction between the compound of formula XXXII, where R2is not the lowest alkylaminocarbonyl received on one of the previous stages, with chloroformiate formula to obtain the compounds of formula XXXIII.

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Stage X.

Carried out the reaction between the compound of formula XXXIIIa, which was received at the stage W with the isocyanate of formula R17-N=C=O, using the same method that was used at the stage T, resulting in the received connection formula IV. After this connection XXXIV was subjected to hydrogenolysis in the usual way known in the art, using a suitable catalyst such as palladium on charcoal, to obtain the compounds of formula XXXV.

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Stage Y:

In accordance with the method described for stage T, the reaction between the compound of formula XXVI, which was obtained in the previous stages, and the isocyanate of the formula R17-N=C=O with obtaining the compounds of formula XXVII.

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Compounds of formulas I and III of the present invention are useful for the treatment of various memory disorders characterized by reduced choline is aminoacids and/or affect the Central 2- adrenalinka receptors and, therefore, are useful as antidepressants.

Activity against facilitate such memory disorders demonstrates the ability of such compounds to inhibit the enzyme acetylcholinesterase and thereby increase the level of acetylcholine in the brain.

Test for inhibition of cholinesterase.

Cholinesterase is found in various parts of the body, as in the brain and in serum. However, only the distribution of acetylcholinesterase in the brain correlates with Central cholinergic innervation. It is assumed that this innervation is attenuated in patients with Alzheimer's disease. In the present work we determined the inhibition of in vitro acetylcholinesterase activity in rat striatum (Striatunu).

Inhibition of in vitro acetylcholinesterase activity in rat striatum.

The acetylcholinesterase (hE), sometimes called true or specific cholinesterase found in nerve cells, skeletal muscle, smooth muscle, various glands and in red blood cells. ChE can be distinguished from other cholinesterase on substrate and inhibitor speciously the innervation, and subfractionated detects higher levels in the nervous system.

It is generally accepted the fact that the physiological role hE is the rapid hydrolysis and inactivation of acetylcholine Inhibitors hE show pronounced cholinomimetic action in holinergiceski-innervation effector organs, and they are used therapeutically in the treatment of glaucoma, myasthenia gravis and paralytic ileus. However, the results of recent studies suggest that ChE inhibitors can also be used for the treatment of Alzheimer's disease.

Described below is the method used in the invention for assessing cholinesterase activity. This method is a modification of the method of Ellman with TCS. Biochem Phasm. 7, 88 (1961).

Methodology:

A. Reagents

1. 0.05 M phosphate buffer, pH 7,2.

(a) 6.85 g NaH2PO4H2O/100 ml of distilled water

(b) 13,40 g Na2HPO47H2O/100 ml distilled H2< / BR>
(c) add (a) to (b) to a pH of 7.2

(d) carry out dilution 1:10

2. The substrate in the buffer

(a) 198 mg of chloride acetylthiocholine (10 mm)

(b) bringing to volume of 100 ml with 0,0 thou NB) (0.5 mm)

(b) bringing to volume of 100 ml with 0.05 M phosphate buffer,

pH of 7.2 (reagent 1)

4. Prepare 22mm original solution of the test drug in a suitable solvent and adjusted to the required volume with 0.5 mm NB (reagent 3). Drugs are serially diluted (1:10) so that the final concentration (in a ditch) is 10-4M, and subjected to screening for the activity. If the activity inhibitory activity subsequent concentrations were determined value IC50.

C. Preparation of tissue

Male rats varieties Wistar subjected decapitate, quickly removed the brains analyzed strips of the base of the brain was weighed and homogenized them in 19 volumes (approximately 7 mg protein/ml) in 0.05 M phosphate buffer, pH to 7.2 using a homogenizer tter Elvehjem. An aliquot of the homogenate volume of 25 μl was added to 1.0 ml of medium for a drug or test drugs of different concentrations and within 10 minutes was preincubator at 37oC.

O. Analysis.

Enzymatic activity was measured using a spectrophotometer Beckman brand DI-50. This method can be used to determine the IC50and measurement of the kinetic constants.

The set of tools is The wavelength of 412 nm;

The dispenser is missing;

Cuvette 2 ml cuvette using an automatic sampler for 6 samples;

Blind experiment 1 for each substrate concentration;

The time interval of 15 s (15 or 30 s for kinetics);

Total time of 5 minutes (5 or 10 min for kinetics);

Schedule available;

The interval scale;

The slope increasing;

Results positive (slope);

In the empty cell and the cell sample was added the following reagents:

Empty cell: 0.8 ml phosphate buffer/NB; 0.8 ml buffer/substrate

The control cuvette: 0.8 ml phosphate buffer/NB/enzyme; 0.8 ml phosphate buffer/substrate

Medicine: 0.8 ml phosphate buffer (NB) drug/enzyme; 0.8 ml phosphate buffer/substrate

For each experiment was determined values in the empty cells with the aim of controlling pensinula hydrolysis of the substrate and these values was subtracted automatically by the program Cendata, which has a kinetic module Soft-Pak. This program also calculates the rate of change of absorption in each cell.

To determine the IC50:

When the definitions of the substrate concentration equal to 10 mm was diluted in the ratio 1:2 final conc the IC50was calculated using log-probit analysis

The test results of some compounds of the present invention and that of physostigmine (exile connection) are presented in table. 1.

This utility is additionally demonstrated by the ability of these compounds to restore the memory associated with a cholinergic deficit, to test the avoidance of darkness, described below.

The test for the avoidance of darkness

In this experiment, the mice were tested on their ability to remember an unpleasant stimulus within 24 hours, the Mice were placed in a cell with a dark office; as a result of exposure to a strong light from the bulb of the mouse ran into the dark compartment, where electrocution through the metal plate on the floor. Animals were removed from the test device and again tested after 24 h on their ability to remember the action of electric shock.

If scopolamine, anticholinergic, which is known to cause memory impairment, is applied to the initial test animal in the test chamber, the animal re-enters the dark compartment shortly after placing it in the test chamber after 24 hours the effect is scopolamine in a dark office.

The effect of the active compounds were expressed in percentage of animals in the group blocked the effect of scopolamine, which was reflected by an increase of the time interval between the location in the test chamber and re-entry into the dark compartment.

The results of this test for certain compounds of the invention and tacrine and pilocarpine (reference compounds) are presented in table. 2.

This utility is additionally demonstrated by the ability of the compounds of the invention inhibit the enzyme monoamine oxidase, increase levels of brain biogenic amines and effect as antidepressants.

Inhibition of the activity of monoamine oxidase type a and type b in the uptake of rat brain.

The purpose of providing selective inhibition of these two forms of formanalysis (MAO).

Introduction.

For the above two forms of monoamine oxidase, which are called type a and type B, known metabolic deamination of amines. The existence of two such forms are based on different specificnosti in relation to substrate and inhibitor. Serotonin (NT), norepinephrine (NE) are substrates for MAO type a-Fratelli bstrate for both types. Clarion is a selective inhibitor for the enzyme type And, deprenil, pargyline selective inhibitors for the enzyme type, and tranilcipromin and iproniazid are not selective inhibitors. It is established that the MAO inhibitors have antidepressant properties.

Although there are various methods for measuring MAO activity, the described method includes extraction radiometric dezaminirovanie metabolites (3H)-NT or (14C)-b-phenethylamine. This method allows to measure the activity of MAO-a and MAO-b-simultaneously or separately.

Technique

A. Reagents

1. Phosphate buffer (0.5 M), pH 7.4: 134 g NaH2PO47H2O bring to 1 liter with distilled water (A), 17.3 g of Na2HPO4bring to a volume of 250 ml with the required quantity of distilled water ().

pH And adjusted to 7.4 by slowly adding (using the required volumes of reagents).

Spend a dilution ratio of 1:10 with distilled water (0.05 M RHO4buffer, pH 7.4).

2. 0.25 M sucrose in buffer RO4):

21,4 g sucrose brought to a volume of 250 ml with 0.05 M buffer RHO4< / BR>
3. Substrate for MAO-A:

A. Serotonin kr is the objects of study were used to dilute the specific activity (3H)-NT.

b. [3N] -5-hydroxytryptamine binocular (20-30 CI, mmol) was obtained from new England nuclear.

S. 12 ál (3H)-NT was added to 2 ml of 5 mm 5 HT solution (final concentration of amine in the analysis was 200 µm, see below).

4. Substrate for MAO-Century

A. b-phenethylamine (REA) was obtained from Sigma Chemical company. Prepared 5 mm of the original solution in 0.01 N. Hcl. This solution was used to dilute the specific activity (14C)-REA.

b. b-[ethyl-1-14 -] phenethylamine hydrochloride (40-50 CI, mmol) was obtained from new England nuclear.

S. 12 ál (14C)-REA was added to 2 ml of a 5 mm solution REA. (The final concentration of amine in the analysis was 200 μm; see below).

5. An equal number of substrates of MAO-a (NT) and MAO-b(REA) were combined for simultaneous testing of both types of MAO, i.e., received a mixed solution of 2.5 mm NT and 2.5 mm REA, 40 μl of this mixed solution gives the final concentration of each amine in the analysis of 200 μm. When testing only one type of MAO individual 5 mm source solutions should be diluted in the ratio 1:1 with distilled water before the addition of 40 μl in the incubation mixture, i.e., has the same final concentration of amine R is ranged and quickly removed brains. The whole cerebral mass without cerebellum was homogenized in about 30. ice 0.25 M sucrose phosphate buffer using a homogenizer tter Elvejhem. The homogenate was centrifuged at 1000 g for 10 min and the supernatant layer (S1) decantation and conducted repeated centrifugation at 18000 g for 20 minutes the resulting precipitate (P2) re-suspended in 0.25 M fresh sucrose. The resulting product served as a tissue source for mitochondrial MAO.

C. Analysis

10 ál of 0.5 M RHO4buffer, pH 7.4.

50 μl of N2Oh or the corresponding concentration of medication

400 μl of tissue suspension.

Tube pre-incubated for 15 min at 37oC and started the analysis by adding 40 μl of the combined substrate ([3H]-NT and [14C] -REA) in 15-second intervals. The tubes were incubated for 30 min at 37oC, and the reaction was stopped by adding 0.3 ml of 2 standards. HCl. Fabric blank values were determined by adding acid before radioactive substrate. The oxidation reaction products were extracted with a mixture of ethyl acetate/toluene (1: 1). 5 ml of this mixture was added in a test tube. The mixture was mixed in a content of inorganic fillers phase, which gave the opportunity to separate from the aqueous phase. The tubes were placed in a tub with a mixture of acetone/dry ice with the aim of freezing the water layer. After freezing the layer of the upper organic layer was poured into a scintillation vial. Added 10 ml of liquescent and count the samples using device for Windows14C in one channel and3H in the second channel. The values of the IC50were determined using log-probit analysis.

The results of the analysis for the inhibition of monoamine oxidase of the compounds of the present invention are presented in table. 3.

The authors of the invention was also carried out analysis on the binding of clonidine, described below, to establish the interaction of the compounds of the invention with a2-receptors.

The binding of 3H-clonidine: 2the receptor.

Introduction.

It has been shown that some antidepressants enhances neuronal secretion of norepinephrine in the alleged blockade presinapticheskogo2-receptor, and such property may be important in the mechanism of action of such compounds. The interaction of compounds with the Central2receptors evaluated in the analysis of SV is of the lead up to 1 liter (0.5 M Tris buffer, the pH of 7.7)

b. Were diluted in the ratio 1:10 with distilled water (0.05 M Tris buffer, pH 7,7)

2. Tris buffer containing physiological ions

A. the source buffer

NaCl 7,014 g

KCl 0,372 g

l20,222 g made up to 100 ml in 0.5 M Tris buffer

gCl20,204 g

b. Were diluted with distilled H2About in the ratio of 1:10. As a result of this received 0.05 M Tris Hcl, pH 7,7; containing NaCl (120 mm), KCl (5 mm), l2(2 mm) and gCl2(1 mm)

3. [4-3H]-Clonidine hydrochloride (20-30 CI/mmol) was obtained from new England Nuclear. The determination of the values of IC50: solution3H-clonidine brought to a concentration of 120 nm, and in each tube was added 50 μl (resulting in the analyzed volume of 2 ml was obtained final concentration of 3 nm).

4. Clonidine-Hcl was obtained from Boehringer-Ingelheim. Prepared the original solution of 0.1 mm clonidine order to determine nonspecific binding. In the analysis this gave a final concentration of 1 μm (20 µl 20 ml).

5. Compound. In most analyses in a suitable solvent prepared 1 mm of the original solution and subjected to serial dilution so that the final concentration in the analysis ranged from 10-5the STV can be used in higher or lower concentration.

C. Tissue preparation.

Rats varieties Wistar were killed by decapitation and quickly dissected cortical tissue. This tissue is homogenized in 50 ml of 0.05 M Tris buffer, pH 7.7 (buffer 1b) using Polytron of Brinkmann and then centrifuged for 15 min at 40,000 g. The upper layer was discarded and the precipitate re-homogenized in the original volume of 0.05 M Tris buffer pH of 7.7 and re-centrifuged as described above. The upper layer is discarded and the final precipitate is re-homogenized in 50. buffer 2b. This tissue suspension was then kept on ice. The final concentration of tissue was 10 mg/ml Specific binding was 1% of the total number of added ligand and 80% of the total number of bound ligand.

C. Analysis.

100 μl of 0.5 M Tris-physiological salts, pH 7.7 (buffer 2A)

830 μl of N2ABOUT

20 µl of the environment for a drug (for total binding) or 0.01 mm clonidine (for nonspecific binding) or appropriate concentration of drug

50 μl of 3H-clonidinum raw material

1000 μl of tissue suspension

Tissue homogenates were incubated for 20 min at 25oC 3 nm3H-clonidine and various concentrations lecial 5 ml chilled on ice 0.05 M Tris buffer, the pH of 7.7, and then transferred to scintillation vials. To each sample was added to 10 ml of a solution of Liquescent, after which it was carried out by counting using a liquid scintillation spectroscopy. Specific binding of clonidine was determined as the difference between total binding and the fact that it was determined using log-probit analysis. A specified percentage of inhibition at each concentration of the drugs is the average value of the three definitions.

The results of the analysis on the binding of 3H-clonidine compounds of the invention are presented in table. 4.

To assess the degree of safety of the compounds of the present invention below provides data on the toxicity of some compounds, expressed as 50% of the acute lethal dose ALD50when tested on mice.

The test compounds were administered intraperitoneally, and in some cases

subcutaneously.

In particular, the compounds of examples 2, 8, 10, 12, 13, 16, 17, 18, 19 intraperitoneal injection and examples 22, 23, 30, 38, 39 and 41 in a subcutaneous showed values ALD50>80 (mg/kg). This indicator for the connection of example 6 was >40, but<80.

The acid used to obtain pharmaceutically acceptable salts accession acids of the present invention include such inorganic acids as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric and perchloric acid and such organic acids as tartaric, citric, acetic, succinic, maleic, fumaric, 2-naphthalenesulfonate and sorrel.

Active compounds of the present invention can be used orally, for example, in the presence of an inert diluent or edible carrier, or they can be placed in gelatin capsules or zapressovanny in tablets. For oral therapeutic use, the active compounds can be administered in the presence of excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, chewing gum, etc. Such drugs bits concrete forms and can range 4-70% by weight of the dosage form. The number of active compound in such compositions is such, to get the appropriate dosage. Preferred compositions and preparations according to the present invention receive so that an oral dosage form contains from 1.0 to 300 mg of active compound.

Tablets, pills, etc. can also contain the following ingredients: a binder such as microcrystalline cellulose, Arabic gum, or gelatin; excipients, such as starch or lactose, disintegrity agent, as alginic acid, Primogel, wheat starch, etc., lubricating agents like magnesium stearate or Sarotex; slip agents, such as colloidal silicon dioxide, and sweetening agents as sucrose or saccharin, may also be added such perfumes as peppermint, methyl salicylate or orange flavoring. In the case when the unit dosage form is a capsule, the latter may contain, in addition to the above materials, a liquid carrier such as fatty oil. Other unit dosage forms can contain various other materials which modify the physical form of a unit dosage, for example, by formation of the coating.and agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives agents, dyes, colorants and fragrances. The materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the quantities used.

For purposes of parenteral therapeutic application of the active compounds of the present invention can be administered in solution or suspension. These preparations should contain at least 0.1% of active compound, but this number may vary in the range of 0.5-30 wt. The number of active compound in such compositions is such that to get the right dosage. Preferred compositions and preparations according to the present invention are prepared so that a single parenteral dose contains 0.5 to 100 mg of active compound.

The solutions or suspensions may also include the following components: a sterile diluent such as water, saline solution, fixed oils, polyethylene glycols, propylene glycol or other synthetic solvents; antibacterial agents like benzyl alcohol, methylparaben; and SNA acid; such buffers as acetates, citrates or phosphates and agents for regulating toychest such as sodium chloride or dextrose. The parenteral preparation can be placed in the available syringes or ampoules with multiple dose, made of glass or plastic.

Examples of compounds of the invention include the following substances:

1,2,3,4-tetrahydrocyclopent[b]indole-3-amine;

4-methyl-1,2,3,4-tetrahydrocyclopent[b]indole-3-amine;

1,2,3,4-tetrahydrocyclopent[b]indol-3-cyclopropylamino;

4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-3-cyclopropylamino;

1,2,3,4-tetrahydrocyclopent[b]indol-3-(2-PROPYNYL)amine;

1,2,3,4-tetrahydrocyclopent[b]indol-3-(N-formyl)amine;

1,2,3,4-tetrahydrocyclopent[b]indol-3-(N-phenylmethanesulfonyl);

1,2,3,3 and,4,8 b-hexahydroazepin[b]indole-3-amine;

1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b]indole-3-amine;

1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b]indol-3-(2-PROPYNYL)- 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent(b)- indole-7-Il methylcarbamate;

3-(N-cyclopropyl)-amino-4-methyl-1,2,3,4-tetrahydrocyclopent-[b] - indol-7-ol;

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent-[b] indol-7-yl methylcarbamate;

3 cyclopropylamino-1,2,3,3 and 8b-hexa is talkabout;

3-(N-cyclopropyl-N-methylaminomethyl)amino-1,2,3,3 and, 4,8 b - hexahydroazepin[b] indol-7-yl fenilmetilketenom; 3-(N-cyclopropyl-N-methylaminomethyl)amino-1,2,3,3 and,4,8 b-hexahydro-4 - methylcyclopentene[b]indol-7-ol;

3 cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent [b] -indol-7-yl methylcarbamate;

1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-phenylethylamine-cyclopent[b] indol-7-ol;

1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-aminocyclopent[b] indol-7-ol;

1,2,3,3 and, 4,8 b-hexahydro-4-methyl-3-phenylethylenediamine [b]indol-7-ol;

1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-(N-phenylmethanesulfonyl)- aminocyclopent[b]indol-7-yl methylcarbamate;

1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-methylaminomethyl-aminocyclopent [b] indol-7-ol;

1,2,3,3 and, 4,8 b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminomethyl) aminocyclopent[b]indol-7-ol;

4-tert.-butyloxycarbonyl-1,4-dihydrocyclopenta[b] indole-3(2H)-he;

7-chloroacetyl-1,4-dihydro-4-methylcyclopentene[b]indol-3-(2H)-he;

7 chloroacetoxy-1,4-dihydro-4-methylcyclopentene[b]indole-3(2H)-he;

1,4-dihydro-7-hydroxy-4-methylcyclopentene[b] indol-3-(2H) -; 1,4-dihydro-7-methylaminorex-4-methylcyclopentene[b]indole-3(2H)-he;

3 hydroxyimino-7-methoxy-1,2,3,4-tetrahydrocyclopent[b]indole;

3 gidroksilamina-1,2,3,4-is l)oximino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indole;

3 cyclopropylamino-1,2,3,4-tetrahydrocyclopent[b]indole;

3 cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indole;

3 hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7 - acetate;

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indole;

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol methylcarbamate;

4-methyl-3-[(2-vinylcyclopropyl)imino] -1,2,3,4-tetrahedrite[b] indol-7-ol;

4-methyl-3-[(2-vinylcyclopropyl)imino] -1,2,3,4-tetrahedrite[b] indol-7-yl methylcarbamate;

3 cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol;

3 methylaminoanthraquinone-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl methylcarbamate;

3 cyclopropylamino-1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b]indol-Il methylcarbamate;

3-amino-1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b]indol-7-yl;

-1,2,3,4-tetrahydroisoquinolinium;

5-bromo-3-cyclopentylamine-1,2,3,3 and, 4,8-hexahydro-4-methylcyclopentene [b] indol-7-yl fenilmetilketenom;

3-[2-morpholinoethyl]-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-Il generationbased;

4-methyl-3-(4-piperidinyl)-amino-1,2,3,4-tetrahydrocyclopent[b] indol-Il generationbased.

P R I m e R 1.

3-hydroxyimino-7-metocean (6.0 g) in 100 ml of 10% aqueous solution of N2SO was heated on the steam bath for 4 h and then was allowed to cool to room temperature and was filtered to obtain 1,4-dihydro-7-methoxy-cyclopent[b]indole-3(2H)-it is in the form of a solid substance. The indole (2.6 g) in 25 ml of 95% aqueous solution t was added hydroxylamine hydrochloride (1.7 g) in 15 ml of water and then sodium acetate (2.1 g) in 15 ml of water. The resulting mixture was heated under reflux for 2.5 h and then left to stand overnight. t was removed in vacuo and the resulting solid material was collected and purified using flash chromatography to obtain 0.8 g of a mixture of isomers of the oxime, so pl. 169-175oC (decomp.).

Elemental analysis:

Calculated for C12H12N2O2:

WITH 66,65% H 5,95% N 12,95%

Found: C 66,39% H 5,51, N 12,91%

P R I m m e R 2.

3 hydroxyimino-1,2,3,4-tetrahydrocyclopent[b]indole.

To a stirred solution of 1,4-dihydrocyclopenta[b]indol-3-(2H)-it (10 g) in 100 ml of 95% t was added hydroxylamine hydrochloride (8,3 g) in 20 ml of water then was added sodium acetate (9.7 g) in 20 ml of water. The resulting mixture was heated under reflux for 2 h, then left to stand overnight at room temperature. t was removed in vacuo, and the single isomer of the oxime in the first game and 3.0 g of a mixture of isomers of the oxime in the second game. 1.5 g sample of one isomer was recrystallized to obtain 0.9 g of an analytically pure material, so pl. 185-189oC.

Elemental analysis:

Calculated for C11H10N2O2:

WITH 70,95% H 5,41, N 15,04%

Found: C 70,71% H 5,32% N 14,94%

The elks with TCS. J. Chem. Soc. 624 (1944).

P R I m e R 3.

3 hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indole.

To a stirred solution of 1,4-dihydro-4-methylcyclopentene[b]indole-3(2H)-she (3.0 g) in 30 ml of 95% t was added hydroxylamine hydrochloride (2.25 g) in 9 ml of water followed by the addition of sodium acetate (4.4 g) in 9 ml of water. The mixture was heated under reflux for 4 h, then was added 1.1 g of hydroxylamine hydrochloride in 5 ml of water and 2.2 g of sodium acetate in 5 ml of water. After 2 h additional boiling under reflux the mixture was left to stand overnight at room temperature. Precipitated material was collected and recrystallized from 95% t with the receipt of 1.9 g of analytically pure material, so pl. 197-199oC.

Elemental analysis:

Calculated for C12H12N2O2:

WITH 71,98% N 6,04% N 13,99%

Found: C 72,18% H 6,14% N 14,00%

P R I m e R 4.

3-(2-amino-ethyl)oximino-4-methyl shall cyclopent[b] indole (5.0 g) in methylene chloride (50 ml) was added a 50% solution Paon (50 ml) followed by addition of tetrabutylammonium bromide (800 mg) and the hydrobromide of bromethalin (7.6 g). The reaction mixture was stirred at room temperature overnight. The layers were separated, and the aqueous layer was extracted with methylene chloride (50 ml). The organic layers were combined, dried (NaS4) and concentrated. The product was purified using flash chromatography on silica gel, carrying out elution with a mixture of 10% methanol/methylene chloride to obtain 1.1 g of purified material.

P R I m e R 5.

1,2,3,4-tetrahydrocyclopent[b]indole-3-amine.

To a stirred solution of 3-hydroxyimino-1,2,3,4-tetrahydrocyclopent[b]indole (6 g) in 16 ml of 95% t at 0oC was added Nickel alloy (Harshaw Ni-OR, 10 g), after which was added 12.9 g of sodium hydroxide in 150 ml of water. Bath ice was removed after 0.5 h, and the resulting mixture was stirred for another 1 h and filtered. t was removed in vacuo, and the resulting product crystallized, giving 5.0 g of a solid substance. A sample of this substance was recrystallized from toluene to obtain analytically pure material, so pl. 158-160oC.

Elemental analysis:

Calculated for C11H12N2:

C 76,71% H 7,02% N 16,26%

Found: 76,44% N 6,98% N 15,99%

P R I m e R 6.

4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-3-aminogidrohlorid.

To peremeci the Yali Nickel alloy (9 g), then was added 11 g of sodium hydroxide in 200 ml of water. The ice bath was removed after 0.25 h, and the resulting mixture was stirred for another hour. Added additional amount of Nickel alloy (2 x 1 g), and the resulting mixture was stirred for 2 hours, the Catalyst was removed by filtration, t was removed in vacuo, and the product was extracted into CH2Cl2(2 x 100 ml). CH2Cl2the extracts were dried (Na2SO4) and concentrated to obtain an oil (4.5 g). Oil (2.0 g) was dissolved in diethyl ether (100 ml) was added ethereal Hcl to a slight acidification of the solution. The resulting solid was filtered and dried overnight to obtain 1.6 g of 4-methyl-1,2,3,4-tetrahydrocyclopent[b]indole-3-amine in the form dichloride, T. pl. 169-173oC (decomp.).

Elemental analysis

Calculated for C12H14N2, HCl:

C 64,72% H 6,79% N 12,58%

Found: C 64,41% H 6,82% N 12,18%

P R I m e R 7.

4-tert-butyloxycarbonyl-1,4-dihydrocyclopenta[b]indol-3-(2H)-he

To a stirred solution of 1,4-dihydrocyclopenta[b]indol-3-(2H)-she (10.0 g) in acetonitrile (100 ml) was added di-tert.butylparaben (15 g) followed by addition of 4-dimethylaminopyridine (700 mg). The resulting mixture was stirred techenie method evaporative column chromatography to obtain 4-tert.-butylochki carbonyl-1,4-dihydrocyclopenta[b]indol-3-(2H)she (4.5 g) as a solid.

Elemental analysis:

Calculated for C16H17NO3: 70,83% N 6,32% N 5,16%

Found: 71,04% N 6,35% N 5,16%

P R I m e R 8.

1,2,3,4-tetrahydrocyclopent[b]indol-3-cyclopropylamine hydrochloride.

1,4-Dihydrocyclopenta[b] indole-3(2H)-he (5.0 g) was divided into two parts and placed in sealed tubes, each of which contained toluene (20 ml), cyclopropylamine (2.0 ml) and molecular sieves (1 g). The mixture was placed in an oil bath and was heated under reflux for 7 hours Each tube was allowed to cool at ambient temperature, the molecular sieve was filtered, and the filter was concentrated to obtain a brown solid, which was identified as Imin by NMR/MS. United imine product was dissolved in isopropanol (125 ml) and methanol (25 ml) and then was added sodium borohydride (2.66 g) and the resulting mixture was stirred in nitrogen atmosphere at ambient temperature over night. The mixture was cooled at 0oC, was slowly added water, and the mixture was stirred for 0.5 hours, the Mixture was extracted with tAc (2 x 200 ml), layer t was extracted with 10% Hcl (2 x 200 ml), and the acid extracts are neutralized (10% Paon) and was extracted with tOAc (3 x 200 ml). tOAc extremely in Et2O (100 ml) was added an ethereal solution of Hcl, the precipitate was collected and dried to obtain 1,2,3,4-tetrahydrocyclopent[b]indol-3-cyclopropylamine hydrochloride, T. pl. 165-167oC.

Elemental analysis:

Calculated for C14H16N2HCl: C 67,60% H 6,89, N 26%

Found: C 67,22% H 6,87% N 10,79%

P R I m e R 9.

4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-3-cyclopropylamino-2-naphthalene sulfonate.

1,4-Dihydro-4-methyl-cyclopent[b] indole-3(2H)-he (2 g) and cyclopropylamine (3.0 g) was dissolved in 30 ml of toluene and cooled to -10oC. Chetyrehhloristy titanium (0,70 ml) was dissolved in 10 ml of toluene and added to the first solution. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Imin was separated by filtering the mixture through a layer of silicon oxide, and the solvent was removed in vacuum. Imin (2.4 g) was dissolved in 100 ml of a mixture of ISO-LON/Meon in the ratio of 5:1, and then was added sodium borohydride (1.2 g). The reaction mixture was stirred over night. The solvents were removed in vacuo, and the reaction product purified by chromatography, was isolated as a yellow oil (1.6 g).

Part of cyclopropylamine (0.75 g) was dissolved in 75 ml of E t2Oh and stirred, slowly adding a solution of the d N2off , washed with 2 x 50 ml Et2O and dried to obtain 1.04 g of 4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-3-cyclopropylamino-2-naphthalene sulfonate, T. pl. 140-142oC.

Elemental analysis:

Calculated for C15H18N2C10H8O3: C 69,10% H 6,03% N 6,45%

Found: C 68,98% H 6,04% N 6,39%

P R I m e R 10.

1,2,3,4-tetrahydrocyclopent[b]indol-3-(2-PROPYNYL) amine.

To a stirred solution of 1,2,3,4-tetrahydrocyclopent[b]indole-3-amine (5.0 g) in tetrahydrofuran (30 ml) under nitrogen atmosphere was added triethylamine (2.9 g), and then bury bromide of propargyl (4,45 g 80% solution in toluene) dissolved in tetrahydrofuran (20 ml). The mixture was stirred over night. Added an additional amount of methyl propargyl (0,01 mol) dissolved in tetrahydrofuran (10 ml) and the mixture was stirred for 3 hours the Mixture was concentrated in vacuo, added CH2Cl2(150 ml) and the mixture was extracted with 10% Hcl (2 x 50 ml).

The organic phase was dried (Na2SO4) and concentrated to obtain 0.85 grams of product. The reaction was repeated on the same scale using identical conditions. The products were combined and subjected to chromatographic purification on silica gel, about what), so pl. 110-112oC.

Elemental analysis:

Calculated for C14H14N2: 79,97% H OF 6.71% N 13,32%

Found: C 79,70% H 6,77% N 13,14%

P R I m e R 11.

1,2,3,4-tetrahydrocyclopent[b]indol-3-(N-formyl)amine.

To a stirred solution of 1,2,3,4-tetrahydrocyclopent[b]indole-3-amine (2.0 g) in 25 ml of methylene chloride at room temperature was added 4-dimethylaminopyridine (1.4 g) then was added and 0.46 ml of formic acid. Was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.24 g) and the mixture was stirred overnight under nitrogen atmosphere. The reaction mixture was diluted with CH2Cl2(100 ml) was extracted with water (I ml), dried (Na2SO4) and concentrated in vacuum to obtain solid, which was recrystallized from t and toluene to obtain 1,2,3,4-tetrahydrocyclopent[b]indol-3-(N-formyl)amine (1.1 g), so pl. 167-169oC.

Elemental analysis:

Calculated for C12H12N2O: 71,98% N 6,04, N 13,99%

Found: C 71,91% H 5,86, N 13,54%

P R I m e R 12.

1,2,3,4-tetrahydrocyclopent[b]indol-3-(N-phenylmethanesulfonyl)amine.

To a stirred solution of 1,2,3,4-tetrahydrocyclopent[b]indole-3-amine (5 g) in 50 ml of CH2Cl2ro>2Cl2. The mixture was stirred for 2 h and then sequentially washed with water (50 ml), 10% Hcl (50 ml) and water (50 ml). The solution of CH2Cl2dried (Na2SO4), concentrated in vacuo and purified using flash chromatography, carrying out elution with hexane/acetone 2:1, to obtain 2.0 g of 1,2,3,4-tetrahydrocyclopent[b]indol-3-(N-phenylmethanesulfonyl)Amin, I. pl. 145-146oC.

Elemental analysis:

Calculated for C19H18N2O2: 74,49% N OF 5.92% N 9,14%

Found: C 74,23% H of 5.99% N 8,96%

P R I m e p 13.

1,2,3,3 and, 4,8 b-hexahydroazepin[b] indole-3-amine-2-naphthalenesulfonate hemihydrate.

1,2,3,4-tetrahydrocyclopent[b]indole-3-amine (2.0 g) were placed in a three-neck flask under nitrogen atmosphere and using the syringe bury 34 ml of 1.0 M complex, borane-tetrahydrofuran in tetrahydrofuran. The mixture was stirred for 0.5 h at 0oC and then bury triperoxonane acid (34 ml). After stirring for 2 h, the tetrahydrofuran was removed in vacuo and the residue was podslushivaet 10% Paon, was extracted with CH2Cl2(G ml) and concentrated in oil (2 g). A sample of this oil in the amount of 1.0 g was dissolved in ether (200 ml) and stirring was bury the solution (1, (decomp.).

Elemental analysis:

Calculated for C11H15N2:C10H8O3C10H8O3: C 66,64% H 6,10% N 7,10%

Found: C 66,74, H 6,66% N 6,77%

P R I m e R 15.

1,2,3,3 and, 4,8 b-hexahydro-4-methylcyclopentene[b] indol-3-(2-PROPYNYL)-amine hydrochloride.

1,2,3,3 and, 4,8 b-hexahydro-4-methylcyclopentene[b] indole-3-amine (5.0 g) was dissolved in 50 ml of tetrahydrofuran (THF with triethylamine (2.7 g). The solution was cooled to 0oC and slowly added bromine of propargyl (3.2 g) in 20 ml of tetrahydrofuran. Once added, the mixture was brought to room temperature and was stirred overnight. Was otparyvali tetrahydrofuran, and the residue was transferred into 200 ml of CH2Cl2. The organic layer was extracted with 10% Hcl (2 x 70 ml). The aqueous fractions were combined and podslushivaet 10% Paon. The aqueous layer was extracted with CH ml of CH2Cl2and the organic layers were combined and dried over sodium sulfate. The solvent was removed in vacuum. In the cleaning method on a flash chromatography on silica gel received 1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b]indol-3-(2-PROPYNYL)amine (2.0 g) as a reddish brown oil.

1.45 g of the sample indoline was dissolved in ether and intensively stirred. The ethereal solution of Hcl was added to the obtained with getting 1,2,3,3 and, 4,8 b-hexahydro-4-methyl-cyclopent[b] indole-3-(2-PROPYNYL)amine hydrochloride in the form of a fine white powder (1,46 g), so pl. 195-200oC.

Elemental analysis:

Calculated for C15H18N2HCl: 68,56% N 7,30% N IS 10.68%

Found: C 68,21% H 7,27% N 10,54%

P R I m e R 16.

7-chloroacetyl-1,4-dihydro-4-methylcyclopentene[b]indol-3-(2H)-he.

Aluminium chloride (8.5 g) suspended in CH2Cl2(20 ml) at 0oC, was slowly added chloroacetyl chloride (7.2 g) and the mixture was stirred for 5 min. and the Mixture was bury to mix a solution of 1,4-dihydro-4-methyl-cyclopent[b] indole-3(2H)-she (6.0 g) in 100 ml of CH2Cl2at 0oC. the resulting mixture was stirred at 0oC for 45 min, and then bury extract additional pre-obtained solution of aluminum chloride and chloroacetyl chloride. After 30 min the reaction mixture is slowly poured into the stirred mixture of ice/water. The layers were separated and CH2Cl2layer washed with NaHCO3, dried (Na2SO4) and concentrated to oil. In the cleaning method on a flash chromatography on silica gel, carrying out elution with hexane/acetone, received 7-chloroacetyl-1,4-dihydro-4-methyl-ciclope,62% N 5,35%

Found: C 64,35% H br4.61% N 5,24%

P R I m e R 17.

7 Chloroacetoxy-1,4-dihydro-4-methylcyclopentene[b]indole-3(2H)-he.

To a stirred solution of 7 chloroacetyl-1,4-dihydro-4-methyl-cyclopent[b] indole-3(2H)-she (2.0 g) in chloroform (100 ml) was added sodium phosphate (1,02 g) then was added m-chlormadinone acid (2.5 g, 50-60% purity). The mixture was stirred at room temperature under nitrogen atmosphere for 14 hours was Added a saturated aqueous solution of NaHCO3(50 ml), the layers were separated and the organic layer was washed with water (I ml). The solution was dried (Na2SO4), filtered and concentrated to obtain a yellow oil, which crystallized upon standing. By recrystallization from t received 7 chloroacetoxy-1,4-dihydro-4-methylcyclopentene[b]indole-3(2H)-he (1.1 g).

Elemental analysis:

Calculated for C14H12NlO3: C 60,55% H 4,36% N 5,04%

Found: C 60,47% H 4,33% N 4.98% OF

P R I m e R 18.

1,4-Dihydro-7-methylaminorex-4-methylcyclopentene[b]indole-3(2H)-he.

7 Chloroacetoxy-1,4-dihydro-4-methylcyclopentene[b] indole-3(2H)-he (5.0 g) is suspended in t (100 ml) and then was added 10% NaOH solution, and the resulting mixture was stirred for 3 h at room temperature. Mixture to the aqueous layer. The layers were separated and the aqueous phase was extracted with CH2Cl2(G ml). The organic portion was dried (Na2SO4) and concentrated, and the residue was recrystallized from 95% t obtaining 1,4-dihydro-7-hydroxy-4-methylcyclopentene[b] indole-3(2H)-it is in the form of a white solid. IN CH2Cl2dissolved phenol (100 ml) and then was added 1,8-diazabicyclo-/5.4.0/undec-7-he (0.4 g), after which was added methyl isocyanate (1.4 g), and the resulting mixture was stirred over night. The mixture was concentrated in vacuum to obtain an oily solid, which was recrystallized from t obtaining 1,4-dihydro-7-methyl-aminocarbonyl-4-methyl-cyclopent[b]indole-3(2H)-she (1.1 g).

Elemental analysis:

Calculated for C14H14N2O3: 65,11% N 5,46% N 10,85%

Found: C 65,20% H 5,32% N A 10.74%

P R I m e R 19.

3 acetylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl acetate

7 chloroacetoxy-1,4, -dihydro-4-methylcyclopentene[b]indole-3(2H)-he (8.0 g) suspended in t (100 ml) and the solution was added NaOAc (15.6 g) in water (25 ml) and a solution of hydroxylamine hydrochloride (8.0 g) in water (25 ml) and the resulting mixture was heated for 3 h under reflux. The resulting mixture kontsentrirovannoe[b]indol-7-ol as a white solid. The oxime was dissolved in tetrahydrofuran (100 ml) and then was added acetic anhydride (8.1 g) and 4-dimethylaminopyridine (400 mg), and the resulting mixture was stirred in a stream of nitrogen at room temperature over night. The mixture was concentrated in vacuo, added CH2Cl2(100 ml) and the solution was washed with water (50 ml), 5% NaHCO3(50 ml) and water (50 ml). After drying (Na2SO4) the solvent was removed in vacuo, and the reaction product was recrystallized in t with 3-acetylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-acetate (1.7 g), so pl. 150-152oC.

Elemental analysis:

Calculated for C16H16N2O2: 63,99% N 5.37 PERCENT N WAS 9.33%

Found: C 63,56% H 5.37 percent N 9,29%

P R I m e R 20.

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.

To a stirred suspension of 7-chloroacetoxy-1,4-dihydro-4-methylcyclopentene[b] -indole-3(2H)-she (6.0 g) in toluene (50 ml) was added benzylamine (9.2 grams), and the mixture was heated under reflux at a temperature of reflux distilled azeotropic removal of water using traps Dean-stark. After 4 h, analysis by TLC, it was shown that there is a complete conversion in the reaction product. The mixture was allowed to cool down to podcasti United, concentrated and purified using flash chromatography on silica gel (eluent hexane/acetone in a ratio of 2:1). The crystals formed in the fractions containing the product were collected by filtration to obtain 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (1.1 g), and the filtrate was concentrated to obtain an oil (3.0 g), which crystallized upon standing, so pl. 172-173oC.

Elemental analysis:

Calculated for C19H18N2O: 78,58% N 6,25% N 9,65%

Found: 78,26% N 6,21% N 9,63%

P R I m e R 21.

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol

To mix the solution obtained from 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol (16.0 g), isopropanol (200 ml) and methanol (50 ml), was added borohydride sodium (4.8 g) and the mixture was stirred in a stream of nitrogen at ambient temperature for 3 hours the Mixture was cooled to 0oC, was slowly added water and stirred for 0.5 h the mixture was extracted with CH2Cl2(G ml) and CH2Cl2the extracts were dried (Na2SO4), concentrated and subjected to chromatographic purification on silica gel, carrying out elution with a mixture of hexane/acetone in the ratio of lopen[b] indol-7-ol, so pl. 159-160oC.

Elemental analysis:

Calculated for C19H20N2O: 78,05% N 6,89% N 9,58%

Found: 78,20% N 6,97% N 9,54%

P R I m e R 22.

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl methylcarbamate.

To a stirred solution of 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol (2.0 g) in CH2Cl2(40 ml) was added 1,8-diazabicyclo (5.4.0)undec-7-ene (0.16 g), and then bury the methyl isocyanate (0.39 g) in CH2Cl2(10 ml). Over the course of the reaction was monitored by TLC, and after 3 h the solution was concentrated to obtain 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl of methylcarbamate (1.85 g), so pl. 184-185oC.

Elemental analysis:

Calculated for C21H21N3O2: 72,60% N 6,09% N 12,09%

Found: C 72,59% H 6,01% N 12,05%

P R I m e R 23.

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate maleate

To a stirred solution of 4-methyl-3-phenylmethyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl of methylcarbamate (1.8 g) in acetic acid (25 ml) was added cyanoborohydride sodium (0.8 g). Over the course of the reaction was monitored by TLC and after 2 h was added CH2Cl2(50 ml) and the solution UB>SO4, filtered and concentrated to obtain oil, which was purified using flash chromatography, carrying out elution with hexane/acetone in a ratio of 2:1. The fractions containing the product were collected and concentrated to an oil, which was dissolved in ether, and then was added an ethereal solution of maleic acid for acidification of the mixture. Collected maleate 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methyl carbamate (0.8 g), which was deposited in the form of a colorless solid substance, so pl. 104-106oC.

Elemental analysis:

Calculated for C21H21N3O2C4H4O4: C 64,51% H 5.85% OF N 9,03%

Found: 64,13% N OF 5.75% N 8,97%

P R I m e R 24.

4-methyl-3-[(2-vinylcyclopropyl)imino] -1,2,3,4-tetracyclin[b] indol-7-yl methylcarbamate

To a stirred suspension of 1,4-dihydro-7-hydroxy-4-methylcyclopentene[b]indole-3(2H)-she (5 g) in acetonitrile (100 ml) was added phenylcyclopropanecarboxylic (4,2 g) and then was added triethylamine (2.5 g). The solution was stirred at room temperature in a nitrogen atmosphere, prokopeva while isopropyl titanium (IV). The mixture was stirred for 3 h, and then rapidly cooled system ice/water. The mixture was filtered, Tole concentration the crude product was purified using flash chromatography carrying out elution with hexane/acetone (2: 1) to obtain 4-methyl-3-[(2-vinylcyclopropyl)imino]-1,2,3,4-tetrahydrocyclopent[b] indole.

To a stirred solution of this product (1.0 g) in CH2Cl2(9.0 ml) was added 1,8-diazabicyclo-/5.4.0/undec-7-ene (68 mg) followed by precapitalism of methyl isocyanate (0.18 g) in CH2Cl2(1.0 ml). Over the course of the reaction was monitored by TLC, and after 0.5 h the solution was concentrated and the precipitate was collected and recrystallized twice from acetonitrile to obtain 4-methyl-3-[(2-vinylcyclopropyl)imino] -1,2,3,4-tetrahydrocyclopent[b] indol-7-yl of methylcarbamate (0.55 g), so pl. 166oC (decomp.).

Elemental analysis:

Calculated for C21H21M3O2: C 73,97% H 6,21% N 11.25% PER

Found: C 73,57% H% and 6.25% N 11,13%

P R I m e R 25.

3 cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl

7 chloroacetoxy-1,4-dihydro-4-methylcyclopentene[b] indole-3(2H)-he (15.0 g) and cyclopropylamine (9.6 g) was dissolved in 300 ml of toluene and cooled to -10oC. titanium Tetrachloride (6.3 g) was dissolved in 50 ml of toluene, and the mixture was slowly added to the first solution. The reaction mixture was brought to room temperature and was stirred overnight. The next day the reaction mixture is C layer of silica gel, carrying out elution with a mixture of hexane/ethyl acetate in a ratio of 3:1, getting after removal of the solvent a yellow oil. After purification using flash chromatography and recrystallization from ethyl acetate as a pale yellow solid was isolated 3-cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol, I. pl. 176-179oC.

Elemental analysis:

Calculated for C15H16N2O: C 74,97% H OF 6.71, N 11,66%

Found: C 74,57% H 6,54% N 11,37%

P R I m e R 26.

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol maleate

3 cyclopropylamino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] -7-ol (17.3 g) was dissolved in a mixture of isopropanol/methanol in the ratio of 5:1 (250 ml) in a stream of N2and stirred at room temperature. Was added sodium borohydride (8,2 g) and the reaction mixture was stirred over night. By thin-layer chromatography, it was found that the reaction was completed. The solution was cooled to 0oC and slowly added water (100 ml). Added ethyl acetate (250 ml) and after separation of the layers the organic portion was sequentially washed with brine (CH ml), water (I ml) and dried over Na2SO4, after which the solvent was removed in vacuum. The crude material was purified methodology is a basis was provided in the form of a light brownish-yellow oil (7.8 g). Mix a solution of free base (0.6 g) in ether (200 ml) was slowly treated with a solution of 0.3 mg of maleic acid, 50 ml of Et2About 5 ml t.

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol maleate was isolated as a pale yellow solid (0.8 g) after filtration and drying in a stream of N2so pl. 135oC (decomp.).

Elemental analysis:

Calculated for C15H18N2OC4H4O4: C 63,68% H IS 6.19% N OF 7.82.

Found: C, 63.47 per cent H 6,13% N 7.69% OF

P R I m e R 27.

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol (5.5 g) was dissolved in 250 ml of CH2Cl2together with triethylamine (2.8 g) and the mixture was cooled to 0oC under stirring. The first solution was slowly added benzylchloride (3,9 g), dissolved in 50 ml of CH2Cl2. After completion of the reaction the reaction mixture was allowed to warm to room temperature, washed with N2About (2 x 150 ml) and dried over Na2SO4and the solvent was removed in vacuum. The crude material was purified using flash chromatography on a column using the solvent tOAc. 3-(N-cyclopropyl)-amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7:

Calculated for C23H24N2O3: C 73,38% H TO 6.43% N 7,44%

Found: C 73,41% H 6,80, N OF 7.48%

P R I m e R 28.

3-(N-cyclopropyl)amino-1,2,3,3 and, 4,8 b-hexahydro-4-methyl-cyclopent[b] indol-7-ol.

3 cyclopropylamino-4-methyl-1,2,3,3 and,4,8 b-hexahydro-4-methyl-cyclopent[b] indol-7-ol (8.7 g) were placed in a 3-necked flask and cooled to 0oC in a bath with a mixture of ice-water. Was bury 1M solution of borane in THF (540 ml). The mixture was stirred for 1 h with slow warming to room temperature. The mixture was cooled to 0oC and bury triperoxonane acid (119 ml). The solution was stirred for 15 min and the THF was removed in vacuum. The mixture was neutralized 10% solution Paon, was extracted with methylene chloride (4 x 500 ml), dried (Na2SO4) and concentrated to obtain 3-(N-cyclopropyl)amino-1,2,3,3 and, 4,8 b-hexahydro-4-methyl-cyclopent[b] indol-7-ol (8.8 g), so pl. 155oC (decomp.).

P R I m e R 29.

3-(N-cyclopropyl-N-methylaminomethyl)amino-1,2,3,3-4,8 b-hexahydro-4 - methylcyclopentene[b]indol-7-yl hydrochloride.

3-(N-cyclopropyl)amino-1,2,3,3 and, 4,8 b-hexahydro-4-methyl-cyclopent [b] indol-7-ol (8.8 g) was dissolved in CH2CH2(400 ml) together with triethylamine (4.4 g). The solution was cooled to 0oC THE SUB>2Cl2(50 ml). The reaction course was monitored by thin layer chromatography adding additional equivalent of 6.1 g) chloroformiate until then, until the reaction. The solution was warmed up to room temperature before washing with water (2x 100 ml), dried over Na2SO4and concentrated to an oil, which was then purified by the method of preparative HPLC using the solvent system hexane/acetone in a ratio of 3: 1. Allocated 3-(N-cyclopropyl)amino-1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b] indol-7-yl fenilmetilketenom (7.0 g), which okharakterizovali NMR, MS and IR. This material was dissolved in CH2Cl2(250 ml) and the solution was treated with 1,8-diazabicyclo(5.4.0)undec-7-Yong (DBU; 0.4 g). The mixture was cooled to 0oC and stirred while adding a solution of methyl isocyanate (1.1 g) in 50 ml of CH2Cl2. Over the course of the reaction was monitored by TLC (hexane/acetone in a ratio of 1:1), adding another 2.5 equivalent (2.7 g) of methyl isocyanate to complete the reaction. The solution was heated to room temperature, washed with brine (g ml) and water (I ml), dried over Na2SO4and concentrated. The oil was purified by the method column flash chromatography using as RA is t[b] indol-7-yl fenilmetilketenom (4.5 g). This material was dissolved in absolute ethanol (190 ml) was added 10% palladium on coal (10 wt. 0.4 g). The solution was placed in a Parr shaker missed the H2(45 lb/in2and for 2 h were shaking. The catalyst was filtered and the filtrate was concentrated. The oil was treated t (50 ml) and CH2Cl2(5 ml) to give white solids (1,05 g).

3-(N-cyclopropyl-N-methylaminomethyl)amino-1,2,3,3-4,8 b-hexahydro-4 - methylcyclopentene[b]indol-7-ol okharakterizovali NMR, MS and IR. The solid is initially dissolved in a mixture of E2O/Et (200 ml) in a ratio of 8:1 and was slowly added to the ethereal solution of hydrogen chloride until neutral pH of the solution then was added an additional amount of E2O (800 ml). 3-(N-cyclopropyl-N-methylaminomethyl)amino-1,2,3,3-4,8 b-hexahydro-4 - methylcyclopentene[b] indol-7-yl hydrochloride was isolated as a white solid after filtration and drying in a stream of N2(0.66 g), so pl. 155oC (decomp.).

Elemental analysis:

Calculated for C17H23N2O3HCl: C 60,44% H 7.16 percent to 12.44 N%

Found: C 60,77% H 7,41% N 12,67%

P R I m e R 30.

3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indole is whether in CH2Cl2(200 ml) in the presence of 1,8-diazobicyclo/5.4.0/undec-7-ene (DBU, 0.21 g) and the solution was cooled to 0oC. To the cooled solution was slowly added a solution of methyl isocyanate (0.52 g in 30 ml of CH2Cl2), and the reaction course was monitored by thin layer chromatography (silica gel, 11: 1 hexane/ethyl acetate). After heating to room temperature the mixture is then washed with water (I ml), brine (g ml) and again water (I ml). The organic layer was dried over Na2SO4and the solvent was removed in vacuum. The crude material was recrystallized from acetonitrile. 3-(N-cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-Il methylcarbamate was isolated as light-yellow-white plates (1.0 g), so pl. 159-160oC.

Elemental analysis:

Calculated for C17H21N3O2: C 68,21% H 7,07% N 14,04%

Found: C 68,08% H 6,57% N 13,97%

P R I m e R 31.

1,2,3,3 a, 4,8 b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminomethyl) aminocyclopent[b]indol-7-yl fenilmetilketenom.

To mix the solution 1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-phenylethylenediamine[b]indol-7-ol (12.0 g) in CH2Cl2(125 ml) was added triethylamine (4,08 g). The mixture was cooled to 0oC and slowly prickly water (I ml), dried over Na2SO4and focused, getting 17.0 g of oil. Crude 4-methyl-3-phenylethylamine-1,2,3,3 and,4,8 b-hexahydroazepin[b] indol-7-yl fenilmetilketenom (17.0 g) was dissolved in CH2Cl2(125 ml) was added 1,8-diazabicyclo(5.4.0) undec-7-ene (0.9 g), then bury a solution of methyl isocyanate (2.0 g) in CH2Cl2(25 ml). The reaction mixture was stirred for 2 h and was added 0.5 g of methyl isocyanate. The reaction mixture was stirred for 15 min and then concentrated in vacuo to obtain an oil, which was purified using flash chromatography on silica gel, carrying out elution with a mixture of hexane/ethyl acetate 2:1 ratio. The fractions containing the product were collected and concentrated to obtain an oil (5.5 g).

Elemental analysis:

Calculated for C22H25N3O4: C 71,73% H TO 6.43% N 8,65%

Found: C 71,67% H 6,59% N 8,67%

P R I m e R 32.

1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-phenylethylenediamine cyclopent[b]indol-7-ol

A solution of 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (14.0 g) were placed in a 3-necked flask and cooled to 0oC in a bath with a mixture of ice-water. Did bury a solution of 1 M borane (THF and THF (145 ml). The mixture was stirred for 1 h is refloxology acid. The solution was stirred for 15 min, neutralized with 10% Paon, was extracted with CH2Cl2, dried (Na2SO4) and concentrated to obtain 1,2,3,3 and, 4,8 b-hexahydro-4-methyl-3-phenylethylenediamine[b] indol-7-ol (14 g), this material was dissolved in ethanol (100 ml) and the mixture was first made at a pressure of H245 lb/in2(3,167 kg/CSM) in a Parr apparatus for 5 h at 50oC. the Mixture was filtered and the solution was concentrated to obtain 3-amino-1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b]indol-7-ol (10.7 g).

To a solution of 3-amino-1,2,3,3 and,4,8 b-hexahydro-4-methylcyclopentene[b]indol-7-ol (10.7 g) in methylene chloride (125 ml) was added triethylamine (5.6 g), followed by precapitalism of benzylchloride (10.0 g) in methylene chloride (25 ml). The mixture was stirred for 2 h, were extracted with water, dried (Na2SO4) and concentrated. The product was purified by chromatography on silica gel, carrying out elution with hexane/acetone in a ratio of 2:1 to receive and 2,2,3,3, 4,8 b-hexahydro-4-methyl-3-phenyl-methyl-externaldocument[b]indol-7-ol in the form of butter.

P R I m e R 33.

1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-(11-phenylmethanesulfonyl)aminocyclopent[b] indol-7-yl methylcarbamate.

To peremen2Cl2(75 ml) was added 1,8-diazabicyclo/5.4.0/undec-7-ene (0.12 g), followed by precapitalism solution of methyl isocyanate (0.36 g) in CH2Cl2(25 ml). The reaction mixture was stirred for 2 h and added additional amount (0.1 g) of methyl isocyanate. The reaction mixture was stirred for 15 min and concentrated in vacuo to obtain an oil, which was purified using flash chromatography on silica gel, carrying out elution with a mixture of hexane/ethyl acetate 2:1 ratio. The product, which crystallized from pure fractions were collected by filtration to obtain 600 mg of the substance, and the filtrate was concentrated to obtain an oil (800 mg) which crystallized upon standing, so pl. 180-181oC.

Elemental analysis:

Calculated for C22H25N3O4: C 66,82% H OF 6.73% N 10,63%

Found: C 66,91% H 6,47% N 10,66%

P R I m e R 34.

3 methylaminoanthraquinone-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl methylcarbamate hemihydrate.

To a stirred suspension of 3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol (3.0 g) in CH2Cl2(100 ml) was added 1,8-diazabicyclo/5.4.0/undec-7-ene (630 mg), after which was added methyl isocyanate (109 g) and the mixture was stirred in the e solid is recrystallized from ethanol to obtain 3-methylaminoanthraquinone-4-methyl-1,2,3,4-tetrahydrocyclopent [b]indol-7-yl of methylcarbamate hemihydrate (1.7 g), so pl. 198-200oC.

Elemental analysis:

Calculated for C16H18N4O40.5 H2O: C 56,68% H 5,66% N 16,53%

Found: C 56,57% H 5,64% N 16,68%

P R I m e R 35.

1,2,3,3 and, 4,8 b-hexahydro-4-methyl-3-methylennorbornanchlorid [b] indol-7-ol hydrochloride monohydrate.

The solution 1,2,3,3 and, 4,8 b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminomethyl) aminocyclopent[b]indol-7-yl of phenylmethyl carbonate (1.7 g) in glacial acetic acid (100 ml) was first made at a pressure of H245 lb/in2(3,164 kg/CSM) and 50oC in the presence of 20% hydroxide PD on coal by using a Parr apparatus. After 4 h by TLC, it was found that the reaction was completed with the formation of both primary and by-product. PD-catalyst was filtered in a stream of nitrogen, and the filtrate was concentrated in vacuum. The material was subjected to chromatographic purification on silica gel, conducting elution 10% Meon/CH2Cl2. The fractions containing the product were collected and concentrated. The resulting oil was dissolved in t (25 ml) and Et2O (150 ml), the solution was filtered and to the filtrate was added an ethereal solution of Hcl for acidification of the solution. The resulting colourless solid was collected is [b] indol-7-ol hydrochloride monohydrate (0.25 g), so pl. 120oC (decomp.).

Elemental analysis:

Calculated for C14H19N3O2ClH2O: C 53,25% H 7,02% N 13,31%

Found: C 53,26% H 6,54% N 12,78%

P R I m e R 36.

1,2,3,3 and, 4,8 b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminomethyl) aminocyclopent[b]indol-7-ol hydrochloride.

The solution 1,2,3,3 and, 4,8 b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminomethyl) aminocyclopent[b]indol-7-yl of phenylmethyl carbonate (2.0 g) in absolute ethanol (100 ml) was first made when hydrogen pressure of 45 lb/in2(3,164 kg/CSM) in the presence of 5% PD on coal by using a Parr apparatus. After 2 h by TLC, it was found that the reaction is complete to form one product. PD-catalyst was filtered in a stream of nitrogen, and the filtrate was concentrated in vacuum. The resulting oil was dissolved in t (25 ml) and Et2O (150 ml), the solution was filtered and to the filtrate was added an ethereal solution of Hcl for acidification of the solution. The resulting colourless solid was collected current of the N2and dried over night at 40oC in vacuum to obtain 1,2,3,3 and,4,8 b-hexahydro-4-methyl-3-(N-phenylmethyl-N-methylaminomethyl) aminocyclopent[b]indol-7-ol hydrochloride (1.4 g), so pl. 130oC (decomp.).
P R I m e R 37.

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol hemihydrate.

To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydrocyclopenta[b]-3-one (5.0 g) in acetonitrile (100 ml) was added phenethylamine (6.0 g) and isopropyl titanium (14.1 g), and the resulting mixture was stirred in nitrogen atmosphere at ambient temperature for 3 hours the Mixture was poured into a mixture of ice water (200 ml) and then added CH2Cl2(500 ml). The mixture was filtered and the organic layer was separated from the filtrate, dried over sodium sulfate and concentrated in vacuum. By recrystallization from CH2Cl2/hexane was obtained 4-methyl-3-phenyl-ethylamino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol hemihydrate (3.0 g), so pl. 75-77oC.

Elemental analysis:

Calculated for C20H20N2O0,5H2O: C 76,65% H 6,75% N 8,94%

Found: C 76,53% H 6,38% N 8,89%

P R I m e R 38.

4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl methylcarbamate.

To a stirred solution of 4-methyl-3-phenylethylamine-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol hemihydrate (1,43 g) in CH2Cl2(25 ml) was added 1,8-diazabicyclo/5.4.0/undec-7-ene (0.11 g). To the reaction mixture Aivali CH2Cl2. The brown residue was recrystallized from acetonitrile, so pl. 164-166oC.

Elemental analysis:

Calculated for C22H23N3O2: C 73,11% H 6,41% N 11,63%

Found: C 73,03% H 6,35% N 11,65%

P R I m e R 39.

4-methyl-3-(2-phenylethyl)amino-1,2,3,4-tetrahydrocyclopent-indol-7-yl methylcarbamate hydrochloride hemihydrate.

To a stirred solution of 4-methyl-3-(2-phenylethyl)imino-1,2,3,4-tetrahydrocyclopent[b] indol-methyl carbamate (0,80 g) in acetic acid (8 ml), ethanol (8 ml), isopropanol (8 ml) and tetrahydrofurane (8 ml) was added cyanoborohydride sodium (0.35 g) in a stream of nitrogen. Over the course of the reaction was monitored by TLC, and after 1 hour the solution was neutralized with a saturated solution of NAHCO3, were extracted t, dried over Na2SO4and concentrated in vacuum. The resulting yellow oil was dissolved in minimum amount of t, diluted with ether and then was added an ethereal solution of Hcl. The resulting white solid was collected by filtration. As a result of recrystallization from ethanol was obtained 4-methyl-3-(2-phenylethyl)-amino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methyl carbamate hydrochloride hemihydrate (0.68 g). The reaction pastorelas the UB>N3O2HCl0,5H2O: C 64,62% H 6,65% N 10,28%

Found: C 64,56% H 6,72, N 9.91% IN

P R I m e R 40.

4-methyl-3-(2-PROPYNYL)amino-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl methylcarbamate.

To a stirred suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopenta[b] indol-3-(2H)-she (5.5 g) in acetonitrile (100 ml) was added propargylamine (3.0 g), the solution was stirred at room temperature in a nitrogen atmosphere at prikatyvanie isopropylate titanium (IV) (15:6 g). The mixture was stirred for 16 h and cooled water. The resulting mixture was filtered, the solids washed with CH2Cl2the layers were separated, and the organic portion was dried (Na2SO4). After concentration the crude product was purified using flash chromatography, carrying out elution with hexane/acetone (2:1) to obtain 4-methyl-3-(2-PROPYNYL)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.

To a stirred solution of 4-methyl-3-(2-PROPYNYL)imino-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol (3.4 g) in CH2Cl2(15.0 ml) was added 1,8-diazabicyclo /5.4.0.under/7-ene (326 mg), and then bury the methyl isocyanate (0.8 g) in CH2Cl2(5.0 ml). Over the course of the reaction was monitored by TLC, and after 1 h the solution was concentrated and the crude product was purified using flash is birali to obtain 4-methyl-3-(2-PROPYNYL)imino-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl of methylcarbamate (1.2 g) and fractions were concentrated to obtain additional quantities of substance (0.9 g).

Elemental analysis:

Calculated for C17H17N3O2: C 69,14% H 5,80% N 14,23%

Found: C 68,94% H 5,81% N 13,94%

P R I m e R 41.

4-methyl-3-(2-PROPYNYL)amino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate hydrochloride monohydrate.

To a stirred solution of 4-methyl-3-(2-PROPYNYL)imino-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl of methylcarbamate (1:1 g) in acetic acid (10 ml) was added cyanoborohydride sodium (0,57 g). Over the course of the reaction was monitored by TLC and after 2 h was added methylene chloride (50 ml) and the solution was washed with saturated solution of NaHCO3to neutral pH values. The methylene chloride layer was dried (Na2SO4), filtered and concentrated. The resulting material was subjected to chromatographic purification on silica gel, carrying out elution with hexane/acetone 2:1, and the pure fractions were collected and concentrated. The resulting solid was dissolved in mineral quantity t, diluted with ether, and then was added an ethereal solution of Hcl. The resulting solid was collected by filtration in a stream of nitrogen to obtain 4-methyl-3-(2-PROPYNYL)amino-1,2,3,4-tetrahydrocyclopent[b] indol-7-yl methylcarbamate hydrochloride manage the>/BR>Calculated for C17H19N3O2HClH2O: C 58,04% H 6.30%, AND N 11,94%

Found: C 57,99% H 6,03% N 11,82%

P R I m e R 42.

4-methyl-3-(2-phenylethyl)amino-1,2,3,4-tetrahydrocyclopent[b]indol-Il benzylcarbamoyl hydrochloride hemihydrate.

To a stirred solution of 4-methyl-3-(2-phenylethyl)amino-1,2,3,4-tetrahydrocyclopent[b] indol-7-ol (2.70 g) in CH2Cl2(100 ml) was added 1,8-diazabicyclo/5.4.0/undecen (0.21 g). To the reaction mixture with a syringe and added benzylsuccinic (0,83 g) and the mixture was stirred in nitrogen atmosphere. After 120 and 180 min was added an additional amount benzylisothiocyanate in the amount of 1/4 and 1/2 equivalent, respectively. Over the course of the reaction was monitored by TLC and after 185 min the solution was concentrated in vacuum. The crude residue (2,72) in accordance with the analysis of NMR and MS were a carbamate. This residue was dissolved in glacial acetic acid (75 ml) with stirring in a stream of nitrogen. When adding cyanoborohydride sodium formed yellow precipitate, which was dissolved after 30 minutes After 3 h was added one equivalent of cyanoborohydride sodium. After 30 min, according to the analysis by TLC, it was found that the reaction is complete. The reaction mixture was neutralized with saturated of rest the IU. The free base was dissolved in ether and added an ethereal solution of Hcl. The resulting white solid was collected by filtration, so pl. 165-166oC.

Elemental analysis:

Calculated for C28H30N3O2HCl0,5H2O: C 69,34% H 6.44% OF N 8,66%

Found: C 69,45% H 6,30, N 8,72%

P R I m e R 43.

4-methyl-3-[2-(4-morpholinyl)ethyl]imino-1,2,3,4-tetrahydrocyclopent [b]indol-7-ol.

To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydrocyclopenta[b]indol-3-one (8.00 g) in acetonitrile (125 ml) under nitrogen atmosphere was added 4-(2-amino-ethyl)morpholine (10,35 g) and isopropyl titanium (22,60 g). Over the course of the reaction was monitored by TLC and after 2 h was added an additional amount of 4-(2-amino-ethyl)research (of 5.17 g) and isopropylate titanium (11,30 g). After 14 h the reaction mixture was cooled water (200 ml). Added t (200 ml) and the mixture was stirred for 15 min, then was filtered. The layers were separated, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried (Na2SO4) and concentrated in vacuum. The resulting yellow solid was dried to obtain of 6.65 g of the product. A sample of this product in the amount of 2 g was further purified precrystallizer the NT[b]indol-7-ol, so pl. 158-159oC.

Elemental analysis:

Calculated for C18H23N3O2: C 68,98% H 7,40% N 13,41%

Found: C 68,78% H 7,52% N 13,26%

1. Substituted tetrahydro - or hexahydroazepin(b)indoles of General formula I

< / BR>
where R1hydrogen, lower alkylaminocarbonyl, benzyloxycarbonyl;

R2hydrogen, lower alkyl, cycloalkyl, phenylselenenyl lower alkyl, quinil, formyl, benzyloxycarbonyl, lower alkylaminocarbonyl;

R3hydrogen, lower alkyl;

R4hydrogen, hydroxy, lower alkylaminocarbonyl;

indicates the absence of a relationship or single bond,

or their pharmaceutically acceptable salt additive.

2. Connection on p. 1 with acetylcholinesterase activity.

3. The method of obtaining compounds of General formula I on p. 1,

where R1and R2hydrogen;

R3hydrogen, lower alkyl;

R4hydrogen, hydroxy,

characterized in that a derivative of indole of General formula

< / BR>
where R3and R4have the specified values,

subject to recovery.

4. The method of obtaining compounds of General formula I on p. 1,

where R1hydrogen;

R2nezameshchenny the sea,

characterized in that a derivative of indole of General formula

< / BR>
where R3and R4have the specified values,

subjected to interaction with the primary amine and isopropylate titanium, followed by reduction of the resulting imine with sodium borohydride.

5. The method of obtaining compounds of General formula I on p. 1,

where R1hydrogen;

R2lower alkyl, cycloalkyl, phenylselenenyl lower alkyl, quinil;

R3hydrogen, lower alkyl;

R4hydrogen, hydroxy,

characterized in that a derivative of indole of General formula

< / BR>
where R2R4have the specified values,

subjected to recovery.

6. Substituted tetrahydro - or hexahydroazepin(b)indoles of General formula

< / BR>
where R3lower alkyl, alkoxycarbonyl;

R4hydrogen, hydroxy, halogen-substituted lower alkanoyl, halogen-substituted lower alkylcarboxylic.

 

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The invention relates to medicine, namely to obstetrics

FIELD: medicine.

SUBSTANCE: it is suggested to apply tris-(2-hydroxyethyl)ammonium salt of 1-benzylindolyl-3-thioacetic acid earlier known as a stabilizer of cell membrane as preparation to treat autoimmune diseases. The property of the above-mentioned salt to inhibit T-dependent activation of B-lymphocytes, under conditions of decreased medullary function and body leukopenia should enable to develop new pharmacological preparation for treating autoimmune diseases, such as, for example, systemic lupus, rheumatoid polyarthritis, transplant's detachment at transplanting either organs or bony marrow.

EFFECT: higher efficiency of application.

4 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: agent comprises glucosamine salt as saccharide, dimethylsulfoxide, ointment base and ibuprofen or nimesulide, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen as a nonsteroid anti-inflammatory agent. Glucosamine hydrochloride, glucosamine sulfate sodium, potassium or calcium salt is used as glucosamine, and diclofenac potassium or sodium salt is used as diclofenac salt. New ointment shows high perfusion rate of active substances to the articulation zone and enhanced effectiveness. Invention expands assortment of agents used in treatment of articulations.

EFFECT: improved, enhanced and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: invention relates to agents of topical applying used in treatment of articulation diseases. Proposed agent comprises mixture of chondroitin sulfate and glucosamine salts as a saccharide, the compound taken among the group nonsteroid anti-inflammatory agents, in particular, ibuprofen or nimesulid, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen, dimethylsulfoxide and an ointment base taken in the definite ratio of components. Invention provides enhancing effectiveness due to the content a mixture of low-molecular and high-molecular saccharides in it that results to increasing diffusion rate of active component to the articulation zone and also the compound taken among the group of nonsteroid anti-inflammatory agents. The combined using these agents provides the curative synergetic effect.

EFFECT: improved and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to manufacturing solid medicinal formulations of preparations. Invention proposes a medicinal formulation consisting of a core comprising the following components: indometacin, lactose, calcium phosphate, hydroxypropylcellulose, magnesium stearate, sodium croscarmellose and envelope comprising collicute MAE 100P, propylene glycol, pigment titanium dioxide, talc, collidon-30, brown sycovite-70. Also, invention discloses a method for preparing the formulation. Invention provides enhancing stability of envelope to effect of stomach juice, rapid and complete release of active substance, simultaneous simplifying the process of applying the envelope for a single step.

EFFECT: improved and valuable pharmaceutical properties of formulation.

3 cl, 1 tbl

FIELD: medicine, neurooncology.

SUBSTANCE: one should carry out chemotherapy and irradiation till radical dosage. Moreover, 2-3 d before the onset of radiation therapy and during the whole course of irradiation one should indicate the intake of indometacin at daily dosage being 300 mg, and 8-14 d before the end of therapy course or the stage of radiation therapy it is necessary to conduct chemotherapeutic cycle with vincristine at total dosage being 4 mG and lomustine at total dosage 160-240 mg. At performing a split course of irradiation the intake of indometacin should be indicated between the stages. The innovation enables to increase radio sensitivity of malignant tumor, suppress angiogenesis, proliferative activity and increased cytotoxic activity of chemopreparations.

EFFECT: higher efficiency of therapy.

1 cl, 3 ex

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